Scientist Stories: Jay Bradner, Molecular Glues for Intractable Targets

All right, let me do a little introduction here. Good afternoon. Welcome to the annual cancer symposium of the UMass Boston Dana-Farber Harvard Cancer Center Comprehensive P54 Partnership to Advance Cancer Health Equity. I'm Jill McCoska, a PI of the UMass Boston side of the partnership, along with— and you should be able to see these individuals here— along with Adan Juan-Carmona. You also see here the PIs of the Dana-Farber Harvard Cancer site of the partnership, Drs. Vish Viswanath and Gregory Abel. We are pleased to present the symposium virtually and to a large audience composed of scientists and trainees from UMass Boston, the Dana-Farber Harvard Cancer Center, Novartis, the National Cancer Institute, colleagues at other PHE partnership sites, and many others. Glad to have you here today. The goal of this symposium is to talk about cancer science and cancer scientists. Today's symposium will blend the topics of therapeutic development to treat cancer patients and best practices for training and diversifying the cadre of cancer scientists in industry. Our speaker today is Jay Bradner. Jay is the president of the Novartis Institutes for Biomedical Research and member of the Novartis Executive Committee A scant 5 years prior to that, Jay was an associate professor of medicine at the Harvard Medical School and a practicing medical oncologist at the Dana-Farber Cancer Institute. He's a graduate of Harvard University and the University of Chicago Pritzker School of Medicine. After that, he returned to Boston to complete his residency in medicine at Brigham and Women's Hospital and a fellowship in medical oncology and hematology at the Dana-Farber Cancer Institute. While at the DFCI, Jay interacted significantly with this U54 partnership and was a funded investigator along with Wei Zhang at UMass Boston on a very productive pilot and full project to develop and test novel bromodomain inhibitors for cancer treatment. Jay has been involved in the partnership in other ways as well, generously giving his time to review project applications and in activities like today's symposium. We are very grateful for Jay's continued interest and contributions to the partnership. We will have a question and answer session after Jay's talk. You may submit questions using the Q&A function, which you should see at the bottom of your Zoom screen. And without further ado, I'm pleased to present Dr. Jay Bradner.

