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

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• 作者：Niall Igoe ; Elliott D. Bayle ; Oleg Fedorov ; Cynthia Tallant ; Pavel Savitsky ; Catherine Rogers ; Dafydd R. Owen ; Gauri Deb ; Tim C. P. Somervaille ; David M. Andrews ; Neil Jones ; Anne Cheasty ; Hamish Ryder ; Paul E. Brennan ; Susanne Müller ; Stefan Knapp ; Paul V. Fish
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：January 26, 2017
• 年：2017
• 卷：60
• 期：2
• 页码：668-680
• 全文大小：620K
• ISSN：1520-4804

文摘

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 (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.