Interesting post! One note -traditionally, "undruggable" didn't really have anything to do with protein localization. For small molecules, getting inside a cell is not typically a major problem -for example, virtually all classical chemotherapeutic agents target intracellular processes, and most antibiotic targets are intracellular, with the major exception of the cell wall. Rather, druggability was primarily a question of whether a potential target has one or more potential small molecule binding pockets (for example, a catalytic site or allosteric regulatory pocket), and whether the binding pocket can be specifically targeted without off-target effects on similar proteins.
For example, KRAS was traditionally considered undruggable because it had no clear binding pockets other than a GTP binding site that binds GTP with extremely high affinity -in the past few years drugs that target a specific oncogenic KRAS mutation have been developed because that mutation produces a cysteine on the protein surface that can be targeted for covalent bonding. Until Gleevec, kinases were considered undruggable because their ATP binding pockets were too similar to each other, and ATP concentrations were too high in the cell. And when I started grad school, protein-protein interactions were thought to be undruggable, as protein-protein binding interfaces are typically large and relatively flat, with no clear binding pockets; since then, a number of PPI inhibitors have been developed, such as the NS5A inhibitors for hepatitis C.
Cell surface localization *does* matter enormously for antibody therapeutics, since antibodies are massive molecules that have no desire to get inside cells. These days so many companies are focused on antibodies that perhaps some people have started to think of cellular localization as the primary determinant of druggability -but it was not always thus.
whoa thanks! having picked up stuff by osmosis from contemporary biotech is very different from having a real academic background. it is *wild* to think of kinases as being "undruggable" once!!!
though tbh most of my knowledge of pharma development doesn't come directly from my academic background (only recently have I begun to dip my toes into pharma relevant work) but from obsessively reading derek lowe
An old colleague of mine dedicated ~10 years building an argument that echoes these. Directionally, it seems correct that we're not getting proportionate progress at NCI. I'd love to see more high risk bets that pay dividends like radiopharma / adc / checkpoint inhibitors or even bigger new categories and think it's kind of disappointing we have underinvested there
The issue with all of the old school broad spectrum anticancer agents is that they have really really bad side effect profiles. Like targeting cell division will predictably be devastating for immune system and rapidly dividing epithelial tissues. Targeted therapies are narrower spectrum but are also way more tolerable and I would bet the side effect/broad spectrum activity tradeoff generalizes
For example per your surface charge suggestion, people have tried targeting cancer with anticancer peptides (disrupt negatively charged membranes via basically same mechanism as antimicrobial peptides) for a long time but without much success, maybe some promise as an adjuvant for immunotherapy I think, but it’s just not specific enough as a mono therapy.
Curious your opinions on immunotherapy that seems naively like a better candidate for broad spectrum than cancer targeting agents
I also don't buy the side effect story because all those horrible 70s chemo drugs are still first line! oncologists today clearly think they're worth it! if a new drug was similarly side-effect-y but more effective or effective on a currently untreatable cancer, do you not think it would be approved today? and if so, isn't that more a policy than a scientific issue?
A common claim is that a single drug would be approved if it cured a cancer with side effects like traditional chemo; but traditional chemo isn't one drug and it took experimentation to find the cocktail. If that kind of experimentation isn't possible today, it's a policy problem, but it's not clearly an FDA policy problem.
Edit: or maybe they were approved as monotherapies against a very low bar of no existing treatment and the cocktail experimentation was after approval.
It's clearly very good that we have classic chemo drugs, but I'm pretty sure targeted drugs like imatinib are the first-line treatments where applicable and immunotherapy is working its way up the ladder toward first-line.
Regarding if new chemo would be approved today, I don't know! It's plausible to me that we've hit diminishing returns on classic chemo, basically if you're just killing fast-dividing cells there's only so much selectivity you can have, therefore there's a "better than the Beatles" phenomenon (per the famous Eroom's Law paper) making development of new drugs slower. Regulatory strictness maybe makes it too difficult, that does tend to be my default belief, but I think cancer is a rare case where very nasty side effects are permitted.
Regarding the scalable "more things like checkpoint inhibitors" there's several pathways to go down. One is to turn cold tumors hot via, for example, intratumoral injection of STING inhibitors, or anticancer peptides to lyse cancer cells and release random inflammatory stuff, or tumor-targeted mRNA-LNPs encoding inflammatory cytokines (https://www.strandtx.com/pipeline/) to name a few. How broad spectrum these things turn out to be is an open question but in the ideal case they could generalize well.