Well, Jill, thank you so much for the invitation to return, albeit virtually, to talk with UMass and Dana-Farber's p54 program, as well as guests from the NIH and Novartis and more broadly. I have the fondest memories of our time working together and with Dr. Zhang to make, um, bromodomain-4 inhibitors, hybrid bromodomain-4 JAK2 inhibitors, as prototype cancer medicines, and chemical tools to dissect the complex biology of gene activation and gene control. But truthfully, the fondest memories are working with all the students that came through on this remarkable program project grant that has really, I think, had a big impact for sure among those who participated, but an even more amplified impact on those of us on the faculty who really through this program got to see just had a front row seat to see the way in which having a greater diversity of background, of training, of perspective can really make a biomedical research project all the richer, all the more nuanced in insight. And working with all of you was a source of real energy for so many years. I think we're still publishing papers from that time, and there's probably one or two in my inbox. I brought a seminar as requested that really tells a pretty hardcore science story. And so full disclosure, there will be some small molecule structures, but I think also highlights the way in which we need more ideas around a table, diversity in all dimensions, because the monosynaptic way that our field has approached the science of therapeutics for so many years We have antibody, what can I bind and remove from the serum? We have a small molecule, where can I bind and inhibit? Really isn't going to get us where we need to go for most of the most severe diseases. Then we need, I think, a whole reconsideration of what it means to be a therapeutic in order ultimately to develop, to deliver on the expectations that society rightly has for us. So that's the punchline. You go, everybody go to sleep now. As this is an academic seminar, I wanted to share these disclosures, some of which, Jill, you were kind enough to introduce. I may, through the seminar, talk about the off-label use of medicines, if only to show the myriad of possibilities that exist for a new therapeutic beyond the narrow and focused spectrum of the development path most medicines take. Well, I thought because it's a cancer symposium to really begin with the cancer patient. This gentleman, I think, well exemplifies the burden of cancer that is today still so impossible despite incredible insights, even atomic resolution into the cause of these diseases and the unprecedented therapeutic modalities that we have before us. Still, at the bedside, cancer remains an almost intractable problem. Here's a 53-year-old man with shortness of breath. This is a real patient courtesy of Dr. Zhu. Extensive smoking history of 74 pack-years, was diagnosed with non-small cell lung carcinoma, Stage 4 metastatic. As you can see the lesions, I'll try to use my cursor on both sides of the chest. These shadows, for those that aren't used to looking at CAT scans of the chest, are all tumors. Normally this would be dark, air-filled, healthy lung tissue. Here's a tumor on the contralateral side of the chest, as well as large lesions cancer deposits in the liver and other distal sites. This gentleman's tumor is not surgically removable, can't be radiated owing to how extensive it is. Systemic therapies are then considered. This gentleman received really everything that modern medicine has to offer: chemotherapy, immune checkpoint therapy, combination chemotherapy and immune checkpoint therapy., and then a host of targeted therapies that are being investigated for their use in patients with certain genetic mutations. And this gentleman had a mutation of the master oncogene called KRAS, and it was the 12th amino acid that was mutated to become a cysteine, or so-called G12C. And this gentleman received 3 months of G12C therapy with an excellent medicine, investigational today, from Amgen, and then subsequently got what's called a SHIP-2 inhibitor. I'll talk about that more more in a moment, combined with a MEK inhibitor. I mean, and then CDK4/6 inhibition. This fellow received a lot of therapy, and unfortunately still his disease persisted. And so what will we do to treat this man? What types of medicines would need to be imagined and then invented and then investigated to have ready for him the medicine that patients like him expect from us? In science. And I can tell you, having devoted my career to inventing and developing medicines, that we do not have the answer to this. And that for those in training listening today, if you should become curious about the science of therapeutics, we so need and welcome your thoughts. Because it will take, I think, a new way of thinking ultimately to address the profound burden of metastatic solid tumors. Now NIBR is one such environment that is fully dedicated to this science of therapeutics. These Novartis Institutes for Biomedical Research, just to introduce so you get a sense of where the project I'm about to present to you hails from and, and why it's sort of a unique environment for that type of research, but it's also a shameless plug for those that might want to explore a job in biopharma, is 6,000 drug hunters. We have actually 270 drug discovery projects. We work in 8 disease areas, and the portfolio— because we have been performing drug discovery now for almost 20 years in this way— we have 90 clinical-stage molecules, 500 clinical trials, and every year we devote about $9 billion to the invention and the study of new medicines. And so we have a great resource, most importantly our human resource,— to Jill's point about science and scientists— all focused on the concept of a drug, a target, its study, its validation, all the way through to the proof of concept of an investigational drug in a Phase 2 clinical trial. And then we hand off to the development organization within our Swiss pharmaceutical intergalactic giant Novartis AG in Switzerland, and our colleagues there perform the Phase 2 and Phase 3 studies needed to get a drug approved. And so where I work is more focused on science and pathways, targets, invention, and early clinical investigation. Well, these are the disease areas where we work, and you can see by the proportionate spend that we are about 40% of our total spend is invested in cancer. And so we're pretty serious about being a part of the cure for common cancers. You might know a medicine that Novartis made a few years back called imatinib or Gleevec. This was a medicine that targets the ABL tyrosine kinase that is mutated by a translocation in chronic myeloid leukemia. And it's a remarkable discovery that has really changed the lives of patients with chronic myeloid leukemia. It also opened our minds as drug hunters to the idea that you could bind and inhibit a kinase selectively by binding into this ADP binding site, as shown here in blue. This little molecular key fits into a little macromolecular keyhole, displacing ADP and blocking the catalytic activity of the kinase. At the time this work was done by one of my heroes, Jürg Zimmermann, it wasn't perceived that you could really drug a kinase selectively.. And so I like this story because this is for us a calibration to the type of medicines we want to make, definitive medicines for life-threatening diseases. When I was a stem cell transplant doctor starting out, about half the wards were full of CML patients. But with medicines like imatinib, most of these patients are home now taking a once-a-day oral therapy, no longer distracted by their disease. So we're very serious about small molecules in cancer, and the story I'll tell you today is a discovery chemistry story. But there are 4 other modalities that we use and deploy for cancer therapeutic discovery. One you might know about are called CAR T-cell therapies. These are stem progenitor cell therapies, T-cells isolated from a patient, infected with a virus that expresses a gene that normally T-cells don't have. It's a a chimeric gene that we invent that has a binding protein that recognizes a protein on the surface of a cancer cell, and then an activation domain that upon binding, the T cell is activated to both kill and to divide. And this is then like a living therapeutic inside of your body. And the first such medicine is now approved from Novartis and the University of Pennsylvania collaborating together called Kymriah. We have a host of other medicines of this type for other blood cancers. Then the third platform that we use for cancer therapy is called radioligand therapy. These are little binders that we make either as peptides, proteins, natural products, or even small molecules. We append in a little chemical cage radioactive lutetium or other radionuclides. Upon injection, these molecules swim through the bloodstream to the site of cancer and light it up for diagnostics and kill it for therapeutics. These are 3 of our platforms. We also make biotherapeutics for cancer, such as antibodies or antibody-drug conjugates. More on that another time. I will tell you a story of chemistry today, which I delight to share because I myself am a cancer doctor, but also a chemical biologist. And the chemical biology mindset at NIBR is the idea that there need to be new types of therapeutics to address some of the most grand historic challenges in cancer therapy today. And