Ross Cagan (left) and Kevan Shokat (right)Professor Kevan Shokat is a pioneer in the development of chemical tools for novel drug and drug target discovery. He has made breakthrough discoveries when targeting KRAS, PI3K and mTOR, all of which have enabled profound advances in the treatment of cancer and neurodegenerative diseases. Kevan challenged dogma when he ‘drugged the undruggable’ by successfully developing the first covalent inhibitor of mutated KRAS and, in an oncology landmark, this inhibitor has recently been approved for the treatment of non-small cell lung cancer.Initially, Kevan pursued his passion for chemistry receiving a BA from Reed College and continuing with a PhD at UC Berkeley with Peter Schultz. He then shifted disciplines as a postdoc into the realm of immunology with Christopher Goodnow at Stanford University. Currently, he is a professor at University of California at San Francisco, where he has become an icon and fixture. He has co-founded many companies that have had remarkable success, won a plethora of awards and is fellow of several prestigious research foundations.Professor Ross Cagan, Regius Professor of Precision Medicine at University of Glasgow, as well as an Editor for Disease Models & Mechanisms, is renowned in the fields of oncology and fly genetics. Ross investigates and therapeutically targets KRAS mutants in cancer and RASopathies. He also pioneered the ‘patient avatar’ technology in Drosophila, a key tool for personalized medicine. Ross and Kevan have previously collaborated to potentiate their expertise and enhance successful translation of therapies into the clinic. In this interview, Ross and Kevan discuss how they have blurred the boundaries between biology and chemistry, and examine the key to a successful collaborative project. They also delve into how young researchers can adapt to the evolving academic landscape and how all scientists can strive to effectively communicate their work to the public to better serve society.Ross: We first connected through your postdoc, Arvin Dar, as my lab had stepped into Src inhibitors, and Arvin was working on this in your lab. I was then at a meeting in Stanford and I wanted somebody to work with, who could turn genetics into chemistry, and everyone suggested talking to you. When we met, I was very impressed by your understanding of fly genetics and how you could turn that knowledge into the evolution of drugs. You dived into the biology of it. How did you become so comfortable speaking with biologists? Do you see this as a fundamental part of who you are, as a chemical geneticist? And how is that different, for example, from drug development?Kevan: I became really interested in biology, during my PhD with Pete [Schultz], because he was one of the first chemists to think very deeply about biology. Not biological problems, like biologists think of them, but biological opportunities, like a chemist would look at them. So, when I worked on catalytic antibodies, and learned about B cells, it prompted me to go to Chris [Goodnow]'s lab and work on B cell tolerance. That's where I thought about genetics, because Chris set up an unbelievable system using genetics to make a monoclonal B cell repertoire. These were elegant systems that use genetics to create this perfect microscope to look at an amazingly complex biological question, like the antibody repertoire and how this diversity is kept in check so as not to attack ‘self” – and it really took hold.Ross: There's certainly a skill that you have, you make people feel comfortable to work with and, in the type of chemistry you do, it's fundamental that you're able to work well with others. I know that you've had people, from your parents to your mentors, that have influenced you in this. But if you could talk to a young chemist today, what would you tell them in terms of how to approach others? What is the key to being successful, and to drag your chemistry into different directions?Kevan: There's an infinite number of things you could do with your time and science. And I find the best way to collaborate with people is when there's an ease of interaction, because when we get deep into the science, as you and I did, there are always times when the data don’t line up. You also want to be very curious about the biological question. I could have a lot of things seem right in a collaboration, but if the biological question is too far away from the chemistry, I just won't have the same motivation.Ross: Have you actually declined or walked away from a collaboration?Kevan: We've had projects in the lab where a student really wanted to pursue it, and I have agreed as it sounded like it was going to be close to what we do. If the student is great, they take it on, but if the project gets layer upon layer away from the chemistry, it gets harder. Then, because it's a student in my lab, I try to bring in another collaborator that I know has the right expertise. That part is fun, but I'd rather know at the beginning roughly the parameters of the project.Ross: I know that you're expanding into other arenas; PINK-1 with Parkinson's and even COVID. In your lab, do you decide to work on any interesting questions or do you try to rein in your lab?Kevan: I try to just work on interesting questions. I don't try to say what we will or won't do. Working on COVID was amazing, but I think when you come from chemistry, there are certain holes in your knowledge. I think the most important thing is to always ask the question that's on your mind because nobody knows everything, and this helps you to make sure you don't have gaps.Ross: You have a willingness to plunge in and take on challenging problems, which I know people, such as Frank McCormick, have pushed you towards.Your specialty, at least initially, was kinase inhibitors. During that time, the ‘bump-and-hole’ method for identifying targets was really powerful, and very clever. But in what may turn out to be one of your most-impactful identifications, you developed the first covalent inhibitor of KRAS [the most commonly mutated oncogene, associated with poor responses to standard cancer therapies], specifically with the G12C mutation. KRAS was known for so long as being one of the ‘undruggables’ and was called the Death Star of cancer targets. Excitingly, sotorasib [the compound inspired by your breakthrough] has recently been approved [for adult non-small cell lung cancer patients with KRASG12C]. So, a broad congratulation is in order but, I think, what is equally amazing is how fast everything happened. You published your original paper in 2013; eight years later, add COVID, and now you have an approved therapy. Were you surprised with how quickly things moved? And why do you think things moved so quickly?Kevan: There were a lot of pieces that contributed to it happening quickly. When we published our paper in 2013, people were already coming up with molecules that could bind to RAS. In 2012, there was a paper from Genentech (Maurer et al., 2012) and another from Stephen Fesik at Vanderbilt University (Sun et al., 2012), where they had done a screen using nuclear magnetic resonance spectroscopy and found a little pocket [in the RAS 3D structure] and a small molecule that would bind, but it was weak with low affinity. Then Nathanael Gray's lab at Harvard described a compound that could inhibit RASG12C (Lim et al., 2014), which was a covalent molecule based on the structure of GTP. At this point, we were getting ready to publish our approach – this other pocket we had identified in RAS and called the switch-II pocket, which was distinct from the others (Ostrem et al., 2013). Our molecule that bound in this pocket also pretty weak, although we saw the beginning of cellular activity. I think what really saved it and made it progress very fast was that I started working with Yi Liu, Pingda Ren and Troy Wilson, and we started a company called Araxes. They just launched into optimization and published a paper in 2016 that showed the first really good molecule with potent cellular activity (Patricelli et al., 2016). Then a couple of years later they published a beautiful active molecule that worked in vivo (Janes et al., 2018). If we had just published the 2013 switch-II paper and had not started a company, I think pharma would have looked at the paper, played around with the compound, and not taken it further. That was the period when people at companies thought there was a reproducibility crisis in academia. I've heard from pharma companies that they took our paper, synthesized every single key molecule and reproduced our activity – but didn't see developable activity. However, because I had a great relationship with Yi and Pingda, they believed in this molecule and optimized it. Now, the scaffold they discovered is in the core of every other G12C inhibitor. So, to me, the fast part was really credited to them. Also, RAS-mutant tumours are very ‘RAS addicted’ and once there was a chemical that you could target it with, the drug progressed very fast, which was also the case for inhibitors of viral Src and BCR-ABL1.Ross: That's really interesting because your job is to solve the RAS problem and, in part, you did that by establishing or encouraging a company to help drive it forward.The molecule shows efficacy for months but not years, which is fairly typical for precision medicine molecules. My lab focuses on this as well, so I'm obviously a believer – but it's a little frustrating that the patient doesn't get a cure. What do you think is the ceiling for drugs, in general? And how are we going to break through that initial ceiling?Kevan: I think this is, right now, the key question in oncology. If we just keep making drugs that give us six months extra [survival], that isn't the real breakthrough. To me, a cure would be a patient has cancer, gets treatment and, when they pass away, it's not because of their cancer. For example, my colleague Neil Shaw told me that ∼30% of [chronic myeloid leukaemia] patients treated with BCR-ABL1 inhibitors can be cytologically converted to be tumour free. Even when there are patients that can be cured, we still don't quite understand why 70% of patients aren't. I think we need better molecules, like inhibitors that drive the signalling down to ∼2% of the existing [level]. So that, to me, is one answer.The other answer is molecules that are more specific for the mutant and don't inhibit the wild type. As we know, that's a challenge. The G12C drug is great because it's only inhibiting the mutant, which is only present in the tumour. This inhibitor is now a backbone for many [drug] combinations that, I think, will lead to some cures; because when we get the right combination, there should be a profound response.