A functional map of CDK-drug interactions at single amino acid resolution.

ABSTRACT: Proteins that drive or support human disease phenotypes are attractive molecular targets for precision therapy, yet most are nominated by knockout studies and then targeted with drugs that inhibit core catalytic pockets. These strategies cannot resolve which residues are essential, whether non-catalytic sites offer better selectivity or potency, or identify on-target resistance mechanisms. We introduce a framework that integrates precision genome editing, mechanistically diverse therapeutics, and computational sequence-structure-function analysis to map protein essentiality and potential druggability at single amino acid resolution. Applying this framework across 9 cyclin-dependent kinases (CDKs) and 15 cancer therapeutics-including ATP-competitive inhibitors, PROTACs, and molecular glue d

SUBMITTER: Gould SI 

PROVIDER: S-EPMC12637707 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature