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J Med Chem. 2017 Jan 26;60(2):668-680. doi: 10.1021/acs.jmedchem.6b01583. Epub 2017 Jan 9.

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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UCL School of Pharmacy, University College London , 29/39 Brunswick Square, London WC1N 1AX, U.K.
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
Pfizer Worldwide Medicinal Chemistry , 610 Main Street, Cambridge, Massachusetts 02139, United States.
Leukemia Biology Laboratory, Cancer Research UK Manchester Institute , Manchester M20 4BX, U.K.
AstraZeneca Discovery Sciences , Darwin Building, Cambridge Science Park, Cambridge CB4 0FZ, U.K.
CRT Discovery Laboratories , Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, U.K.
Buchmann Institute for Molecular Life Sciences , Max-von-Laue-Strasse 15, D-60438 Frankfurt am Main, Germany.
Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.


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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