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Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM
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Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM
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Journal Article
Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM
2024
Overview
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.
Cellular target engagement technologies enable quantification of intracellular drug binding, but the simultaneous assessment of drug-associated phenotypes is challenging. Here, the authors develop CeTEAM (cellular target engagement by accumulation of mutant), a platform that can simultaneously evaluate drug-target interactions and phenotypic responses for holistic assessment of drug pharmacology using conditionally stabilized drug biosensors.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/63
/ 42/44
/ 42/70
/ 49/47
/ 49/98
/ 59/5
/ 9/10
/ Animals
/ Binders
/ Binding
/ Biosensing Techniques - methods
/ DNA Repair Enzymes - genetics
/ DNA Repair Enzymes - metabolism
/ High-Throughput Screening Assays - methods
/ Humanities and Social Sciences
/ Humans
/ Marking and tracking techniques
/ Mice
/ Mutants
/ Mutation
/ Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors
/ Poly (ADP-Ribose) Polymerase-1 - genetics
/ Poly (ADP-Ribose) Polymerase-1 - metabolism
/ Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
/ Pyrophosphatases - metabolism
/ Ribose
/ Science
/ Tracking
