2. Academic Validation
  3. Discovery of a Highly Selective BET BD2 Inhibitor from a DNA-Encoded Library Technology Screening Hit

Discovery of a Highly Selective BET BD2 Inhibitor from a DNA-Encoded Library Technology Screening Hit

  • J Med Chem. 2021 Aug 12;64(15):10806-10833. doi: 10.1021/acs.jmedchem.1c00412.
Francesco Rianjongdee,  Stephen J Atkinson,  Chun-Wa Chung,  Paola Grandi 1,  James R J Gray,  Laura J Kaushansky 2,  Patricia Medeiros 2,  Cassie Messenger,  Alex Phillipou,  Alex Preston,  Rab K Prinjha,  Inmaculada Rioja,  Alexander L Satz 3,  Simon Taylor,  Ian D Wall,  Robert J Watson,  Gang Yao 2,  Emmanuel H Demont
Affiliations

Affiliations

  • 1 IVIVT Cellzome, Platform Technology and Science, GlaxoSmithKline, Meyerhofstr. 1, Heidelberg 69117, Germany.
  • 2 Encoded Library Technologies, R&D Medicinal Science and Technology, GSK, 200 Cambridge Park Drive, Cambridge 02140, Massachusetts, United States.
  • 3 WuXi AppTec (Shanghai) Co., Ltd., Shanghai 200131, China.
PMID: 34251219 DOI: 10.1021/acs.jmedchem.1c00412
Abstract

Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified 60 (GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of Epigenetics research.

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