Y'all, KRAS small molecule drugs are sort of my jam and I have exactly zero guesses of how this drug could possibly work. My calendar is packed today, though, and I'm going to drop this here without looking it up.
Here is the idea, though: KRAS by itself is generally not bad. The problem is that the active sites get mutated and then the stupid new version of the protein stays active all the time. As KRAS and it's cousins NRAS and HRAS sit on top of pro-proliferation pathways, having them active all the time is a terrible idea.
This new drug, currently RMS-7977 (the name generally changes if it has success in human trials, you can guess by the designation that it's probably not there yet, so a healthy grain of skepticism should be involved here for this exact molecule) appears to only inhibit the active sites.
Imagine a KRASG12C mutation where you've got a cysteine very actively holding onto GTP so that it is activating those proliferation pathways. You've got too much active stuff around. This drug doesn't block the GTP site, it blocks the activity of the active GTP bound protein.
What's surprising is that there is a very different shape for a G12D mutated pocket and a G12V or G12R, etc., but this thing doesn't care!
What's funny is that they did some awesome proteomics and it didn't really make the paper. TMT proteomics and phosphoproteomics on an Exploris 480 using the turbo TMT mode.
If you're as interested as I am, the files are here. There appears to be a second repository, but there is a typo in the paper so I can't find it without some digging.
Really really cool stuff. And some of the early small molecule RAS inhibitors aren't really doing well in the clinic at all right now, despite being approved for use. However, the molecules based on those are rapidly evolving and each one is better than the last. Even if this one doesn't go forward, the fact that you can inhibit a bunch of deleterious mutations with a single drug is a super promising development!!
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