2. Academic Validation
  3. Selective Targeting of Bromodomains of the Bromodomain-PHD Fingers Family Impairs Osteoclast Differentiation

Selective Targeting of Bromodomains of the Bromodomain-PHD Fingers Family Impairs Osteoclast Differentiation

  • ACS Chem Biol. 2017 Oct 20;12(10):2619-2630. doi: 10.1021/acschembio.7b00481.
Julia C Meier 1,  Cynthia Tallant 1,  Oleg Fedorov 1,  Hanna Witwicka 2,  Sung-Yong Hwang 2,  Ruud G van Stiphout 3,  Jean-Philippe Lambert 4,  Catherine Rogers 1,  Clarence Yapp 1,  Brian S Gerstenberger 5,  Vita Fedele 1,  Pavel Savitsky 1,  David Heidenreich 6,  Danette L Daniels 7,  Dafydd R Owen 5,  Paul V Fish 8,  Niall M Igoe 8,  Elliott D Bayle 8,  Bernard Haendler 9,  Udo C T Oppermann 10,  Francesca Buffa 3,  Paul E Brennan 1,  Susanne Müller 1 11,  Anne Claude Gingras 4 12,  Paul R Odgren 2,  Mark J Birnbaum 13,  Stefan Knapp 1 11 6 14
Affiliations

Affiliations

  • 1 Target Discovery Institute and Structural Genomics Consortium, Oxford University , Oxford, United Kingom.
  • 2 Department of Cell and Developmental Biology, University of Massachusetts Medical School , Worcester, Massachusetts, United States.
  • 3 Department of Oncology, Oxford University , Old Road Campus Research Building, Oxford OX3 7DQ, United Kingdom.
  • 4 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital , 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
  • 5 Pfizer Worldwide Medicinal Chemistry , 610 Main Street, Cambridge, Massachusetts 02139, United States.
  • 6 Goethe-University Frankfurt, Institute of Pharmaceutical Chemistry , Riedberg Campus, 60438 Frankfurt am Main, Germany.
  • 7 Promega Corporation , Madison, Wisconsin, United States.
  • 8 Department of Pharmaceutical & Biological Chemistry, UCL School of Pharmacy, University College London , 29-39 Brunswick Square, London, WC1N 1AX, United Kingdom.
  • 9 Drug Discovery, Bayer Pharma AG , Müllerstrasse 178, D-13353 Berlin, Germany.
  • 10 Botnar Research Centre, Oxford University , Oxford, United Kingdom.
  • 11 Buchmann Institute for Life Sciences (BMLS) , Riedberg Campus, 60438 Frankfurt am Main, Germany.
  • 12 Department of Molecular Genetics, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
  • 13 Department of Biology, Merrimack College , North Andover, Massachusetts, United States.
  • 14 German Cancer Network (DKTK) , Frankfurt site, 60438 Frankfurt am Main, Germany.
PMID: 28849908 DOI: 10.1021/acschembio.7b00481
Abstract

Histone acetyltransferases of the MYST family are recruited to chromatin by BRPF scaffolding proteins. We explored functional consequences and the therapeutic potential of inhibitors targeting acetyl-lysine dependent protein interaction domains (bromodomains) present in BRPF1-3 in bone maintenance. We report three potent and selective inhibitors: one (PFI-4) with high selectivity for the BRPF1B isoform and two pan-BRPF bromodomain inhibitors (OF-1, NI-57). The developed inhibitors displaced BRPF bromodomains from chromatin and did not inhibit cell growth and proliferation. Intriguingly, the inhibitors impaired RANKL-induced differentiation of primary murine bone marrow cells and human primary monocytes into bone resorbing osteoclasts by specifically repressing transcriptional programs required for osteoclastogenesis. The data suggest a key role of BRPF in regulating gene expression during osteoclastogenesis, and the excellent druggability of these bromodomains may lead to new treatment strategies for patients suffering from bone loss or osteolytic malignant bone lesions.

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