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The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that 13-d had properties compatible with oral dosing in mouse models of disease (Fpo 49%). We propose that NI-42 (13-d) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins.

Original publication

DOI

10.1021/acs.jmedchem.6b01583

Type

Journal article

Journal

J Med Chem

Publication Date

26/01/2017

Volume

60

Pages

668 - 680

Keywords

Adaptor Proteins, Signal Transducing, Animals, Antineoplastic Agents, Cell Line, Tumor, Drug Screening Assays, Antitumor, Humans, Leukemia, Myeloid, Acute, Mice, Microsomes, Liver, Nuclear Proteins, Protein Domains, Quinolones, Structure-Activity Relationship, Sulfonamides