Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM

Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM

Abstract 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 eval...

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Main Authors: Nicholas C. K. Valerie, Kumar Sanjiv, Oliver Mortusewicz, Si Min Zhang, Seher Alam, Maria J. Pires, Hannah Stigsdotter, Azita Rasti, Marie-France Langelier, Daniel Rehling, Adam Throup, Oryn Purewal-Sidhu, Matthieu Desroses, Jacob Onireti, Prasad Wakchaure, Ingrid Almlöf, Johan Boström, Luka Bevc, Giorgia Benzi, Pål Stenmark, John M. Pascal, Thomas Helleday, Brent D. G. Page, Mikael Altun
Format: Article
Language:English
Published: Nature Portfolio 2024-12-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-024-54415-7
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Summary:Abstract 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.
ISSN:2041-1723

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