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Fragment optimization and elaboration strategies – the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits
Here we describe the early stages of a fragment-based lead discovery (FBLD) project for a recently elucidated synthetic lethal target, the PRMT5/MTA complex, for the treatment of MTAP-deleted cancers. Starting with five fragment/PRMT5/MTA X-ray co-crystal structures, we employed a two-phase fragment...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
RSC
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9749961/ https://www.ncbi.nlm.nih.gov/pubmed/36545438 http://dx.doi.org/10.1039/d2md00163b |
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author | Smith, Christopher R. Kulyk, Svitlana Ahmad, Misbha Ud Din Arkhipova, Valentina Christensen, James G. Gunn, Robin J. Ivetac, Anthony Ketcham, John M. Kuehler, Jon Lawson, J. David Thomas, Nicole C. Wang, Xiaolun Marx, Matthew A. |
author_facet | Smith, Christopher R. Kulyk, Svitlana Ahmad, Misbha Ud Din Arkhipova, Valentina Christensen, James G. Gunn, Robin J. Ivetac, Anthony Ketcham, John M. Kuehler, Jon Lawson, J. David Thomas, Nicole C. Wang, Xiaolun Marx, Matthew A. |
author_sort | Smith, Christopher R. |
collection | PubMed |
description | Here we describe the early stages of a fragment-based lead discovery (FBLD) project for a recently elucidated synthetic lethal target, the PRMT5/MTA complex, for the treatment of MTAP-deleted cancers. Starting with five fragment/PRMT5/MTA X-ray co-crystal structures, we employed a two-phase fragment elaboration process encompassing optimization of fragment hits and subsequent fragment growth to increase potency, assess synthetic tractability, and enable structure-based drug design. Two lead series were identified, one of which led to the discovery of the clinical candidate MRTX1719. |
format | Online Article Text |
id | pubmed-9749961 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | RSC |
record_format | MEDLINE/PubMed |
spelling | pubmed-97499612022-12-20 Fragment optimization and elaboration strategies – the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits Smith, Christopher R. Kulyk, Svitlana Ahmad, Misbha Ud Din Arkhipova, Valentina Christensen, James G. Gunn, Robin J. Ivetac, Anthony Ketcham, John M. Kuehler, Jon Lawson, J. David Thomas, Nicole C. Wang, Xiaolun Marx, Matthew A. RSC Med Chem Chemistry Here we describe the early stages of a fragment-based lead discovery (FBLD) project for a recently elucidated synthetic lethal target, the PRMT5/MTA complex, for the treatment of MTAP-deleted cancers. Starting with five fragment/PRMT5/MTA X-ray co-crystal structures, we employed a two-phase fragment elaboration process encompassing optimization of fragment hits and subsequent fragment growth to increase potency, assess synthetic tractability, and enable structure-based drug design. Two lead series were identified, one of which led to the discovery of the clinical candidate MRTX1719. RSC 2022-09-27 /pmc/articles/PMC9749961/ /pubmed/36545438 http://dx.doi.org/10.1039/d2md00163b Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Smith, Christopher R. Kulyk, Svitlana Ahmad, Misbha Ud Din Arkhipova, Valentina Christensen, James G. Gunn, Robin J. Ivetac, Anthony Ketcham, John M. Kuehler, Jon Lawson, J. David Thomas, Nicole C. Wang, Xiaolun Marx, Matthew A. Fragment optimization and elaboration strategies – the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits |
title | Fragment optimization and elaboration strategies – the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits |
title_full | Fragment optimization and elaboration strategies – the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits |
title_fullStr | Fragment optimization and elaboration strategies – the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits |
title_full_unstemmed | Fragment optimization and elaboration strategies – the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits |
title_short | Fragment optimization and elaboration strategies – the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits |
title_sort | fragment optimization and elaboration strategies – the discovery of two lead series of prmt5/mta inhibitors from five fragment hits |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9749961/ https://www.ncbi.nlm.nih.gov/pubmed/36545438 http://dx.doi.org/10.1039/d2md00163b |
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