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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: RSC 2022
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.
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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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