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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
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)