this is a serious group of people. It might be 800 medicinal chemists and maybe 600 chemical biologists, but you can't beat cancer with scale. Although we have an incredible human resource, and I think an era-appropriate investment in drug hunting of about $2.6 billion a year, you cannot defeat cancer with scale. We actually have to, as a leadership team, fragment this human and fiscal resource up into small and nimble teams that think creatively and try to violate the dogma of science to make new types of medicines. Definitive medicines for life-threatening diseases. We have no cosmetics branch, regrettably, amidst this pandemic, we have no vaccines unit. We're just totally focused on new types of medicines to reach this highest hanging fruit. Our story today begins with the oncogene KRAS that I mentioned that gentleman had mutated in his tumor. This is a picture of KRAS. KRAS, as shown here with the ribbon and a surface translucent overlay, looks to have any number of pockets. There's a pocket right here, there's a pocket over here, there's a pocket down here. You might think that a conventional drug molecule might bind and inhibit KRAS. This is the way that a lot of medicinal chemistry works, is by having the structure of the keyhole, you could imagine a small molecule that fits the pins and invaginations of the keyhole so as to have excellent shape complementarity, Then we match up the positive and the negative charges on the molecule with those on the protein. Remember, opposites attract. Then ultimately, we have also electronic parity between the molecule and its target. Here's that molecule Gleevec or imatinib in this kinase active site. You can see this solubilizing piperazine sticking out of the pocket and the way these heterocycles thread the needle and fit inside and shown sliced open as a cross-section. This is the work of the medicinal chemist, to be a molecular locksmith, making small molecules that fit in small protein pockets to inhibit or to activate. And to be clear, you can still make a lot of really important medicines with that thesis. But for some of the most intractable targets, we need a new way of thinking. And hence this term undruggable, which I don't like at all in our field of study, but it's broadly utilized. Means it hasn't been drugged yet. There's a lot of proteins that haven't been drugged yet. There are great reviews on that subject. When I was a professor working on this p54, we were interested to make the first drugs for what I'll call bromodomain proteins, as shown in the lower left on this slide. The bromodomain protein here is an anti-parallel bundle of 4 alpha helices that have these 2 interhelical loops in a pocket. And into that pocket, we position thienodiazepines and many other chemical features that might bind. And when we made the first inhibitors of the bromodomain, BRD4, it sort of opened up the mindset of our field that, hey, maybe drug bromodomains are druggable. And the, you know, 50 to 60 other bromodomains quickly came under rapid study, and many bromodomain-directed medicines were built. Here's another fold that looks like this piece of pasta, the rotelle. This is called the WD-repeat domain, and like a bromodomain, it functions by protein-protein interaction. And so people think, well, maybe that's not druggable. It's, it's not like an enzyme. It doesn't have like a catalytic site. And unfortunately, that's still a way a lot of science and scientists think. But scientists at NIBR saw a little donut hole here in the middle in this great region with our Dunkin' Donuts. This is quite thematic. And made first small molecules that bind this little hole in the middle of the WD repeat domain of a protein called EED, which is an allosteric modulator of the polycomb repressive 2 complex. If the bromo domains turn genes on, this one turns genes off. And so we have these two molecules now that can switch cancer genes on or switch, switch cancer genes off, or switch developmental genes on. Well, what happens if there's a family of proteins, as shown here, the helix-loop-helix transcription factors, and there's no pocket? These are like spaghetti. In fact, they're intrinsically disordered. As soon as the molecule binds, the protein adapts. And so all of our rules about drug discovery must be sort of thrown out the window, and we need a new way of thinking to go after undruggable targets. In cancer, they're everywhere. If all we did were to look at those genes that are mutated and activated to cause cancer, and here's a list of blood cancers as I'm a blood cancers doctor. There's a long list on the right of genes that are altered to activate cancer, and most of these don't have a direct-acting therapeutic, and some of them, like Myc, like Mib, like ID3, like MAF, it's going to be very hard to drug them because they don't have a pocket. Some of them, like p53, are mutated to be inactivated, and we don't have as yet small molecules that reactivate protein targets. We have a lot of work cut out for us. This was driven home in a really painful way when I joined Vardis and I got to see all the data. This is now published in 2017, but We had functionally mapped all of the Achilles heels of 200 or 300 different cancer cell lines. I think ultimately 500 cancer cell lines. We did it initially by hairpin RNAs, but then subsequently did it with CRISPR-Cas9. And if you look here in the middle, every one of these little bars is a different cancer cell line color-coded by the tissue it's from. And the vertical axis is whether they're alive up here or dead, deflected down. You can see that this ESR1, that's the estrogen receptor, and so breast cancer cell lines and ovarian cancer cell lines will die when that gene is removed. Here's another one called MITF, and in green, these are melanoma cell lines. Unlike the estrogen receptor drives the development of the glandular cell in the breast, MITF actually is a state-specific and stage-specific transcription factor that is important for melanocyte development and growth. And so it's no surprise that that would turn up. Here's the challenge. Unlike the estrogen receptor, MITF doesn't bind estrogen or some other molecule. It has no pocket. When we looked at all of the genes that showed these types of asymmetries suggesting possibly a therapeutic index with selective modulation of cancer cell line viability, all of the kinases had already been drugged. And so there wasn't much in the way of low-hanging fruit for these cell-autonomous cancer drivers. In fact, when you look at genes like MITF and the genes I studied as a professor, gene control or transcription factors, only two of them had been drugged: the estrogen receptor and the androgen receptor. So if all we're to do is deliver on the most validated targets the mutated genes, or the targets that are involved in cell specification, the transcription factors. We're going to need a whole revolution in the way we think about drug discovery to do this. The same is true for KRAS. KRAS has a pocket, but it's well occupied by GDP. You might say, well, let's just pry that out of there with a small molecule like ADP and a kinase. But the GDP binds way too tightly, And at the concentrations of GDP that are so high in a cell, it would take a pretty special molecule to remove that ligand. And so we needed a new way of thinking for KRAS. The second concept I'm going to talk about is called synthetic lethality. And that is, if undruggables is the first concept, concept 2 is synthetic lethality, or context-specific dependency. And this is where a protein target is hard to drug, and so you go after its nearest collaborator. So, I'm going to tell you a story today about drugging KRAS and about drugging one of KRAS's most important, most proximal collaborators, a protein called SHP2. And drugging SHP2 required a total reconsideration of how small molecules work, called molecular glues. I don't know if this term is going to take on or not. This is what we've been calling it in the laboratories at work. So, don't feel obliged to use that terminology. What's a molecular glue? Well, a molecular glue, as much as it sounds like, is a low molecular weight, small molecule that glues two proteins together. Now, it could be an intermolecular glue, like a protein that glues a target to the garbage disposal system for degradation. We had in my old lab at the time of the p54 invented the chemical solution for targeted protein degradation. Using bifunctional molecules initially, and ultimately glues. There's a new type of glue that I really think should deserve much more attention, and that's the intramolecular glue, and so I'm going to talk about that today. An intramolecular glue conformationally restricts a single protein, a single polypeptide, by engaging different domains of the protein and gluing them together. A glue, biophysically defined, is— for the scientists on the line, we define it here, at least in the parlance of how we use the term, as engendering non-saturable interactions. And this is different from protax or bifunctional molecules. Now, of course, we didn't invent this, nature did. And there's some really brilliant examples from the natural world of small molecules that will bring two proteins that normally in human or eukaryotic biology don't bind each other, but cause chemical-induced proximity. Here's two great examples, cyclosporine A and FK506, that bind calcineurin A and B as shown here in blue and light