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Design of a biased potent small molecule inhibitor of the bromodomain and PHD finger-containing (BRPF) proteins suitable for cellular and in vivo studies.
Igoe, N Bayle, E Fedorov, O Tallant, C Savitsky, P Rogers, C Owen, D Deb, Gauri Somervaille, Tim C P Andrews, D
Igoe, N
Bayle, E
Fedorov, O
Tallant, C
Savitsky, P
Rogers, C
Owen, D
Deb, Gauri
Somervaille, Tim C P
Andrews, D
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Abstract
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.
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Date
2017-01-09
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Article
Citation
Design of a biased potent small molecule inhibitor of the bromodomain andPHD finger-containing (BRPF) proteins suitable for cellular and in vivo studies. 2017, J Med Chem