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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
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.
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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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