Small Molecule Ligands of the BET-like Bromodomain, BRD3, Affect Survival, Oviposition, and Development

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2023 Dec 4

PMID 38048437

Authors

Matthias Schiedel

Darius J B McArdle

Gilda Padalino

Anthony K N Chan

Josephine Forde-Thomas

Michael McDonough

Helen Whiteland

Manfred Beckmann

Rosa Cookson

Karl F Hoffmann

Stuart J Conway

Affiliations

Soon will be listed here.

Abstract

Schistosomiasis is a disease affecting >200 million people worldwide, but its treatment relies on a single agent, praziquantel. To investigate new avenues for schistosomiasis control, we have conducted the first systematic analysis of bromodomain-containing proteins (BCPs) in a causative species, . Having identified 29 putative bromodomains (BRDs) in 22 proteins, we selected BRD3, a tandem BRD-containing BCP that shows high similarity to the human bromodomain and extra terminal domain (BET) family, for further studies. Screening 697 small molecules identified the human BET BRD inhibitor I-BET726 as a ligand for BRD3. An X-ray crystal structure of I-BET726 bound to the second BRD of BRD3 [BRD3(2)] enabled rational design of a quinoline-based ligand () with an ITC = 364 ± 26.3 nM for BRD3(2). The ethyl ester pro-drug of compound (compound ) shows substantial effects on sexually immature larval schistosomula, sexually mature adult worms, and snail-infective miracidia in assays.

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