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Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains

Journal Article · · Journal of Medicinal Chemistry
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  1. Genentech, Inc., South San Francisco, CA (United States)
  2. Constellation Pharmaceuticals, Inc., Cambridge, MA (United States)
  3. Wuxi AppTec Co., Ltd., Shanghai (China)
+ Show Author Affiliations
The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. A ligand-efficient nonselective bromodomain inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing the N-methyl group were designed directing toward the conserved bromodomain water pocket, and two distinct binding conformations were then observed. The substituents either directly displaced and rearranged the conserved solvent network, as in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent to the lipophilic shelf, as in BRD9 and CECR2. Here, the preference of distinct substituents for individual bromodomains provided selectivity handles useful for future lead optimization efforts for selective BRD9, CECR2, and TAF1(2) inhibitors.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE
OSTI ID:
1347788
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 11 Vol. 59; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (16)

Mapping the Ligand Binding Landscape journal November 2018
Protein dynamics and structural waters in bromodomains journal October 2017
Flavonoids as Putative Epi-Modulators: Insight into Their Binding Mode with BRD4 Bromodomains Using Molecular Docking and Dynamics journal July 2018
Solvents to Fragments to Drugs: MD Applications in Drug Design journal December 2018
Structural Analysis of Small-Molecule Binding to the BAZ2A and BAZ2B Bromodomains journal June 2018
Advancements in the Development of non‐BET Bromodomain Chemical Probes journal January 2019
Biological function and histone recognition of family IV bromodomain-containing proteins journal June 2017
In silico design and molecular basis for the selectivity of Olinone toward the first over the second bromodomain of BRD4 journal October 2019
Water molecules in protein–ligand interfaces. Evaluation of software tools and SAR comparison journal February 2019
Structural Insights into the Recognition of Mono- and Diacetylated Histones by the ATAD2B Bromodomain journal October 2020
Bromodomains: a new target class for drug development journal July 2019
Importance of a crystalline water network in docking-based virtual screening: a case study of BRD4 journal January 2019
Structure investigation, enrichment analysis and structure-based repurposing of FDA-approved drugs as inhibitors of BET-BRD4 journal November 2018
Structural insights into the recognition of mono- and di-acetyllysine by the ATAD2B bromodomain posted_content May 2000
Solvents to Fragments to Drugs: MD Applications in Drug Design journal October 2018
Structural Analysis of Small-Molecule Binding to the BAZ2A and BAZ2B Bromodomains interactiveresource January 2018

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
mixtures
molecules
peptides and proteins
substituents
water