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GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2)

Journal Article · · ACS Medicinal Chemistry Letters
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  1. Genentech Inc., San Francisco, CA (United States)
  2. Constellation Pharmaceuticals, Cambridge, MA (United States)
  3. Wuxi Apptec Co., Ltd., Shanghai (China)
+ Show Author Affiliations
The biological function of bromodomains, epigenetic readers of acetylated lysine residues, remains largely unknown. Herein we report our efforts to discover a potent and selective inhibitor of the bromodomain of cat eye syndrome chromosome region candidate 2 (CECR2). Screening of our internal medicinal chemistry collection led to the identification of a pyrrolopyridone chemical lead, and subsequent structure-based drug design led to a potent and selective CECR2 bromodomain inhibitor (GNE-886) suitable for use as an in vitro tool compound.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1374633
Journal Information:
ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 7 Vol. 8; ISSN 1948-5875
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (18)

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The rotating black hole in renormalizable quantum gravity: The three-dimensional Hořava gravity case journal January 2013
The bromodomain: a chromatin-targeting module? journal July 1999
Progress in the Development of non-BET Bromodomain Chemical Probes journal January 2016
Genome-wide screen of human bromodomain-containing proteins identifies Cecr2 as a novel DNA damage response protein journal June 2012
Chemical Studies of Histone Acetylation journal October 1968
Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family journal March 2012
CECR2 Is Involved in Spermatogenesis and Forms a Complex with SNF2H in the Testis journal February 2012
Disrupting Acetyl-Lysine Recognition: Progress in the Development of Bromodomain Inhibitors journal April 2015
Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains journal May 2016
Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300 journal September 2016
Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637) journal March 2016
Small Molecule Inhibitors of Bromodomain–Acetyl-lysine Interactions journal November 2014
Structure and ligand of a histone acetyltransferase bromodomain journal June 1999
Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition journal June 2016
CECR2, a protein involved in neurulation, forms a novel chromatin remodeling complex with SNF2L journal January 2005
The bromodomain: a conserved sequence found in human, Drosophila and yeast proteins journal January 1992
Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions journal July 2009

Cited By (5)

A chemical toolbox for the study of bromodomains and epigenetic signaling journal April 2019
Advancements in the Development of non‐BET Bromodomain Chemical Probes journal January 2019
Bromodomains: a new target class for drug development journal July 2019
A Chemical Toolbox for the Study of Bromodomains and Epigenetic Signaling posted_content August 2018
Cellular Target Engagement Approaches to Monitor Epigenetic Reader Domain Interactions journal December 2019

Figures / Tables (5)

Figure 1(p. 4)figure Figure 1
Figure 2(p. 5)figure Figure 2
Table 1(p. 5)table Table 1
Table 2(p. 6)table Table 2
Figure 3(p. 7)figure Figure 3

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Related Subjects

60 APPLIED LIFE SCIENCES
CECR2
Epigenetics
bromodomain
probe