purple. Then in the case of cyclosporine A, bring a cyclophilin in, and in the case of FK506, bring the protein FKBP12 in. This is a short circuit for immune cell activation, which is why both of these medicines are used today so prevalently in solid organ transplantation and in bone marrow transplantation. If you're interested to go deeper into molecular glues, my postdoctoral mentor, Stuart Schreiber, has written a recent review earlier this year about molecular glues that goes all the way back to these earliest moments. Of characterizing the mechanism of action of these immunosuppressive macrocyclic natural products. At Novartis, we've been working on glues for a while, all the way back to the study of rapamycin, another immunosuppressant that's used as cancer therapy in a couple of very focused indications like renal cell carcinoma. And scientists at our Basel site characterized the mode of rapamycin's function as interacting with two proteins, gluing FKBp12 and mTOR FRB domain together. All right, well, let's get back to intramolecular glues and the protein SHP2. So what is SHP2? It's also called PTPN11. It is a non-receptor, so cytosolic, tyrosine phosphatase. If kinases put phosphate groups on tyrosine, phosphatases remove them. And there's really nothing that makes a kinase more interesting than a phosphatase, just that a kinase is druggable, thanks to Jörg Zimmermann and friends. Now, interestingly, with SHP2, there's a strong rationale in human genetics to go after it. People born with activating mutations of SHP2 are at risk for developing cancers, as shown at the top with Noonan syndrome. People with deactivating mutations may have some developmental abnormalities, but they do grow into adulthood. This would suggest maybe that for a fully developed human who has a cancer, maybe SHIP2 inhibition could be tolerated. But this would remain to be seen. There's a huge field of study out there, and so this science builds on a very strong basic science foundation. It is known in the literature that SHIP2 is required for signaling from receptor tyrosine kinases in many cancers, are driven by activating mutations in receptor tyrosine kinases, such as EGFR, HER2, or ERBB2, ALK, and others. We found back in that big project I told you about that when you knock down SHIP2, only a small number of cancer cell lines will die, which suggests that maybe this drug would have single-agent use, but that might work really well in combination because those cancers that were the most sensitive, were driven by receptor tyrosine kinase alterations. Now, this isn't why we got into it, but it turns out SHIP2 might be important for PD-1 immunooncology signaling, which would be pretty interesting. Now, not all literature validates when you really commit to repeating it in a professional environment, you know, trying to justify a big investment to make a medicine, but the SHIP2 research did. We found within our laboratories that in these agar plates, these 2D growth plates, that knocking down SHIP-2 in breast, esophageal, gastric, lung, other cancers, all driven by mutations and known to be dependent upon receptor tyrosine kinases, that, that growth was arrested. This worked in vivo with Hairpin knockdown, and then a really important experiment was done by our cancer biology group. We knocked down SHIP2 and then we added back wild-type SHIP2, and that's shown here in these red boxes. You can see that adding back SHIP2 causes the cancer cells to grow over time. But when you add back a version of SHIP2 that has this cysteine 459 substituted with a serine, that cysteine is essential for its catalytic function, that these cells don't grow back.. And this means that the phosphatase function itself of SHP2 is needed for these cancers to grow. So let's make a phosphatase inhibitor. Well, it's easier said than done. After these first tyrosine kinase inhibitors were made by Jürgen and colleagues at our Basel site, you know, there's probably 50 or 60 tyrosine kinase inhibitors now in various stages of development. I'm sure it's over 100. There's actually no examples of a tyrosine phosphatase inhibitor, and it's not for lack of trying. We and others went at this very hard for many years. In fact, there was an 8-year run at Novartis where we had 30 chemists at least trying to make inhibitors of a different protein tyrosine phosphatase in our metabolism group called PTP1B. We had crystal structures, we had 200 picomolar inhibitors, But the problem is that the active site of the phosphatase binds phosphate, which is very polar. And so the potent molecules that we invented to be the keys for that keyhole were also very polar. And polar molecules don't get into cells very well, and polar molecules are not frequently orally bioavailable and long-lasting in blood. So interestingly, it's easy to make a potent biochemical inhibitor, but hard to make a potent biological inhibitor. It would take a whole new way of thinking. I'm going to share that way of thinking in this story of an intramolecular glue, the first-ever inhibitor of a protein tyrosine phosphatase. This is a model of how SHP2 works. SHP2, shown here, has a phosphatase catalytic domain in beige, and then it has these two Mickey Mouse ears on it. These are regulatory SH2 domains. SH2 domains bind phosphotyrosine peptides, and so you can see the way that this IRS-1 substrate comes along and it's like spring-loaded. As soon as it binds the SH2 domains, they release themselves off of this tyrosine phosphatase domain, and now the enzyme is active. Shown here biochemically, as we add this peptide, the activity of the phosphatase increases. And so, we did two high-throughput screens. First, we looked at the tyrosine phosphatase domain itself to look for inhibitors, and then next, we would look and ask how many of those inhibitors only work when all the domains are present. And we screened 1.5 million molecules this way in a DIFMUP assay, if anybody here is familiar with phosphatase biochemistry. And a whole load of secondary assays in cells. Ironically, we threw out 90% of all of the hits because they didn't work in the full-length assay. And we ultimately stumbled upon a few classes of very special molecules that bind at this middle interface of all three domains, intramolecular glues. We thought, well, maybe these are molecules that conformationally restrict this big protein, ultimately causing it to be inhibited. The crystal structure, this is a model, and I'll tell you when we get to the crystal structure right now, the yellow small molecule prototype drug binds into this pore in the middle of the protein. When it binds into this pore, it brings the white and the green regulatory domains down,, and this little loop sticks itself into the phosphatase active site, thus sterically occluding a productive substrate engagement. So how does this do this? Well, the small molecule actually is a glue that creates a lattice in the dotted lines of electrostatic hydrogen bond interactions that connect to each of the three domains of the phosphatase. More on that in a minute. Well, I know that at least the work we did with Dr. Zhang and this P54 was all about small molecule lead optimization. So I know a handful of you are really interested in how do you take a hit from a screen and turn it into what might be a real drug someday. And it's a real science, actually, and I've surely learned more about that at NIBR than I came in the door with. It all starts with these assay positives, these molecules that hit in the primary screen. Shown here are 5 different chemical classes from which we had some starting point. Now you can see these are all micromolars. These are all very weak starting points, and so they would require real chemistry to advance them. One thing that medicinal chemists do is they look at the molecules and they say, well, are there any similarities in these molecules? These two have this dichloroaryl feature shown here and here, and most of these molecules have a basic amine over here on the East Coast. And we build what's called a pharmacophore model. And the pharmacophore model is helpful because it gives you some immediate hypotheses to test. Like, let's get rid of these amines and see how these molecules do. Do they still work? Or is that basic amine, that nitrogen, really important? And so there was this basic feature, there was this more typically, um, aliphatic spacer in blue, and then there was in green something a little bit greasy here on the end. All right, well, then we solved high-resolution crystal structures of these molecules, and indeed the pharmacophore model proved correct. You can see the way in which these two dichloroaryl features are sort of similarly positioned, and the way the basic amine reaches over to the east coast on the right side of this protein interaction. And so we chose to begin with this aminopyrimidine group, as shown right here, as a lead series because it was 12 micromolar. It didn't have a lot of rotational bonds. It looked nice and rigid for potentially a rigid pocket. And it was nice and small that we could work with. And so we started off with this eastern papyrazine here that was perceived not to be that pivotal, and it was surrounded by polar residues. And so we worked to change the display vector of this primary amine. And in the process of bringing in extra cyclic and stabilizing it with this gemethyl group, we picked up an order of magnitude of activity.

