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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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54415-7 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Nicholas C. K. Valerie |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-da8b368cca654c56b35ce8a1e37b2285 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-da8b368cca654c56b35ce8a1e37b22852025-08-20T02:31:00ZengNature PortfolioNature Communications2041-17232024-12-0115112210.1038/s41467-024-54415-7Coupling cellular drug-target engagement to downstream pharmacology with CeTEAMNicholas C. K. Valerie0Kumar Sanjiv1Oliver Mortusewicz2Si Min Zhang3Seher Alam4Maria J. Pires5Hannah Stigsdotter6Azita Rasti7Marie-France Langelier8Daniel Rehling9Adam Throup10Oryn Purewal-Sidhu11Matthieu Desroses12Jacob Onireti13Prasad Wakchaure14Ingrid Almlöf15Johan Boström16Luka Bevc17Giorgia Benzi18Pål Stenmark19John M. Pascal20Thomas Helleday21Brent D. G. Page22Mikael Altun23Science for Life Laboratory, Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University HospitalScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstitutetScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstitutetScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstitutetScience for Life Laboratory, Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University HospitalScience for Life Laboratory, Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University HospitalScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstitutetScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstitutetDépartement de Biochimie and Médecine Moléculaire, Faculté de Médecine, Université de MontréalDepartment of Biochemistry and Biophysics, Stockholm UniversityScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstitutetScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstitutetScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstitutetScience for Life Laboratory, Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University HospitalScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstitutetScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstitutetScience for Life Laboratory, Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University HospitalScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstitutetScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstitutetDepartment of Biochemistry and Biophysics, Stockholm UniversityDépartement de Biochimie and Médecine Moléculaire, Faculté de Médecine, Université de MontréalScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstitutetScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstitutetScience for Life Laboratory, Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University HospitalAbstract 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.https://doi.org/10.1038/s41467-024-54415-7 |
| spellingShingle | 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 Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM Nature Communications |
| title | Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM |
| title_full | Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM |
| title_fullStr | Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM |
| title_full_unstemmed | Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM |
| title_short | Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM |
| title_sort | coupling cellular drug target engagement to downstream pharmacology with ceteam |
| url | https://doi.org/10.1038/s41467-024-54415-7 |
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