Other thing you can try (I think this is Moderna's grand vision of what they'd like to do for example) is what you might call scalable personalization: have a very automated system where you take a cancer biopsy, sequence it, print a personalized neoantigen vaccine, give it to the patient. Alternatively you could print a personalized CAR gene and deliver it via in vivo LNP targeting of T cells (design of intracellular neoantigen-targeting CARs can in principle be done which is nuts! https://www.biorxiv.org/content/10.1101/2024.11.28.625793v1).
Immunotherapy is the great success story of our time, of course. It would be silly to argue that.
Checkpoint inhibitors are arguably broad-spectrum, but CAR-T & other cell therapies are very much the opposite; the whole point is specifically attacking a cell type or cells with a given set of surface markers, which will vary between cancers.
I feel a bit lost trying to imagine how we might do a scalable brute-force search to find "more things like checkpoint inhibitors", since to have a functioning immune system you have to have an organism (afaik). Checkpoint inhibitors seem like the sort of discovery that grows out of deep knowledge of the immune system, and I don't have that, or an idea how to make the process repeatable.
Oh also it’s not just p53 being nuclear that makes it hard, since it’s a tumor suppressor you need a drug that restores function not inhibits it, and inhibiting a protein is way easier than activating, especially since I’m guessing (not sure) there is a broad spectrum of p53 inactivating mutations. Targeting MDM2 probably a better bet but everyone is already trying really hard to do that
Huh that's super interesting! Are there any other approaches targeting mutations in tumor suppressors? Eg could you somehow seed the cells with the healthy version of the protein/gene somehow?
You can deliver p53 via gene therapy vector like LNP or a virus. Personally I’ve never thought that was amazingly likely to work since you have to hit every cell or the tumor will just bounce back but your mileage may vary. You can also try to do stuff like trigger nonsense mutation readthrough with drugs but readthrough drugs don’t work very well and also you limit yourself to subset of patients with p53 nonsense mutations specifically
This was incredibly interesting, i didn't know how much our technology had advanced!! it's absurd to me that we have gotten to this point. Thank you so much for writing, i learned a lot :)
Interesting post! One note -traditionally, "undruggable" didn't really have anything to do with protein localization. For small molecules, getting inside a cell is not typically a major problem -for example, virtually all classical chemotherapeutic agents target intracellular processes, and most antibiotic targets are intracellular, with the major exception of the cell wall. Rather, druggability was primarily a question of whether a potential target has one or more potential small molecule binding pockets (for example, a catalytic site or allosteric regulatory pocket), and whether the binding pocket can be specifically targeted without off-target effects on similar proteins.
For example, KRAS was traditionally considered undruggable because it had no clear binding pockets other than a GTP binding site that binds GTP with extremely high affinity -in the past few years drugs that target a specific oncogenic KRAS mutation have been developed because that mutation produces a cysteine on the protein surface that can be targeted for covalent bonding. Until Gleevec, kinases were considered undruggable because their ATP binding pockets were too similar to each other, and ATP concentrations were too high in the cell. And when I started grad school, protein-protein interactions were thought to be undruggable, as protein-protein binding interfaces are typically large and relatively flat, with no clear binding pockets; since then, a number of PPI inhibitors have been developed, such as the NS5A inhibitors for hepatitis C.
Cell surface localization *does* matter enormously for antibody therapeutics, since antibodies are massive molecules that have no desire to get inside cells. These days so many companies are focused on antibodies that perhaps some people have started to think of cellular localization as the primary determinant of druggability -but it was not always thus.
whoa thanks! having picked up stuff by osmosis from contemporary biotech is very different from having a real academic background. it is *wild* to think of kinases as being "undruggable" once!!!
I know, right?
though tbh most of my knowledge of pharma development doesn't come directly from my academic background (only recently have I begun to dip my toes into pharma relevant work) but from obsessively reading derek lowe
An old colleague of mine dedicated ~10 years building an argument that echoes these. Directionally, it seems correct that we're not getting proportionate progress at NCI. I'd love to see more high risk bets that pay dividends like radiopharma / adc / checkpoint inhibitors or even bigger new categories and think it's kind of disappointing we have underinvested there
https://www.taylorfrancis.com/chapters/edit/10.4324/9781315674162-13/cancer-spreads-reconceptualizing-disease-katherine-liu-alan-love-michael-travisano
The issue with all of the old school broad spectrum anticancer agents is that they have really really bad side effect profiles. Like targeting cell division will predictably be devastating for immune system and rapidly dividing epithelial tissues. Targeted therapies are narrower spectrum but are also way more tolerable and I would bet the side effect/broad spectrum activity tradeoff generalizes
For example per your surface charge suggestion, people have tried targeting cancer with anticancer peptides (disrupt negatively charged membranes via basically same mechanism as antimicrobial peptides) for a long time but without much success, maybe some promise as an adjuvant for immunotherapy I think, but it’s just not specific enough as a mono therapy.
