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Discovery of a Highly Selective BET BD2 Inhibitor from a DNA-Encoded Library Technology Screening Hit
- Source :
- Journal of Medicinal Chemistry. 64:10806-10833
- Publication Year :
- 2021
- Publisher :
- American Chemical Society (ACS), 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.
- Subjects :
- Dose-Response Relationship, Drug
Molecular Structure
Chemistry
Drug Evaluation, Preclinical
Proteins
chemical and pharmacologic phenomena
hemic and immune systems
Chemical probe
Clinical settings
DNA
Computational biology
Highly selective
Bromodomain
Small Molecule Libraries
Structure-Activity Relationship
Safety profile
Protein Domains
Drug Discovery
Humans
Molecular Medicine
A-DNA
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 64
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....a6ff4ecfe9cbf342e44c1ed73c09a9fc