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Valerie NCK, Sanjiv K, Mortusewicz O, Zhang SM, Alam S, Pires MJ, Stigsdotter H, Rasti A, Langelier MF, Rehling D, Throup A, Purewal-Sidhu O, Desroses M, Onireti J, Wakchaure P, Almlöf I, Boström J, Bevc L, Benzi G, Stenmark P, Pascal JM, Helleday T, Page BDG, Altun M
Nat Commun 15 (1) 10347 [2024-12-06; online 2024-12-06]
Cellular target engagement technologies enable quantification of intracellular drug binding; however, simultaneous assessment of drug-associated phenotypes has proven challenging. Here, we present cellular target engagement by accumulation of mutant as a platform that can concomitantly evaluate drug-target interactions and phenotypic responses using conditionally stabilized drug biosensors. We observe that drug-responsive proteotypes are prevalent among reported mutants of known drug targets. Compatible mutants appear to follow structural and biophysical logic that permits intra-protein and paralogous expansion of the biosensor pool. We then apply our method to uncouple target engagement from divergent cellular activities of MutT homolog 1 (MTH1) inhibitors, dissect Nudix hydrolase 15 (NUDT15)-associated thiopurine metabolism with the R139C pharmacogenetic variant, and profile the dynamics of poly(ADP-ribose) polymerase 1/2 (PARP1/2) binding and DNA trapping by PARP inhibitors (PARPi). Further, PARP1-derived biosensors facilitated high-throughput screening for PARP1 binders, as well as multimodal ex vivo analysis and non-invasive tracking of PARPi binding in live animals. This approach can facilitate holistic assessment of drug-target engagement by bridging drug binding events and their biological consequences.
Chemical Biology Consortium Sweden (CBCS) [Service]
PubMed 39643609
DOI 10.1038/s41467-024-54415-7
Crossref 10.1038/s41467-024-54415-7
pmc: PMC11624193
pii: 10.1038/s41467-024-54415-7