“We've got a lot of six-month treatments, which is great, but now let's go for a functional cure.”And then, of course, starting treatment earlier. We've got to start it before [the cancer cell accumulates too many additional mutations], to target the truncal mutants. I think [this ‘cure’] is going to come in the next five years, certainly in ten years – but it's going to require chemistry, a drug combination and early detection. Early detection seems like a panacea, but I don't want us to put all our eggs in that basket. I think we should be focusing on getting earlier therapy and the right molecules. We've got a lot of six-month treatments, which is great, but now let's go for a functional cure.Ross: Do you think that your research is in the right chemical space and you just need to mature it? Or do you think there's going to be a need for new scaffolds? Also, while we're talking about this, I'll throw in polypharmacology [when a drug has multiple targets or disease pathways], which itself is somehow controversial. So maybe talk a little bit about all of these.Kevan: I think when you get a target, you can swap in and out scaffolds. The question is, can you get durable and potent inhibition, which can come from a brand-new screen. That's how Plexxikon and Genentech came up with vemurafenib, the breakthrough RAF inhibitor. They started with sorafenib but took a step back and said “Let's start with tiny scaffolds at Plexxikon, find a starting point and then grow it out”, which is the basis of fragment-based drug discovery and probably the biggest breakthrough in drug discovery in the last 20 years. It's a very powerful way to get the most drug-like, low-molecular-weight and highly ligand-efficient molecule, all of which are properties of very good drugs. Now there's also the covalent approach that helps achieve more-potent and full inhibition, and there's the Proteolysis Targeting Chimeras (PROTACs) approach, which degrades proteins. What is awesome is that, every way you perturb a biological system, there's a difference between getting rid of the protein, and sticking a drug in its active site and leaving the scaffold there. I think the molecular glues have opened people's eyes to bringing [two proteins] together, which even without their degradation can create a signal to the cell. And that, I think, is going to be a very big, continuing and emerging area of research.“[…] when there's something special about a molecule, it's probably a polypharmacological property, and finding the special molecules is what drug discovery is all about.”And when you say polypharmacology, I really think that's how drugs are special – not only because we worked together on this so much and believe that it has such a promise. I think it's also worth keeping in mind that, when there's something special about a molecule, it's probably a polypharmacological property, and finding the special molecules is what drug discovery is all about. It's great to see more biological thinking around a special molecule and people are digging to find out why it is special. I've heard some talks recently about old kinase inhibitors; and now that we have many of them, you can see which one is special and figure out why it's special. I think there's going to be another surge of polypharmacology coming, which should be really interesting.Ross: So, if we were to have this conversation again in 10 years, where do you hope RAS research will be?Kevan: The immediate answer is molecules that will inhibit each of the alleles. I think these already exist but are hidden in companies. The cysteine (G12C) has already been approved, but the aspartate and the valine variants would be next. Then even the esoteric, the rarer ones, we've already got. Once we get all that chemical matter, I think there will be another group of molecules that will emerge; maybe an ERK inhibitor, a MEK inhibitor, a RAF inhibitor or a SHP2 inhibitor. I feel like that's the second wave of small-molecule research.Then I think the immune–oncology connection will become important because RAS is such a good suppressor of the immune system. Now that we've got agents to eliminate that suppression, the checkpoint inhibitor therapies will probably work. G12C lung tumours are typically caused by smoking, meaning they've got a high mutation burden and are immunogenic. But G12C pancreatic cancer does not have a particularly high mutational burden, so the checkpoint inhibitors may not work [as efficiently]. There's just beautiful work from Bert Vogelstein, Drew Pardoll and Ken Kinzler who've made antibodies against the KRAS-mutant peptide on MHC, they call them MANAbodies. I don't know right now what the next ten years are going to show, but I hope this progress comes in just five years.Ross: We can both agree that it's likely we don't know about it yet. So, beyond RAS and beyond kinase inhibitors, what's on the horizon for the Shokat lab?Kevan: We made a molecule a few years ago to bypass mTOR inhibitor-resistance mutants, which has a bivalent nature. We call it a bitopic inhibitor and it can bind an allosteric and an orthosteric site. Revolution Medicines optimized it and it is now being tested in the clinic. But this compound's high molecular weight [complicates its entry] into cells. So now we're working on better understanding of how molecules actually get into cells. it an it it We know a lot of things but, there are still a lot of my colleague we always come back to the question of how get the If we could get a better understanding of how molecules get I think that up new then, the other thing I want to think more of is a brand-new of which is not the of but their We've got we've got we've got so we can with in the good has beautiful from Peter lab, which the in a have worked on in and for many years but, in we've always and key There was a molecule that was discovered at in a screen for a certain target called of molecules, they found one that its but they figure out what it was They found out that it bound and out of in the of the while the was going It's a pretty We know from the that there are that do that, but this was the first of So, I would like to that because that gets you a new target really a lot of of the things I about chemistry as a is that, much like genetics and there's a line and a to what you're to for how is the chemistry different and what are the of a successful That's a great question to think about. In the of chemical many of the same we had still You need to come up with a molecule that will do or you need to be comfortable making of molecules really fast if you