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

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

  • J Med Chem. 2017 Jan 26;60(2):668-680. doi: 10.1021/acs.jmedchem.6b01583.
Niall Igoe 1,  Elliott D Bayle 1,  Oleg Fedorov 2,  Cynthia Tallant 2,  Pavel Savitsky 2,  Catherine Rogers 2,  Dafydd R Owen 3,  Gauri Deb 4,  Tim C P Somervaille 4,  David M Andrews 5,  Neil Jones 6,  Anne Cheasty 6,  Hamish Ryder 6,  Paul E Brennan 2,  Susanne Müller 2 7,  Stefan Knapp 2 7 8,  Paul V Fish 1
Affiliations

Affiliations

  • 1 UCL School of Pharmacy, University College London , 29/39 Brunswick Square, London WC1N 1AX, U.K.
  • 2 Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
  • 3 Pfizer Worldwide Medicinal Chemistry , 610 Main Street, Cambridge, Massachusetts 02139, United States.
  • 4 Leukemia Biology Laboratory, Cancer Research UK Manchester Institute , Manchester M20 4BX, U.K.
  • 5 AstraZeneca Discovery Sciences , Darwin Building, Cambridge Science Park, Cambridge CB4 0FZ, U.K.
  • 6 CRT Discovery Laboratories , Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, U.K.
  • 7 Buchmann Institute for Molecular Life Sciences , Max-von-Laue-Strasse 15, D-60438 Frankfurt am Main, Germany.
  • 8 Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
PMID: 28068087 DOI: 10.1021/acs.jmedchem.6b01583
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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