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

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.

Targeting Bromodomain-Selective Inhibitors of BET Proteins in Drug Discovery and Development

“…77,93 Given that the WPF region is lipophilic, nonaromatic substituents engaging this region reduce the binding potency of small molecules. 101 Through a comprehensive analysis of a series GSK compounds with pyridine, pyridone, and benzene as the cores, it appears that small molecules will lose their affinity and selectivity if only the Kac mimetics and WPF region substituents are contained on these cores. 99,102,103 Modification of the benzylic position in the GSK series can also affect the affinity of the molecule at the Kac-binding site, and polar groups are particularly poorly tolerated at this position.…”

Virtual Special Issue: Epigenetics 2022

“…What is notable about this collection of papers is the diversity of targets and approaches that are described. It is exciting to see a range of contemporary medicinal chemistry techniques applied to epigenetics targets, including covalent inhibitors, fragment-based approaches to ligand development, machine learning, and DNA-encoded libraries …”

“…It is exciting to see a range of contemporary medicinal chemistry techniques applied to epigenetics targets, including covalent inhibitors, 49 fragment-based approaches to ligand development, 50 machine learning, 51 and DNA-encoded libraries. 52 The acetyl-lysine-reading bromodomains continue to be an important target in epigenetics. The maturity of the bromodomain and extraterminal domain (BET) proteins as targets is reflected by the reports of pan-BET ligands developed for clinical studies.…”

CRCM5484: A BET-BDII Selective Compound with Differential Anti-leukemic Drug Modulation

“…Despite a high homology across the BDs in the BET family, several selective inhibitors of the BDI or BDII BET domains have recently emerged in the literature [24][25][26][27] , but few are currently engaged in clinical trials.…”