Whoa.

Then we started to explore this dichloro feature, and because of a critical pi cationic stacking interactions, there wasn't much we could do with this at this moment in the med chem, but we revisited it down the road. And then ultimately, we turned our attention to this central heterocycle, And you can see the way that this ring nitrogen has been spun out, just one click to the left. And this actually— this subtle movement of that ring nitrogen stabilized an interaction with arginine-111. And so we ended up learning that this aminopyrimidine was really preferable to the aminopyrazine, and the ligand efficiency was quite dramatically improved. Okay, so will this inhibit SHIP-1? Now, this is really important because SHIP-2 is important for therapeutic use, but SHIP-1 could only lead to toxicity. And in fact, there was no biochemical activity against SHIP-1, which was curious because the proteins are so similar. But when we saw the crystal structure, working with Mike Eck at the Dana-Farber, you can see how big and open this channel is. And the cytosolic buffer fluid, the aqueous environment of a cell, just flushes that molecule straight out. In fact, this proved to be a really potent and really selective chemical probe of SHIP-2, and we characterized it in all sorts of ways. Differential scanning fluorimetry for biochemical direct binding, surface plasmon resonance to get the on and off kinetics, isothermal titration calorimetry to confirm that it would be a stoichiometric 1-to-1 relationship, and it all looked good. And so we published it, and we put the molecule out there to try to excite the scientific community to use this SHP099, the first-of-its-kind tyrosine phosphatase inhibitor, as a chemical tool and maybe tell us what would be the best use of such a molecule. But while we had a pretty good idea about how to use it in solid tumors, as I mentioned, And as the world started to work with the probe, we needed to complete drug discovery because unfortunately SHP099 is not going to be a drug. It's a great tool, but it has some phototoxicity, and it also causes phospholipidosis owing to vacuolization in hepatocytes. And so we just couldn't develop this molecule. So what do you do? Well, we think, do we have to go back to the drawing board, you know, or do we keep tinkering with this in medicinal chemistry, but there might be something about the relationship of these two aryl rings that would lead to the phototoxicity, because a lot of phototoxicity is transmitted by aromatic features. And so we went back and ultimately settled in on these thioethers, these diaryl thioethers, and made a bunch of derivatives of these molecules, and ultimately found that when we separated this dichloroaryl feature with this thioether, and then installed back in our favorite little spacing heterocycle, we had very potent molecules that were very ligand efficient, meaning they bound powerfully on an atom-by-atom basis to the protein target, and they didn't have any phototoxicity. And now we just needed to make these a little bit more potent, and so I'm going to Avoid telling you a little too much medicinal chemistry. We ultimately were able to substitute out the dichloro feature for this heterocyclic feature that had a trifluoromethyl group, and that made the molecules quite a bit more soluble and drug-like. We swapped out that piperazine and substituted in, again, a little bit more solubilizing, but there was nothing really wrong with that, this cyclo feature. And then here again is that primary amine sticking up. Now, this molecule looked great. It had no phototoxicity, but now we had a new problem, cardiotoxicity. We had to work that out, this so-called inhibition of the HERG channel. With some very subtle modifications, first inserting this ring ether system, then ultimately putting in a methyl group, and then adding the two back together, we were able to bump off, throw an elbow to the HERG channel, So there would be no inhibition of this cardiac channel and find this Goldilocks molecule that was potent, that was selective, that kills cancer cells and doesn't harm the heart. Now that only took 5 minutes to explain, but it was years of medicinal chemistry over these last 5 years and ultimately arrived at TNO-155. And this is the actual structure of our drug molecule. For SHIP-2. So now we're getting excited to put it into a human, and you want to know a little bit about what that dose might be. And so we did a lot of modeling in animal models to look at the exposure in dotted lines. This is pharmacokinetics, how long the drug lasts over time, concentration on the y-axis and time on the x-axis. And then pharmacodynamics, what does this molecule do to cells, and that's shown in the solid lines. And so the high exposure to the drug in purple and orange leads to a decrease in the characteristic response in cells is to downregulate a protein called DUSP6. Here is the impact on DUSP6 at a concentration level. Ultimately, we put these into tumor models and there you can see cancers are regressing in response to TNO155 in animals. So how to bring this medicine to the clinic? We have a couple of ideas where this molecule could work on its own. And you might know that biotech and pharma companies always look to see what the drug could do on its own. We have this mantra at NIBR, medicines first for those who need them most. And it struck us that maybe the best way to use a shift inhibitor would be to combine it with a KRAS inhibitor. And as we were doing this work, a brilliant chemical biologist at UCSF, a professor, Kevan Shokat, published the first blueprint for how to make a KRAS inhibitor for G12C. It turns out, as we've known in our labs for a long, long time, that there's a type of chemistry called electrophilic chemistry that can bind to cysteines. 'cause cysteines are a nucleophile, and opposites attract. And so what Kevan brilliantly showed is that small molecules that have an electrophile can bind the cysteine 12 of G12c in a manner that doesn't require prying out GDP. And this was sort of just like a revelation, just a fresh new idea that might ultimately lead to drug molecules. And with that information published, a lot of companies out there, ours included, made molecules that drug G12c. And so one such molecule is shown here in the lower left from a partner of ours called Merati that has a G12c inhibitor, and here is that little electrophilic feature that will react with this cysteine. And there it is, actually bound. You can see the GDP right here, and then you can see the way in which it ligands onto the cysteine over here. And this molecule looks pretty exciting. As its ability to arrest the proliferation of G12C mutant cancers here, with no effect on G12D or G12V cancers. It's a mutant-specific KRAS inhibitor. We studied our own G12C inhibitor as well as those from other companies, always with our SHIP-2, and every time we observe true synergy. This is a color-coded plot, a heatmap of each drug given in combination, a G12C compound here, a chemical probe, and our TNO155 here. Together, these two molecules kill cancer cells even better than either one would do on its own. That's mathematically what we call synergy. Then in animal models, these two medicines together would flatline cancer cell growth. Now, we think this molecule will also work with tyrosine kinase inhibitors. Today, we have open clinical trials studying TNO155 in combination with a number of tyrosine kinase inhibitors and with KRAS G12C inhibitors. So it's early days, and we hope to share the results of these studies over the coming few months. But let me tell you about this 53-year-old man as just an example. So you remember that he had all of that prior therapy, chemotherapy, immune therapy, and targeted therapy. And just to remind, he received Amgen's very excellent KRAS G12C inhibitor. He received a SHIP-2 inhibitor from Revolution Medicines that made a SHIP-2 inhibitor just after we did, um, and he was out of options. And so we enrolled this man on a combination he had never seen, um, our what we think has some best-in-class properties SHIP-2 inhibitor, um, and this remarkable molecule from Mirati Therapeutics. And at the very first dose level, he had a very dramatic response.. Now we're just not used to seeing this in solid tumors, especially solid lung cancers. We've seen it with mutant EGFR inhibition, sometimes with mutant ALK inhibition, but we're not used to seeing this with, with KRAS mutations. And it's early days and this study is ongoing, but we're so hopeful that patients like this man might benefit and maybe might even receive this therapy a little earlier in their course of their disease. Perhaps they don't need to get so sick so fast. In my heart of hearts, I do not believe G12C inhibition will be curative, though unfortunately for these tumors. Presented this weekend at the AACR annual meeting is a first snapshot as to how KRAS G12C inhibitors breed resistance in tumors. We don't have that data yet for the combination. We are going to need many, many more ideas for patients with KRAS mutant lung cancers and probably to treat these patients at earlier lines of disease. But I'm so inspired by this story because by reconsidering how the drug shipped to, with a new molecule, an intramolecular glue, by reconsidering how to drug KRAS G12C, not to displace the substrate, the cofactor, but to bind into it by engaging a cysteine nearby, covalent chemoproteomics. That these two new revolutionary ideas in molecular pharmacology, glues and covalent chemoproteomics, together could really help a gentleman like I shared with you a moment ago. And so we're just going crazy with these ideas at NIBR right now, and that's not to say we have it all figured out. This is highly collaborative work with scientists such as at the Dana-Farber, the University of California, Berkeley, and Orionis, and many others. Science is the ultimate team sport, and this is really where we need to have the best ideas around the table. But if we are able to drug undruggable proteins— and I didn't even tell you about the work that we've undertaken to drug RNA in a sequence-specific way for severe neurologic diseases— then I think we're pretty close to the end of this idea, undruggable. Now, in the closing few minutes before the Q&A, I was invited by Jill to share some reflections on the state of diversity and inclusivity in science. And surely it must be better than it was 20, 30 years ago. I've only been practicing science for about 20 years. But it's still fair to say we have a really, really long way to go. And I find in the natural and physical sciences, the data when it's sampled to be very troublesome. This week there was a study from Sangeeta Bhatia and MIT, another study from Deerfield, a venture capital firm that I hold in high regard, on just the perilously poor gender diversity in the case of those two studies, statistics from our community, in particular among leaders. I show here The way in which a 50/50 workforce at the time of college science concentration selection ultimately becomes 24% female in tenured faculty in the sciences and 18% female in board of directors in biotech. The Deerfield study recently reported suggests that 48.5% of all biotech companies that they surveyed have no female on the board of directors. Now, I know that the type of diversity that this P54 so cares about goes well beyond gender diversity and thinks about underrepresented communities of science and racial and ethnic diversity. And the data are harder to come by there, but are equally concerning when we and others look at it in our community. We really have to do better. Society expects it. I'm the first here to tell you there's no altruism involved. It surely does. It's a good thing to work on and it feels good to work on it, but the science demands it. I have seen the way the groupthink around some of the principles of medicinal chemistry keeps scientists stuck in their old rabbit hole. I was trained to use a hammer and I'm going to hammer things.. And we need to be in a much more agile, inclusive, challenging, speak-up environment than poorly diverse communities often allow. And so what are we doing about it at Novartis? Well, we start by measuring it. How are we doing it? What are our vital signs? And actually, in our research environment, the trend is strongly positive. I know my predecessor, Mark Fishman, cared desperately. About diversity in science, and it has been a major core focus of our strategic plan, Pillar 5, Invest in Our People. I'm proud to say that across all of Novartis— now this is 106,000 global associates— that it's 50/50 men and women. We're almost to 50/50 in management, which is a stated goal of our executive committee. 150 nationalities represented, and I believe 4 of 13 of our of the Novartis Board of Directors are women. At the executive committee led by our CEO, Vasna Rasiman, who is quite passionate about this subject in more than just gender dimensions, we have stated goals that we as an organization and each of our units are on the hook to deliver, because you don't get what you don't measure. And it starts with listening and focusing on the moments that matter to people. It starts about measuring and assuring pay equity such that there aren't any unintended forces at play that occur after recruitment. It means having a diverse final slate of candidates before extending an offer. It sometimes means working or networking with externals in order to be sure that a candidate list is adequately diverse. I did this just 2 weeks ago. When we announced that our head of NIBR Oncology, Jeff Engelman, will be moving to the biotech sector, I made a list of all of my dream candidates to lead NIBR Oncology—open position, by the way—and, um, and to my taste, the list that I could produce, even as a cancer scientist, was inadequately diverse. And so I scheduled 3 meetings with leaders in the U.S. and in Europe to try to do better. And we have a much better list for it. There are things that you do if you're trying to prioritize equity and inclusivity in your work. And I haven't talked about inclusivity, but here's where culture really matters. It's one thing to have diverse people around a table, a diverse mindset. It's another thing to have a culture that invites everybody to contribute. And in a hierarchical work environment like companies can be, It's really, really important for leaders to be selected who know how to reduce this to practice, to really get the quietest voices in the room to contribute to a weighty scientific matter. And I'm sure all of you have experienced this, but in my time in leadership these last 5 years, I can say there's no correlation between the loudest voice and the best idea. And so here's some data I hope it's okay to share. This is from a presentation our CEO gave a few weeks ago in Europe. Actually, it looks like a few months ago in Europe. And there are certain funds that invest in companies, buy their stocks only if they meet certain goals in these dimensions and other dimensions like environmental dimensions. And we're a big company that's $220 billion. And we want to be sure that everybody inclined to buy the stock can. And so we listen to these so-called ESG investors and share with them our own personal ambitions and leadership ambitions for the company. And we get feedback and we turn in report cards as to how we're doing. I believe that if the academy were on the hook to deliver diversity, equity, inclusivity, to close gender pay gaps, if they were as publicly on the hook as we are, that we would make much better strides in academia and biotech than we have. But right now, it's pharma leading the way. This is my last slide, and this is the shameless plug. So I apologize, Jill, but I'm always recruiting. We have programs at NIBR. We have a postdoc program that's just brilliant. And we believe that having trainees in our labs is very energizing for scientists.. It gets us to think out loud, which brings out a much better brand of science. We also feel like we have an obligation to share a discipline that you really can't train in but for a few academic institutions, like medicinal chemistry. Great at Ohio State University, but there aren't a lot of great programs in Boston, maybe Northeastern. To open up our labs to trainees. And wanting to be a part of like a rising tide that can improve the ecosystem. It's not lost on us that when people leave NIBR, they sometimes go to be the CSO of a biotech company. So could, if that's the pool that these venture capitalists are pulling from, could our effort to raise great leaders that are more balanced in the dimensions of gender and ethnic diversity, could that ultimately read through to a positive impact on the ecosystem. Look, we can't do this alone, and actually there's a lot of companies very, very focused on this. But we have to walk the talk. I can tell you there are deals I did not do last year because we weren't happy with the diversity around the table. So we have these two internships. And we have a summer internship, and it's a 10-week internship. It's thoroughly scientific, but it can focus on other areas of interest, entrepreneurialism, business development, and the like., and it's an all-access pass to Novartis. At this stage, the summer internship is fully recruited because it's April, but we're going to open applications for 2022 in September. And then secondly, we have a post-bac internship, and this is a 2-year research program to really— I call it the definitive passport stamp for people interested in, in, in, in, for, for drug hunters.. And this is before scientists would enter graduate school, and I myself did a period of research study after college and before I went back to medical school. And it was, it was some of the best time in science I've ever had. Not just scientific mentorship, but these are really well-organized programs where you meet a lot of scientists with different career trajectories, network, And this isn't altruistic either. We believe that if we really invest in some of these talents, maybe a few of them come back and work with us as professional scientists someday. And as shown on this slide, there's a real focus to these programs for scientists that arise from underrepresented communities really around the world. Okay, well, I've already said too much, but I have plenty of time if there's any Q&A. Thank you so much for the invitation, Jill, to join today. If I didn't say it already in this seminar, if ever there was a team sport, you know, it's making medicines. And so just for every reason, having a big conference table, you know, with all the right minds, working in a culture of total openness, bravery, curiosity, I think this is the secret sauce of NIBR, and what has made this for 20 years one of the most important and productive drug hunting engines in the world.

