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. 2017 Jun 1;8(7):737-741.
doi: 10.1021/acsmedchemlett.7b00132. eCollection 2017 Jul 13.

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

Terry D Crawford  1 , James E Audia  2 , Steve Bellon  2 , Daniel J Burdick  1 , Archana Bommi-Reddy  2 , Alexandre Côté  2 , Richard T Cummings  2 , Martin Duplessis  2 , E Megan Flynn  1 , Michael Hewitt  2 , Hon-Ren Huang  2 , Hariharan Jayaram  2 , Ying Jiang  3 , Shivangi Joshi  2 , James R Kiefer  1 , Jeremy Murray  1 , Christopher G Nasveschuk  2 , Arianne Neiss  2 , Eneida Pardo  2 , F Anthony Romero  1 , Peter Sandy  2 , Robert J Sims 3rd  2 , Yong Tang  2 , Alexander M Taylor  2 , Vickie Tsui  1 , Jian Wang  3 , Shumei Wang  1 , Yongyun Wang  3 , Zhaowu Xu  3 , Laura Zawadzke  2 , Xiaoqin Zhu  3 , Brian K Albrecht  2 , Steven R Magnuson  1 , Andrea G Cochran  1
Affiliations

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

Terry D Crawford et al. ACS Med Chem Lett. .

Abstract

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.

Keywords: Bromodomain; CECR2; Epigenetics; Probe.

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Conflict of interest statement

The authors declare the following competing financial interest(s): All authors were employed by Constellation, Genentech, and Wuxi, and experiments described were performed in Constellation, Genentech, or Wuxi laboratories.

Figures

Figure 1
Figure 1
(A) Assay data for CECR2 screening hit 1. IC50 values are the average from at least two independent experiments. (B) Model of 1 (cyan) in CECR2 structure (PDB code 3NXB): thick sticks of 1 represent the conformation used to design the tertiary amide, while wire frames of 1 represent other possible conformations from the modeling. The CECR2 protein structure is shown as a gray ribbon with gray sticks for side chains containing the WPF shelf (Trp457, Pro458, and Phe459), the gatekeeper residue (Tyr520), and the conserved Asn514. Also shown are the side chain Tyr467 and its corresponding residue Ile53 in BRD9 (orange).
Figure 2
Figure 2
Compound 6 bound to CECR2 [PDB 5V84]. Compound 6 is shown as green sticks and H-bond interactions are represented as dashes.
Figure 3
Figure 3
Profile of GNE-886. All bromodomain assays were run in FRET format. IC50 data are an average of at least two independent experiments. bLE = −RT ln(IC50)/N heavy atoms. LLE = pIC50 – cLogP.
See this image and copyright information in PMC

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