2. Academic Validation
  3. Design of a Chemical Probe for the Bromodomain and Plant Homeodomain Finger-Containing (BRPF) Family of Proteins

Design of a Chemical Probe for the Bromodomain and Plant Homeodomain Finger-Containing (BRPF) Family of Proteins

  • J Med Chem. 2017 Aug 24;60(16):6998-7011. doi: 10.1021/acs.jmedchem.7b00611.
Niall Igoe 1,  Elliott D Bayle 1,  Cynthia Tallant 2,  Oleg Fedorov 2,  Julia C Meier 2,  Pavel Savitsky 2,  Catherine Rogers 2,  Yannick Morias 3,  Sarah Scholze 3,  Helen Boyd 3,  Danen Cunoosamy 3,  David M Andrews 4,  Anne Cheasty 5,  Paul E Brennan 2,  Susanne Müller 2 6,  Stefan Knapp 2 6 7,  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 AstraZeneca , Innovative Medicines & Early Development, Pepparedsleden 1, 431 83 Mölndal, Sweden.
  • 4 AstraZeneca Discovery Sciences , Darwin Building, Cambridge Science Park, Cambridge CB4 0FZ, U.K.
  • 5 CRT Discovery Laboratories , Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, U.K.
  • 6 Buchmann Institute for Molecular Life Sciences , Max-von-Laue-Strasse 15, D-60438 Frankfurt am Main, Germany.
  • 7 Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
PMID: 28714688 DOI: 10.1021/acs.jmedchem.7b00611
Abstract

The bromodomain and plant homeodomain finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here, we describe NI-57 (16) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor 16 preferentially bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9 was weaker. Compound 16 has excellent selectivity over nonclass IV BRD proteins. Target engagement of BRPF1B and BRPF2 with 16 was demonstrated in nanoBRET and FRAP assays. The binding of 16 to BRPF1B was rationalized through an X-ray cocrystal structure determination, which showed a flipped binding orientation when compared to previous structures. We report studies that show 16 has functional activity in cellular assays by modulation of the phenotype at low micromolar concentrations in both Cancer and inflammatory models. Pharmacokinetic data for 16 was generated in mouse with single dose administration showing favorable oral bioavailability.

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