UMMS Affiliation

Department of Cell and Developmental Biology; Department of Radiology; Odgren Lab

Publication Date

2017-10-20

Document Type

Article

Disciplines

Biochemistry | Cell Biology | Developmental Biology | Medicinal-Pharmaceutical Chemistry | Musculoskeletal Diseases

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.

Rights and Permissions

Copyright © 2017 American Chemical Society. ACS AuthorChoice - This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.

DOI of Published Version

10.1021/acschembio.7b00481

Source

ACS Chem Biol. 2017 Oct 20;12(10):2619-2630. doi: 10.1021/acschembio.7b00481. Epub 2017 Sep 12. Link to article on publisher's site

Journal/Book/Conference Title

ACS chemical biology

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

28849908

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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