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.

中文翻译：

---

Bromodomain-PHD手指家族的bromodomains的选择性靶向损害破骨细胞分化。

MYST家族的组蛋白乙酰基转移酶通过BRPF支架蛋白募集到染色质上。我们探讨了针对骨骼维护中存在于BRPF1-3中的乙酰赖氨酸依赖性蛋白相互作用域（溴结构域）的抑制剂的功能后果和治疗潜力。我们报告了三种有效的和选择性的抑制剂：一种对BRPF1B亚型具有高选择性的（PFI-4）和两种泛BRPF溴结构域抑制剂（OF-1，NI-57）。所开发的抑制剂从染色质置换了BRPF溴结构域，并且不抑制细胞生长和增殖。有趣的是，这些抑制剂通过特异性抑制破骨细胞生成所需的转录程序，损害了RANKL诱导的原代小鼠骨髓细胞和人原代单核细胞向骨吸收性破骨细胞的分化。