title: Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies.
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 (Fpo49%). 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.
authors.affiliation: UCL School of Pharmacy, University College London , 29/39 Brunswick Square, London WC1N 1AX, U.K.
authors.forename: Niall
authors.initials: N
authors.lastname: Igoe
authors.affiliation: UCL School of Pharmacy, University College London , 29/39 Brunswick Square, London WC1N 1AX, U.K.
authors.forename: Elliott D
authors.initials: ED
authors.lastname: Bayle
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tallant
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Pavel
authors.initials: P
authors.lastname: Savitsky
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rogers
authors.affiliation: Pfizer Worldwide Medicinal Chemistry , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Dafydd R
authors.initials: DR
authors.lastname: Owen
authors.affiliation: Leukemia Biology Laboratory, Cancer Research UK Manchester Institute , Manchester M20 4BX, U.K.
authors.forename: Gauri
authors.initials: G
authors.lastname: Deb
authors.affiliation: Leukemia Biology Laboratory, Cancer Research UK Manchester Institute , Manchester M20 4BX, U.K.
authors.forename: Tim C P
authors.initials: TC
authors.lastname: Somervaille
authors.affiliation: AstraZeneca Discovery Sciences , Darwin Building, Cambridge Science Park, Cambridge CB4 0FZ, U.K.
authors.forename: David M
authors.initials: DM
authors.lastname: Andrews
authors.affiliation: CRT Discovery Laboratories , Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, U.K.
authors.forename: Neil
authors.initials: N
authors.lastname: Jones
authors.affiliation: CRT Discovery Laboratories , Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, U.K.
authors.forename: Anne
authors.initials: A
authors.lastname: Cheasty
authors.affiliation: CRT Discovery Laboratories , Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, U.K.
authors.forename: Hamish
authors.initials: H
authors.lastname: Ryder
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Brennan
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Buchmann Institute for Molecular Life Sciences , Max-von-Laue-Strasse 15, D-60438 Frankfurt am Main, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, 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.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: UCL School of Pharmacy, University College London , 29/39 Brunswick Square, London WC1N 1AX, U.K.
authors.forename: Paul V
authors.identifier: 0000-0002-2117-2173
authors.initials: PV
authors.lastname: Fish
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D000072417:Protein Domains; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000096926:Benzenesulfonamides; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D015363:Quinolones; D013449:Sulfonamides; C000620972:4-cyano-N-(1,3-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C086011:BRPF1 protein, human; D000092468:Bromodomain Containing Proteins