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. Meier, J., C., Tallant, C., Fedorov, O., Witwicka, H., Hwang, S., Y., Van Stiphout, R., G., Lambert, J., P., Rogers, C., Yapp, C., Gerstenberger, B., S., Fedele, V., Savitsky, P., Heidenreich, D., Daniels, D., L., Owen, D., R., Fish, P., V., Igoe, N., M., Bayle, E., D., Haendler, B., Oppermann, U., C., Buffa, F., Brennan, P., E., Müller, S., Gingras, A., C., Odgren, P., R., Birnbaum, M., J., & Knapp, S. ACS Chemical Biology, 12(10):2619-2630, American Chemical Society, 10, 2017.

Paper

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

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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 pati...

@article{
 title = {Selective Targeting of Bromodomains of the Bromodomain-PHD Fingers Family Impairs Osteoclast Differentiation},
 type = {article},
 year = {2017},
 pages = {2619-2630},
 volume = {12},
 websites = {http://pubs.acs.org/doi/abs/10.1021/acschembio.7b00481},
 month = {10},
 publisher = {American Chemical Society},
 day = {20},
 id = {151e6c75-0847-3f86-8a8c-950e35217fb3},
 created = {2017-12-06T13:19:15.332Z},
 accessed = {2017-12-06},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:50.095Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Meier2017},
 private_publication = {false},
 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 pati...},
 bibtype = {article},
 author = {Meier, Julia C. and Tallant, Cynthia and Fedorov, Oleg and Witwicka, Hanna and Hwang, Sung Yong and Van Stiphout, Ruud G. and Lambert, Jean Philippe and Rogers, Catherine and Yapp, Clarence and Gerstenberger, Brian S. and Fedele, Vita and Savitsky, Pavel and Heidenreich, David and Daniels, Danette L. and Owen, Dafydd R. and Fish, Paul V. and Igoe, Niall M. and Bayle, Elliott D. and Haendler, Bernard and Oppermann, Udo C.T. and Buffa, Francesca and Brennan, Paul E. and Müller, Susanne and Gingras, Anne Claude and Odgren, Paul R. and Birnbaum, Mark J. and Knapp, Stefan},
 doi = {10.1021/acschembio.7b00481},
 journal = {ACS Chemical Biology},
 number = {10}
}

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