Design of a biased potent small molecule inhibitor of the bromodomain and PHD finger-containing (BRPF) proteins suitable for cellular and in vivo studies

DOI: 10.1021/acs.jmedchem.6b01583

Authors: Niall Igoe (University College London) , Elliott D. Bayle (University College London) , Oleg Fedorov (Structural Genomics Consortium, University of Oxford) , Cynthia Tallant (Structural Genomics Consortium, University of Oxford) , Pavel Savitsky (Structural Genomics Consortium, University of Oxford) , Catherine Rogers (Structural Genomics Consortium, University of Oxford) , Dafydd R. Owen (Pfizer Worldwide Medicinal Chemistry) , Gauri Deb (Cancer Research UK Manchester Institute) , Tim C. P. Somervaille (Cancer Research UK Manchester Institute) , David M. Andrews (AstraZeneca Discovery Sciences) , Neil Jones (CRT Discovery Laboratories) , Anne Cheasty (CRT Discovery Laboratories) , Hamish Ryder (CRT Discovery Laboratories) , Paul E. Brennan (Structural Genomics Consortium, University of Oxford) , Susanne Müller (Structural Genomics Consortium, University of Oxford; Buchmann Institute for Molecular Life Sciences) , Stefan Knapp (Structural Genomics Consortium, University of Oxford; Buchmann Institute for Molecular Life Sciences) , Paul V. Fish (University College London)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 60 , PAGES 668 - 680

State: Published (Approved)
Published: January 2017

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.

Diamond Keywords: Leukaemia

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 08/02/2017 09:30

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)