come from if you're more from the biological make combinations to a new But now, there's a of what to work on that is to both drug discovery and biological The has up so I know this is in my which is that we had to make a lot of when we were at the back in the – but now you can just order it. There are so many that you can just like in molecular biology. So, I if there's more of an now on the because you can more on the Now, there should be a lot more time with new on you're you don't need to all that time and like we to do. The lab would just so many You could think of an go on the order it and, later it would But with the we didn't have much time in the lab because there was a on I like everything got So, I what if we just it around and in the lab comes up with an that they can do with that are already in our lab. That really prompted a lot of from months that was could be with something – and it was a really good thing for us to there's now much more of in and for example, from and like there's a of but it's how you it and find the to an interesting You know, say that they get most when you to them. it you come up with some There were that were just and it us something that the original but was a step that we didn't have That thing on me 10 years with RAS as a perfect I would talk with Frank about say an that's and with There were always things that and others had that just like that you get And it on me that this was actually a great way to I think in chemical biology, you can always do something but in biology and disease there's only one and you have to in That is what I'm really now, and making sure that you the the We know that from cancer in the case of it's not going to go away we find a drug for I know a good and can be very How did he you to work on I to When I first came to he said PI3K is highly mutated and it's an important So, we started working on it and a had a beautiful set of new molecules, with some being tested or approved for use in the clinic. And I thought that Frank really knows his targets before we started on it, PI3K was not that But all years working on it, from to Frank kept that's the And it worked in the because he kept people like and who were both at the in and had done to the and cell biology of RAS. My colleague was working on inhibitors, so were always and had a So, I it was a to put all these pieces together at the right So, Frank a and now it at the been very important to you. I know your for example, were very and I know you and have also been pretty active the years. So, where do you see the of scientists in public the it's so frustrating to have this unbelievable technology so quickly – we all know it took a long lead time – but then to have it there and have it become I'm with how this of discoveries and these have been developed but then have some people look at it and say don't use people about discoveries and how and I think we can get through to people because it's not so if you break it down in an interesting just from Reed and going to do a in and did a great on the of the research group based at called and how people communicate So, I feel like the more we can communicate how is we can help the public I people about discoveries and how and I think we can get through to people because it's not so if you break it down in an interesting I if this would go your to young I as we we could in the between our of scientists and your in terms of The one thing I try to do is get the and in the lab to give talks where they don't deeply into the tiny of their project but give people a better And I feel if we do that then we're going to have the to it to the is a and I did a thing with our a few months ago about COVID and the We a set of on and it was The questions people, who don't do science, come up with to me – when you the to them in When one of my his parents came to to his and then we came to the lab for the And I showed them the structure of a from his project with And I will looked at it and said that like a pocket why doesn't he make a molecule that and I said told to do That's pretty So, if not science, what would you I know you were into when you were I really don't I wanted to go to when I was an but I didn't get But not getting is the best because there are so many other things to do. So, I actually don't know where I would go if you took I but I don't know if I could be a because I like to so that So, is there any question that you think I should have that you would like to answer or like to The first question you had many and one part I didn't answer was how genetics and pharma This gets to the core of why pharma companies work on what they do, and how biological come together there. really me that there's a between biology and drugs. And there doesn't always have to In your fly with the drugs that we've worked on together – they really line up. But there's always the for a between and In my starting back at that was such a profound thing because we things to line and when they we think one of them is a of It's really the of being able to look at a biological and a the in your and not be when they don't just line up but, look into the and then That's what very can do, although beginning to see the of this But I just when that on people because that's when really understanding I can certainly with a biological I don't understand why the chemical would the There's a lot of good discoveries to be made in Professor Kevan Shokat for his willingness to be and for his and with We also Professor Ross Cagan for this and an to their in the This has been and with the by & Editor for from the can be found in The full of the can be on the is part of a RAS and which was launched in a by and Arvin in this at
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