Undruggable Drugs



So I thought maybe we could start about just talking about what the category of undrivable really means to the industry. What is traditionally mean? This is a favourite subject but also for me a sore subject. The term undrivable refers to as yet the inability to drug a protein or protein family or a piece of origny. It said an unfulfilled promise. Imagine Drug hunting with small molecules. Where I've worked and trained as sculpting drug molecule that fits into the pocket of a protein. What if there's no pocket? That protein may be regarded in our discipline as a Priori undrivable. So is it always shifting kind of category or was there a particular group that always was understood to be that kind of undrivable? It's very much both you know. Mars is unworkable right until we arrive there serious. Human Diseases of the non infectious nature are often caused when pathways go awry and these cellular pathways are driven by little machines called proteins. That are globular and They have in where biology occurs. Enzymes that metabolize food and such when these pathways go awry. We tried to identify a critical note in that. Pathway typically a protein and work to understand functionally. If it's too active in which case we tried to inhibit it or not active enough in case we tried to activate it in the discipline of drug discovery. This biological knowledge is very powerful but sometimes we regrettably find out that it's a type of protein or protein. Fold that has never been drug before and this creates real challenges. So this is the undrivable when we have no idea how to get that protein there these are the undrivable proteins and and there are whole families of very tantalizing protein targets creating a conceptual risk that often keeps many scientists away from pursuing coordinated efforts in drug discovery. In my time as a professor I studied the way genes were turned on and off and cancer as a cancer doctor. I was interested in the proteins that would cause the growth program to be activated to turn one cancer cell into two and so on and so on these proteins called transcription factors that bind. Dna turn genes on our consideration be beyond the reaches of drug discovery undrivable. Class which is regrettable because the perception that they may be hard to drug has kept many scientists away from even trying so people. Don't they literally? Don't touch it because it seems like such a challenge. There are a couple of important exceptions. The estrogen receptor binds estrogen. It is therefore drug -able by the sex hormone estrogen rest revile. But the most commonly activated gene all of cancer called Mick the protein that sits around the human genome orchestrating. The Growth Symphony has never been successfully drug even though it is one of the best. Validated targets in Over the last thirty years in cancer science. It's so interesting because I sort of assumed that it had to do with a lack of of biological knowledge. But it's not using the not. The biology is very well understood. But we just haven't understood how to approach it so what is changing now. What are where are we in the landscape of these undrivable? Categories of drugs. I mean one way to think about that. Is that in a sense? When we mean undrivable. It's undrinkable by the way we normally do things. And only when you start to develop these new methods you realize even in the old targets. There's other things you might WanNa hit in other ways to hit it. That's right one of the things that really interests in years. You know we think about targets. We add adjectives to the targets. We HAVEN'T DRUG TARGETS. In the fullness of time there may be no such thing as an undrivable target when you take in sort of the full momentum of different modalities that we might go after a specific target. Can we take the other side of that coin for second? Is there such thing as a novel target a novel target in the language of drug discovery is maybe the first recognition that a protein is really involved in a disease process and the biological experiments have validated that protein or gene in that process novel targets may be fully drug -able like the proteins that sit on the surface of a cell that because of successful prior campaigns to drug kindnesses are now as a group considered easily drug -able but sometimes novel targets are in these undrivable protein families and this gives us pause? I believe that some of the best validated targets in disease biology would have clarified path to helping patients. If only we could get out of our own way and really commit to approaching these proteins as drug -able to challenge the dogma till echo of the the old concept that's right I'd love to hear what some of those successes that really sort of forged a whole new path forward for people were and then also break down the tech behind. What made those possible. I think a very fine example where drug discovery has taken down and undrivable protein. Target is our work to develop the first hitter of what's called foss face in this case a protein called ship to okay. Foss faces are some of the most interesting proteins in disease biology there. Fossil taste is very important for diabetes. And a couple extremely important for cancer you might know what a kind aces. This is a protein that drops what are called phosphate groups onto proteins and there are a great many important kindness. Inhibitor Drugs That followed once. Novartis developed the first if not one of the first called Glee Vic for chronic myeloid leukemia as there are interesting kindnesses that drop phosphates onto proteins. There are counteracting faces that pull them off Interesting and it's for no particular reason that kind aces are so commonly drugged and Fossa tastes are not Except that for twenty years people tried to make phosphates inhibitor drugs and they just couldn't do it. It's one of the most famous protein families in the UNDRIVABLE CLASS. And there's something really peculiar about it. Phosphates drug discovery campaigns almost always produce a very potent and sometimes very selective inhibitor of a pure enzyme studied. Say outside of a cell. Okay but these molecules don't work when the enzyme is inside of the cell the pocket. That's drugged in the phosphate. Tastes is very positively charged. You know how opposites attract the molecules that are discovered are very negatively charged. And they can't get into cells. Scientists Bang their heads against the wall for decades trying to make phosphates drugs for cancer and diabetes and other disease states and were unsuccessful. Well some very creative. Scientists at Novartis did really interesting experiment. They imagined that may be a way to inhibit. The FOSSA taste isn't to go for the most active site But to try to inhibit the enzyme through what we call an alistair excite to sort of sucker punch the phosphates at a different part of the protein and so we perform to high throughput screens. One with the full length phosphates that has two or three globular domains like three beads on a string and second full high throughput screening campaign where we just looked at the active enzyme. Pocket it self. We found two thousand hits in this essay and we through all of them out except to we only kept the molecules that would work in the full length protein but wouldn't work in the small format protein Basically that you'd find the the molecules that would hit the pocket that's only presence when the whole protein is there exactly drug discovery is like trying to find a needle in a haystack. Performed thousands sometimes millions of experiments with chemicals to try to find the one chemical. That does what we want. We threw out all the molecules that would hibbitt inhibit the active site and kept only molecules. That worked when these other sites were present called Alistair excites. After many years of very careful science we produce the very first inhibitor of a phosphate tastes and the way this molecule works is it glues the ship to protein together we call it an intra within the same molecule and Intra Molecular Glue. What a cool

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