Curious your opinions on immunotherapy that seems naively like a better candidate for broad spectrum than cancer targeting agents
I also don't buy the side effect story because all those horrible 70s chemo drugs are still first line! oncologists today clearly think they're worth it! if a new drug was similarly side-effect-y but more effective or effective on a currently untreatable cancer, do you not think it would be approved today? and if so, isn't that more a policy than a scientific issue?
A common claim is that a single drug would be approved if it cured a cancer with side effects like traditional chemo; but traditional chemo isn't one drug and it took experimentation to find the cocktail. If that kind of experimentation isn't possible today, it's a policy problem, but it's not clearly an FDA policy problem.
Edit: or maybe they were approved as monotherapies against a very low bar of no existing treatment and the cocktail experimentation was after approval.
It's clearly very good that we have classic chemo drugs, but I'm pretty sure targeted drugs like imatinib are the first-line treatments where applicable and immunotherapy is working its way up the ladder toward first-line.
Regarding if new chemo would be approved today, I don't know! It's plausible to me that we've hit diminishing returns on classic chemo, basically if you're just killing fast-dividing cells there's only so much selectivity you can have, therefore there's a "better than the Beatles" phenomenon (per the famous Eroom's Law paper) making development of new drugs slower. Regulatory strictness maybe makes it too difficult, that does tend to be my default belief, but I think cancer is a rare case where very nasty side effects are permitted.
Regarding the scalable "more things like checkpoint inhibitors" there's several pathways to go down. One is to turn cold tumors hot via, for example, intratumoral injection of STING inhibitors, or anticancer peptides to lyse cancer cells and release random inflammatory stuff, or tumor-targeted mRNA-LNPs encoding inflammatory cytokines (https://www.strandtx.com/pipeline/) to name a few. How broad spectrum these things turn out to be is an open question but in the ideal case they could generalize well.
Other thing you can try (I think this is Moderna's grand vision of what they'd like to do for example) is what you might call scalable personalization: have a very automated system where you take a cancer biopsy, sequence it, print a personalized neoantigen vaccine, give it to the patient. Alternatively you could print a personalized CAR gene and deliver it via in vivo LNP targeting of T cells (design of intracellular neoantigen-targeting CARs can in principle be done which is nuts! https://www.biorxiv.org/content/10.1101/2024.11.28.625793v1).
Immunotherapy is the great success story of our time, of course. It would be silly to argue that.
Checkpoint inhibitors are arguably broad-spectrum, but CAR-T & other cell therapies are very much the opposite; the whole point is specifically attacking a cell type or cells with a given set of surface markers, which will vary between cancers.
I feel a bit lost trying to imagine how we might do a scalable brute-force search to find "more things like checkpoint inhibitors", since to have a functioning immune system you have to have an organism (afaik). Checkpoint inhibitors seem like the sort of discovery that grows out of deep knowledge of the immune system, and I don't have that, or an idea how to make the process repeatable.
Oh also it’s not just p53 being nuclear that makes it hard, since it’s a tumor suppressor you need a drug that restores function not inhibits it, and inhibiting a protein is way easier than activating, especially since I’m guessing (not sure) there is a broad spectrum of p53 inactivating mutations. Targeting MDM2 probably a better bet but everyone is already trying really hard to do that
Huh that's super interesting! Are there any other approaches targeting mutations in tumor suppressors? Eg could you somehow seed the cells with the healthy version of the protein/gene somehow?
You can deliver p53 via gene therapy vector like LNP or a virus. Personally I’ve never thought that was amazingly likely to work since you have to hit every cell or the tumor will just bounce back but your mileage may vary. You can also try to do stuff like trigger nonsense mutation readthrough with drugs but readthrough drugs don’t work very well and also you limit yourself to subset of patients with p53 nonsense mutations specifically
This was incredibly interesting, i didn't know how much our technology had advanced!! it's absurd to me that we have gotten to this point. Thank you so much for writing, i learned a lot :)
Very, very interesting stuff. Thanks for writing that up!