This isn't news, but it's super pretty data for intacts. I was just digging through an experiment that multiple people had brought up at talks I've given. Largely skepticism that there really are no off-target effects with these small molecule inhibitors. If there are, I'm not seeing them. Maybe I'll write up a confirmatory report or something someday, but given the body of evidence on KRAS inhibitor specificity, it seems a little silly.
This is just a Q Exactive with a 10 cm C4 column that someone threw in the trash and I have kept it in a shoebox for close to a decade. Looks like theses particlar files were 35,000 resolution at MS1. This is like a 15 minute incubation with "purified" KRASG12C in the presence of 10x molar saturation of the drug in water. Deconvolution was performed in Thermo Biopharma finder. Not a perfect experiment by any means. Once I verified it was bound, I S-Trap digested them both and tried to get the exact mass of the covalent peptide + drug. N = 1 but it looks like the drug binding at site 12 blocks trypsin from cleaving at the lysine at 15 which leaves a peptide with ~35 amino acids + drug which has been outside my typical 1/k0 and m/z mass ranges.
Mystery solved, I guess! Pretty proteins below.
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