Discovery of a highly selective BET BD2 inhibitor from a DNA-encoded library technology screening hit

DOI: 10.1021/acs.jmedchem.1c00412

Authors: Francesco Rianjongdee (GlaxoSmithKline) , Stephen J. Atkinson (GlaxoSmithKline; WuXi AppTec (Shanghai) Co., Ltd) , Chun-Wa Chung (GlaxoSmithKline) , Paola Grandi (GlaxoSmithKline) , James R. J. Gray , Laura J. Kaushansky (GlaxoSmithKline) , Patricia Medeiros (GlaxoSmithKline) , Cassie Messenger (GlaxoSmithKline) , Alex Phillipou (GlaxoSmithKline) , Alex Preston (GlaxoSmithKline) , Rab K. Prinjha (GlaxoSmithKline) , Inmaculada Rioja (GlaxoSmithKline) , Alexander L. Satz (WuXi AppTec (Shanghai) Co., Ltd) , Simon Taylor (GlaxoSmithKline; WuXi AppTec (Shanghai) Co., Ltd.) , Ian D. Wall (GlaxoSmithKline) , Robert J. Watson (GlaxoSmithKline) , Gang Yao (GlaxoSmithKline) , Emmanuel H. Demont (GlaxoSmithKline)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: July 2021

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.

Journal Keywords: Ligands; Substituents; Inhibitors; Molecular structure; Selectivity

Diamond Keywords: Epigenetics

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography

Other Facilities: ESRF

Added On: 21/07/2021 09:00

Discipline Tags:

Health & Wellbeing Biochemistry Genetics Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)