Anyway, thanks again. I'll gladly take any questions that you have. Wonderful, thank you. Let me start with a question. Well, first of all, it was a beautiful talk, and I really do commend, especially at the end where you made us aware of the internship and the post-bac opportunities at NIBR, because I think those are critical. You mentioned maybe a slide or two before that, that one of the goals is achieving clinical trial diversity, and that has been a challenge for a lot of comprehensive cancer centers across the country, and I guess in the pharmaceutical industry as well. So can you talk a little bit about how—

what kind of strategies are being employed to try to achieve that. Yeah, absolutely. I just want to be sure that we can see each other. Am I out of screen sharing mode? Yes, we can see you. Okay, okay, good. Thank you. Thanks for the question. So again, just as I should have brought a slide on that, sorry. Just as for our workforce, we measure and have targets and expectations for diversity, not just in the, the individuals that we are able to recruit to our clinical trials, but also for the investigators that participate in our clinical trials. And we are above benchmark, um, based on population norms and also our peer group of pharmaceutical companies in clinical trial diversity. This NIBR is really, in this case, um Um, following the lead of our global development organization that does the much larger and more global Phase 2 and Phase 3 clinical trials. But we do measure for early clinical study, um, to ensure that we are executing these studies in the most diverse way possible. Now, it is important to do this just as a first principle, but I can tell you scientifically and medically It's essential. We've seen many times molecules that would move through clinical study in one region and then not translate to an Asian population that may have polymorphisms in xenobiotic metabolizing enzymes of the liver, and we would see real incongruities. And this has led to a requirement for advanced— advancing medicines to have dedicated studies done, let's say in Japan, in order to ensure that the pharmacology will read through to an East Asian population. And so in one way, our society of drug discovery and the regulatory agencies are, are on it and held to account. But, but the pooled data would suggest that, as in the early moments of the COVID-19 vaccination efforts, that the studies can be inadequately diverse the way that they're operationalized. In any event, John Tsai, who's our Chief Medical Officer, he's my partner that we hand off medicines to John for Phase 3 trials, has a leader, Badri Srinivasan, who measures our diversity on a per-trial basis to ensure that we have an adequate study of, of human genetic backgrounds to interpret our medicines, and importantly, ethically, to ensure that we have adequate access to investigational study. So that's what we're doing at Novartis, but I do think that our ecosystem could do even more. And there's a very active working group of leaders of research and development organizations right now who have been gathering. I'm, I'm on this team as well. Over the last about 6 months, I think catalyzed, it's fair to say, by some of the atrocious but still persistent injustices of last year that really brought a lot of people around the table to share data about their numbers, to share best practices, and to maybe even start to think about industry best practices. So there'll be much more, I think, to share as this work stream starts to converge on a, on a coherent set of expectations. But I can say from all I've seen within our company and within our peer group of large pharmaceutical companies, this question of diversity in clinical investigation is receiving outstanding attention. The flip side is that the data still doesn't look very good. When you look at ultimately equitable access to new medicines, and the outcomes in challenged, socioeconomically challenged communities within the United States, but even more so globally, we can do better. We can do better. Great. Goyo, I think of our colleague Chris Lathan and all I've learned from reading Chris's work around how even in the neighborhoods around the Brigham and Women's Hospital, there's inadequate access to first-world medical care. Though, you know, 3 or 4 blocks away is this extraordinary institution.

So I am feeling very positive about the work stream that we have internally and collectively, but there's more work to do. I'll read one of the questions from the audience. This question is from Changming Cai. It reads, great work on SHIP-2 inhibitor. This is an unrelated question. Can you comment on the clinical future and challenges of developing epigenetic inhibitors such as the BET inhibitors or inhibitors of lysine methylases and demethylases?

