An Internally Controlled Quantitative Target Occupancy Assay for Covalent Inhibitors

Assessing target occupancy is critical for establishing proof-of-mechanism for novel inhibitors and to determine whether robust target inhibition can be achieved at tolerated doses. This is challenging in the clinic using conventional methods due to the need for untreated controls. We describe a new...

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Autores principales: Hansen, Rasmus, Firdaus, Sarah J., Li, Shuangwei, Janes, Matthew R., Zhang, Jingchuan, Liu, Yi, Zarrinkar, Patrick P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156402/
https://www.ncbi.nlm.nih.gov/pubmed/30254226
http://dx.doi.org/10.1038/s41598-018-32683-w
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author Hansen, Rasmus
Firdaus, Sarah J.
Li, Shuangwei
Janes, Matthew R.
Zhang, Jingchuan
Liu, Yi
Zarrinkar, Patrick P.
author_facet Hansen, Rasmus
Firdaus, Sarah J.
Li, Shuangwei
Janes, Matthew R.
Zhang, Jingchuan
Liu, Yi
Zarrinkar, Patrick P.
author_sort Hansen, Rasmus
collection PubMed
description Assessing target occupancy is critical for establishing proof-of-mechanism for novel inhibitors and to determine whether robust target inhibition can be achieved at tolerated doses. This is challenging in the clinic using conventional methods due to the need for untreated controls. We describe a new mass spectrometry approach to quantitatively assess target occupancy for covalent inhibitors that does not require untreated controls, and apply the method to the KRAS(G12C) inhibitor ARS-1620.
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spelling pubmed-61564022018-09-28 An Internally Controlled Quantitative Target Occupancy Assay for Covalent Inhibitors Hansen, Rasmus Firdaus, Sarah J. Li, Shuangwei Janes, Matthew R. Zhang, Jingchuan Liu, Yi Zarrinkar, Patrick P. Sci Rep Article Assessing target occupancy is critical for establishing proof-of-mechanism for novel inhibitors and to determine whether robust target inhibition can be achieved at tolerated doses. This is challenging in the clinic using conventional methods due to the need for untreated controls. We describe a new mass spectrometry approach to quantitatively assess target occupancy for covalent inhibitors that does not require untreated controls, and apply the method to the KRAS(G12C) inhibitor ARS-1620. Nature Publishing Group UK 2018-09-25 /pmc/articles/PMC6156402/ /pubmed/30254226 http://dx.doi.org/10.1038/s41598-018-32683-w Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Hansen, Rasmus
Firdaus, Sarah J.
Li, Shuangwei
Janes, Matthew R.
Zhang, Jingchuan
Liu, Yi
Zarrinkar, Patrick P.
An Internally Controlled Quantitative Target Occupancy Assay for Covalent Inhibitors
title An Internally Controlled Quantitative Target Occupancy Assay for Covalent Inhibitors
title_full An Internally Controlled Quantitative Target Occupancy Assay for Covalent Inhibitors
title_fullStr An Internally Controlled Quantitative Target Occupancy Assay for Covalent Inhibitors
title_full_unstemmed An Internally Controlled Quantitative Target Occupancy Assay for Covalent Inhibitors
title_short An Internally Controlled Quantitative Target Occupancy Assay for Covalent Inhibitors
title_sort internally controlled quantitative target occupancy assay for covalent inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156402/
https://www.ncbi.nlm.nih.gov/pubmed/30254226
http://dx.doi.org/10.1038/s41598-018-32683-w
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