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halvorz's avatar

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.

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Austin Cole's avatar

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

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