Structure-Guided Design of a Domain-Selective Bromodomain and Extra Terminal N-Terminal Bromodomain Chemical Probe

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2023 Nov 15

PMID 37967462

Authors

Erin Bradley

Lucia Fusani

Chun-Wa Chung

Peter D Craggs

Emmanuel H Demont

Philip G Humphreys

Darren J Mitchell

Alex Phillipou

Inmaculada Rioja

Rishi R Shah

Christopher R Wellaway

Rab K Prinjha

David S Palmer

William J Kerr

Marc Reid

Ian D Wall

Rosa Cookson

Affiliations

Soon will be listed here.

Abstract

Small-molecule-mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series. Structure-guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300-1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.

Citing Articles

The Development and Evaluation of a Novel Highly Selective PET Radiotracer for Targeting BET BD1.

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PMID: 39458928 PMC: 11509907. DOI: 10.3390/ph17101289.

Development and Evaluation of [C]I-58: A Novel PET Radiotracer Targeting BRD4 BD2 for Advanced Epigenetic Imaging.

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