Design of a Biased Potent Small Molecule Inhibitor of the Bromodonnain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies

作者：Igoe Niall; Bayle Elliott D; Fedorov Oleg; Tallant Cynthia; Savitsky Pavel; Rogers Catherine; Owen Dafydd R; Deb Gauri; Somervaille Tim C P; Andrews David M; Jones Neil; Cheasty Anne; Ryder Hamish; Brennan Paul E; Mueller Susanne; Knapp Stefan; Fish Paul V

来源：Journal of Medicinal Chemistry, 2017, 60(2): 668-680.

DOI：10.1021/acs.jmedchem.6b01583

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 BED 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 (F-po 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.

• 出版日期2017-1-26