Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM

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 and Mikael Altun
Additional contact information
Nicholas C. K. Valerie: Karolinska University Hospital
Kumar Sanjiv: Karolinska Institutet
Oliver Mortusewicz: Karolinska Institutet
Si Min Zhang: Karolinska Institutet
Seher Alam: Karolinska University Hospital
Maria J. Pires: Karolinska University Hospital
Hannah Stigsdotter: Karolinska Institutet
Azita Rasti: Karolinska Institutet
Marie-France Langelier: Université de Montréal
Daniel Rehling: Stockholm University
Adam Throup: Karolinska Institutet
Oryn Purewal-Sidhu: Karolinska Institutet
Matthieu Desroses: Karolinska Institutet
Jacob Onireti: Karolinska University Hospital
Prasad Wakchaure: Karolinska Institutet
Ingrid Almlöf: Karolinska Institutet
Johan Boström: Karolinska University Hospital
Luka Bevc: Karolinska Institutet
Giorgia Benzi: Karolinska Institutet
Pål Stenmark: Stockholm University
John M. Pascal: Université de Montréal
Thomas Helleday: Karolinska Institutet
Brent D. G. Page: Karolinska Institutet
Mikael Altun: Karolinska University Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54415-7

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