Yeah, thanks for the question. Um, I still remain very interested in, uh, chromatin-associated proteins as drug targets, and we have a small number of those proteins in our active portfolio today, though not BET bromodomain inhibitors. I managed to join the one company that doesn't have a bromodomain drug. So, opportunities. The opportunities are that these can be master switches that open and close whole domains of chromatin, and therefore can have really powerful impact on different tissues in the body. In the case of cancer, there are numerous switches now to flip off euchromatic expression of oncogenes and coregulatory circuitries. We've published on a few. The BET bromodomains, the E-NL YATES protein, CBPP300, and others. And that, I think, field is moving really quickly. So that's the opportunity. Here's the challenge. I think, as you know, these master regulators aren't only expressed in cancer cells, and they don't only collaborate with professional cancer-causing genes. And so there can be off-target toxicity— I should say on-target toxicity of hitting those nodes, especially in rapidly proliferating tissues, because of the blood and the colon. They require— those tissues require the same wiring as cancers arising from those tissues. They just know when to switch them off. And so in the case of the bromodomain inhibitors, there are still a number of them in active clinical investigation. But some of them have encountered hematologic toxicity, which is on target, I perceive, from displacing BRD4 from nuclear chromatin in hematopoietic cells, leading to altered differentiation states. So it could be low platelets or even suppressed proliferation. What this makes me excited about are finding synthetic lethal opportunities where there's more of a context for a chromatin factor than just it is a master regulator of the growth symphony. Maybe with pharmacology, there could be ways to address the same target in different tissues, like a tissue-specific ubiquitin ligase, for example, as I work still on protein degradation chemistry at Novartis. Beyond that, I think that we need to get more proximal to the actual factors that recruit the complexes., and those are these transcription factors that I spoke of a moment ago. But by and large, the way that successful development campaigns for epigenetic targets has materialized is accepting that there's on-target tox, characterizing it and understanding it, and then looking for the left-shifted biology that's even more sensitive to those factors than the physiologic toxicities. I know that's a long answer, but I'm still hopeful for such targets.

It might be beyond cancer where that left-shifted biology exists. If I may ask a question, something that you said during the talk, and the idea of molecular glues is just really, really fascinating and interesting, and I'm curious about whether we should think about these molecular glues as always having an inhibiting function. Oh yeah. You know, could we think of these molecular glues as actually activating? You, you, you, you bind to that protein, but it changes it to this new state, and it's actually now has a new activity, sort of like a dominant negative kind of thing.

Yeah, I wonder if you can comment And the answer is yes. Um, so it's just a funny thing in science how one field kind of gets religion about a certain technology and just runs with it, and other fields like, ah, cancer's dealing with that, I'm not going to do that, cancer's working on that, you know. Um, like the, the study of epigenetic molecules in inflammation, in fibrosis, in cardiac illnesses, a very small number of people, but in cancer there's hundreds, if not thousands. The same is true of these molecular glues, though the example of, of jasmonate from nature, of auxin from nature, of thalidomide and its pharmacology, as we and others have characterized it, it exists in the space of degradation. Bringing otherwise intractable, unapproachable, challenging targets to ubiquitin ligases for degradation and thus pathway inhibition. There's plenty of molecular glues that function in an either activating or in an altered pathway mechanism. I'll give you one example. This isn't a glue. This is just a bifunctional, but it's just to illustrate the point. A friend of mine and I, Asim Ansari, wrote a paper few years ago in Science magazine, where we tried to make a small molecule that would glue the Brd4 bromodomain activating protein. It activates genes and glue it to a part of the genome where there was repression of the Friedreich's ataxia gene for taxin. You might know that because of CAG repeats that Friedreich's ataxia the frataxin protein is epigenetically silenced in that pediatric disease. And Asim had invented a molecule that binds those repeats. And so we took his chocolate and our peanut butter, and we put the molecules together, and lo and behold, these molecules— now they're not the perfect molecule, these aren't good-looking molecules like that TNO155, they're starting points. But this molecule swims into the nucleus, it localizes across that genome, and it recruits Brd4, which we were able to measure by chromatin immunoprecipitation and genome sequencing. It recruits Brd4 to this promoter region where normally it's like a desert of gene activation, and lo and behold, poof, frataxin is turned on. Now, this is a long way away from being a therapeutic. I believe a team may have started a company around this concept. I hope it works. But there's a way to activate euchromatin in the genome using a glue-like small molecule. Yeah. So I think that a more expanded consideration of what glues can do would be really very powerful. And I'll bet you dollars to donuts that a lot of molecules function as glues.

We just haven't considered them. As working in that way. Hey, Jay, we have a question from Dr. Donaldson, who co-leads our outreach core. Um, she writes, thank you for a great scientific talk and your work. I'm also impressed by your discussion about a report card and the benchmarks that you use to measure your success and to get accountability around diversity and inclusion. Can you talk about how you and the leadership came to this, did you get specific training?

Did you inquire about what was needed with the target populations? Short answer is yes and yes. Um, the second is an easier yes. Um, our organization under Vas Narasimhan, our new CEO who started 3 or 4 years ago, has undergone a real transformation, a cultural transformation. I hope that doesn't sound silly. It's very serious to change the culture of a longstanding global company rooted in Basel in Switzerland, which has some very traditional and actually wonderfully traditional behaviors, has been a heavy lift and it's ongoing. And this has been a heavily invested, heavily communicated, thoroughly considered, and I think very inclusive process. And our efforts in diversity and inclusion are like really cornerstones of that culture, but they're not the limit of that culture. There's— we have these 3 cultural tenets we talk about on being curious, inspired, and unbossed. And for managers, being more self-aware. What does unbossed mean? And we've gone very deep with that in our associates. And I think that the D&I workstreams and the equity workstreams have dovetailed with that and have solicited and collected thoughts from the global organization. I can say within NIBR that the 6,000 scientists that we have, we have done the same and we're even more organized in the current strategic plan we're writing this year through Anastasia Awad. I don't know if Dr. Awad's on the phone right now, but is leading I think, a very ambitious effort to collect exactly that information beyond the dimensions of gender, which are for some legal restrictions and union expectations. We're not able to measure everything in every country where we operate. But in the States, either by self-reporting or even without knowing the background, but just being interested in the answer, we're working very hard to collect those opinions. I'm also proud to say that my own office, the Chief of Staff, my Executive Administrator, and I are the strategy team writing the strategy, are so, I think, well connected to the organization that I hear from our associates in the labs all around the world, even just primarily. So yes, systematic, and the doors of communication are open. And we hope coming out of our strategic planning process in 2 months to have some really tightly and well-articulated and also measurable targets in these dimensions, as we've had for the last 5 years. Then about training. Maybe those of you who are really expert in this can even hear in the way that I'm speaking of it, I don't have any training in this critical dimension of leadership. And so I'm still very much in the downloading phase. Very much in the downloading phase. I just attended the first ever lecture from an author that I admire, Ibram Kendi, that has moved to Boston. Actually, Goyo was through the colorectal cancer group at Dana-Farber. And I learned so much in that half hour. So I'm still in the midst of my own download on this. But thankfully, I'm supported by— we call them people in organization, they might be called HR leaders, who have, like Lisa Naylor, studied this, you know, academically and practiced it professionally their whole career.

I think what you're saying about being in the download phase and approaching the process with humility, even though you're such an expert in other areas, is really key to this. Do you know what I mean? To try and understand how to really have an impact. So I think that's terrific. And, um, you know, it's a, it's a process. There's a lot going on at Dana-Farber, you know, in the academic space that I'm involved in, and it's the same sort of thing of really listening and trying to come up with plans and then also really talking to the groups that are most affected as well and getting feedback on that.

So that's terrific to hear, Jay. Well, thanks, Goyal. You know, I'm not ever distracted by these academic versus industry comparisons. The big eye-opener is just how similar they are. But I do think there's something to learn from the way professional organizations approach diversity, inclusivity, and equity. And if you just look at the numbers at our beloved Dana-Farber, at our own Friedrich Miescher Academic Institute, it's behind. It's behind what I know that we can deliver. Now, the luxury of no longer being a scholar is when you're a scholar, you need to have the most authoritative opinion in the room. And now I just have to find the best idea in the room. And so there is humility, but it's also my job.

