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Biased Multicomponent Reactions to Develop Novel Bromodomain Inhibitors
[Image: see text] BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain functi...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234447/ https://www.ncbi.nlm.nih.gov/pubmed/25314271 http://dx.doi.org/10.1021/jm501120z |
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author | McKeown, Michael R Shaw, Daniel L Fu, Harry Liu, Shuai Xu, Xiang Marineau, Jason J Huang, Yibo Zhang, Xiaofeng Buckley, Dennis L Kadam, Asha Zhang, Zijuan Blacklow, Stephen C Qi, Jun Zhang, Wei Bradner, James E |
author_facet | McKeown, Michael R Shaw, Daniel L Fu, Harry Liu, Shuai Xu, Xiang Marineau, Jason J Huang, Yibo Zhang, Xiaofeng Buckley, Dennis L Kadam, Asha Zhang, Zijuan Blacklow, Stephen C Qi, Jun Zhang, Wei Bradner, James E |
author_sort | McKeown, Michael R |
collection | PubMed |
description | [Image: see text] BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions, we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC(50). Iterative synthesis and biochemical assessment allowed optimization of novel BET bromodomain inhibitors based on an imidazo[1,2-a]pyrazine scaffold. Lead compound 32 (UMB-32) binds BRD4 with a K(d) of 550 nM and 724 nM cellular potency in BRD4-dependent lines. Additionally, compound 32 shows potency against TAF1, a bromodomain-containing transcription factor previously unapproached by discovery chemistry. Compound 32 was cocrystallized with BRD4, yielding a 1.56 Å resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors. |
format | Online Article Text |
id | pubmed-4234447 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-42344472015-10-14 Biased Multicomponent Reactions to Develop Novel Bromodomain Inhibitors McKeown, Michael R Shaw, Daniel L Fu, Harry Liu, Shuai Xu, Xiang Marineau, Jason J Huang, Yibo Zhang, Xiaofeng Buckley, Dennis L Kadam, Asha Zhang, Zijuan Blacklow, Stephen C Qi, Jun Zhang, Wei Bradner, James E J Med Chem [Image: see text] BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions, we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC(50). Iterative synthesis and biochemical assessment allowed optimization of novel BET bromodomain inhibitors based on an imidazo[1,2-a]pyrazine scaffold. Lead compound 32 (UMB-32) binds BRD4 with a K(d) of 550 nM and 724 nM cellular potency in BRD4-dependent lines. Additionally, compound 32 shows potency against TAF1, a bromodomain-containing transcription factor previously unapproached by discovery chemistry. Compound 32 was cocrystallized with BRD4, yielding a 1.56 Å resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors. American Chemical Society 2014-10-14 2014-11-13 /pmc/articles/PMC4234447/ /pubmed/25314271 http://dx.doi.org/10.1021/jm501120z Text en Copyright © 2014 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | McKeown, Michael R Shaw, Daniel L Fu, Harry Liu, Shuai Xu, Xiang Marineau, Jason J Huang, Yibo Zhang, Xiaofeng Buckley, Dennis L Kadam, Asha Zhang, Zijuan Blacklow, Stephen C Qi, Jun Zhang, Wei Bradner, James E Biased Multicomponent Reactions to Develop Novel Bromodomain Inhibitors |
title | Biased Multicomponent Reactions
to Develop Novel Bromodomain
Inhibitors |
title_full | Biased Multicomponent Reactions
to Develop Novel Bromodomain
Inhibitors |
title_fullStr | Biased Multicomponent Reactions
to Develop Novel Bromodomain
Inhibitors |
title_full_unstemmed | Biased Multicomponent Reactions
to Develop Novel Bromodomain
Inhibitors |
title_short | Biased Multicomponent Reactions
to Develop Novel Bromodomain
Inhibitors |
title_sort | biased multicomponent reactions
to develop novel bromodomain
inhibitors |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234447/ https://www.ncbi.nlm.nih.gov/pubmed/25314271 http://dx.doi.org/10.1021/jm501120z |
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