期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 2, 页码 668-680出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01583
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资金
- UCL School of Pharmacy Ph.D. studentship
- UCL School of Pharmacy
- UCL Faculty of Life Sciences
- UCL Business
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada through Ontario Genomics Institute, Innovative Medicines Initiative (EU/EFPIA) [115766]
- Janssen
- Merck Co.
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome Trust
- Cancer Research UK [19280] Funding Source: researchfish
- Medical Research Council [MC_PC_13078] Funding Source: researchfish
- MRC [MC_PC_13078] Funding Source: UKRI
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.
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