It's my assignment to really bring forward the most impactful opportunity for such an important organization. I'd like to ask a question from one of the students, it looks like. This is from Marie Rodriguez. She says, excellent presentation. Thank you for sharing your knowledge. I'm a biotech technology major from Brazil, and I am very interested in pursuing a career in this field. Is your institute open to international students?

And if I may add, maybe DACA students as well, or DACA trainees? Yeah. Yes, we're a global organization. We do not have a laboratory in Brazil, but Novartis has a manufacturing facilities and a very strong unit in Brazil. Not that you want to work in Brazil, but just that is my way of saying that, you know, we're as motivated to engage with Brazilian scientists, Brazilian business leaders, as leaders anyplace else. We do have some Brazilian scientists at NIBR, as there's just brilliant, I think, you know, chemistry especially. I've been down in to Brazil to work with a natural products chemistry group. I was blown away by the sophistication. Okay, now having come to the United States to train, as if I'm understanding the question correctly, you have, you know, we're an organization that is pretty used to accessing the best talent from a global pool and have many paths to support scientists from overseas, either on international assignment or to help with visas. Getting a job at NIBR is, is pretty competitive. It was when I applied, and, um, uh, um, and but yes, yes, of course, we are very interested in recruiting scientists irrespective of their nationality or ethnicity.

So I'll ask a question from William Gibson. I'll just get to the punchline because I think it's really intriguing.

He asked What is the next great challenge in cancer therapeutics? Well, the big one is getting big things into cells. If we could get big biomolecules into cells, I think we could lick this thing, but we can't. We can't get big proteins, hairpins, AAVs, we can't get them into cells. We celebrate when it's 90% delivery. We high-five and hug when it's 95% delivery. We get a Nature paper when it's 99% delivery. But that means that, you know, 1 out of 100 tumor cells will not receive the therapeutic payload. They will not be impacted by the therapeutic. And, you know, with a kilogram of tumor on board, That's a lot of cancer still with that patient. And so when I talk to students, I'm always like, help us get big things systematically into cells. Second is heterogeneity. It's— it was really deflating this weekend to see the data published from a biotech company that the patients who demonstrate resistance to the KRAS G12C inhibitor as a single agent have any number of RAS mutations. One patient, if I understand the slide correctly, had 5 cancer-associated translocations in one tumor. This is scary, this degree of heterogeneity. I think therapeutically addressing cancer heterogeneity is a grand challenge. It makes me want to treat people earlier, makes me want to treat people before they have cancer, but when they may have positive circulating tumor DNA for one or two different oncogenes, to think of cancer more in the space of secondary prevention than as primary treatment. But we'll always unfortunately need to have therapeutics for cancer patients. And then the third, if you gave me a third, I know you only asked for one, I would say just better collaborative models. The SHIP-2 project's interesting because we know that SHIP-2 is going to need a G12c inhibitor to become a really important medicine. And so if all we care about is our own drug, which isn't true, but if all we cared about was our own drug, we need a partner. And there's like 7 of these G12c inhibitors out there. So who's going to be the winner? I don't know, and I actually don't care. I want all 7 of those molecules to be used with our molecule because we really, really believe in it. And it's first, and that should matter for something. And so we rang everybody up. Could you do a clinical trial with us? We'd be so willing. Yes, this isn't an approved drug. I know that they're scary to have investigational drugs put together, but could we work? Good people, you know, like, you can hold the IND, just take some tablets and let us know how it goes. Not every company wanted to do that. Not every company was as curious. To work with us. And so I think even when we have tried, and it's not every time we do, but even when we have tried to, you know, really tear down some of the institutional, you know, barriers to collaboration, there can be real challenges. For a price of a cup of coffee when I was a professor, I could get some data, you know, together with a buddy or someone I've just been introduced to. And the science would start that afternoon. In the research environment that we're in today, academic centers are very entrepreneurial. They patent way earlier than we do. We see companies started before papers are even published, which is different than even 5 years ago when I was there. And it can be hard even for us to access ideas and to generate data together with people.

I just feel that the velocity, the efficiency of collaborative interactions is moving in the wrong direction because of, I think, financial expectations. Yeah, I have one question as others are being asked. We just said nothing to do with the cancer therapeutics, but on the other side on the, your leadership on the diversity, inclusiveness, equity issues, which very impressive the way that you articulated it and your commission and passion for this, your commitment and passion come through very loud and clear. So we interviewed for a project that's completely different, about 25 C-suite leaders. Connected to this broader issue of well-being that a company can promote, whether it's in the community, environment, among employees, you know, and as you showed this slide from a neighbor, and Novartis broadly, how you are influencing your suppliers, you know, to adopt some pro-social policies, which I think is one of the most effective ways to do it, irrespective of what the countries are saying, I think the companies can do that. Gap is actually doing that globally among its suppliers. So, one thing we found out from one of the most successful, the more successful C-suite leaders is that they play also a significant role in the local community in promoting those issues of equity and diversity. So I'm just curious, as president of Novartis Labs here, what kind of role are you envisioning, or are you playing, in increasing that pipeline and increasing that diversity locally within the greater Boston community, where you have somewhat more control?

Thanks, Vish. Well, appreciate the warm feedback. It's a work in progress, as you could tell. You know, we always have our global hat on because our company's headquartered overseas and because we don't have an intrinsic bias for the needs of the United States versus Sub-Saharan Africa versus Brazil versus the UK because we have we operate in 40+ countries around the world. So that might be a watch out for us actually, Vish, is that we always have this sort of more global hat. As our research headquarters is in Cambridge, if you know where the NECO Wafer building is or the Flour Bakery, those are our labs. There are ways in which we really roll up our sleeves in this community. In any number of ways, any number of ways, training, education, outreach, philanthropy. But I do think we could do more in the Boston community. I am certain that the members of my leadership team who are really driving our diversity, inclusion, and equity strategy are deeply connected. So I don't wanna say anything that insults their actual connectivity, But hearing your question, I do think we could be better connected locally than we are. And we'll be curious to know, you know, what support is most needed. When Dr. Kendi spoke the other day, that was the question I contributed is, okay, we've just moved here, like, you're building this amazing center on anti-racism, like, what can all these great biotech companies do? To, to weigh in and to be helpful. And I quite appreciated his answer. I think for his center it'll take some follow-up to really know what that might look like. So I would say, Vish, that the, the interest is for sure there. I think we can have a really positive impact locally, but we would also, you know, just welcome the, the direction from those like yourselves who think about this matter you know, as a primary focus and passion.

You will hear from us. Thank you so much. Nice. Thank you. I think we're going to end our conversation for today. Thank you so much for your time. The questions were fantastic. Certainly, you know, speaking personally, I thank you very much for visiting with us, and hopefully we continue to interact as we're— we as a partnership are also interested in engaging more industry in our partnership.

So thank you on my end.

Other PIs, would you like to say anything else? That was fantastic. Thank you, Jay.

Thanks a lot, Jay.

It's great to hear.

Thank you so much. Thank you very much. Great. All right, thank you very much. Appreciate the invitation.

It's great to see so many of you again, and thank you to the audience for joining us today, and we'll see you next year. Take care.

Bye-bye.