开发选择性靶向 BRPF1 的 3-乙酰吲哚衍生物作为 NF-κB 配体 (RANKL) 受体激活剂 (RANKL) 诱导破骨细胞生成的新抑制剂。
Development of 3-acetylindole derivatives that selectively target BRPF1 as new inhibitors of receptor activator of NF-κB ligand (RANKL)-Induced osteoclastogenesis.
发表日期：2023 Aug 09
作者：
Wenqiang Zhang, Ruonan Ning, Ting Ran, Qi Peng, Yong Liu, Tao Lu, Yadong Chen, Min Jiang, Yu Jiao
来源：
Epigenetics & Chromatin
摘要：
布罗莫结构域和 PHD 含指 (BRPF) 蛋白作为表观遗传读取器，特异性识别组蛋白尾部的乙酰化赖氨酸残基。由于其潜在的成药性，BRPF 的乙酰基赖氨酸结合袋已成为开发蛋白质相互作用抑制剂的一个有吸引力的靶标。在这项研究中，我们通过进行基于结构的虚拟筛选和命中优化，确定了 3-乙酰吲哚作为具有新型支架的骨抗吸收剂。在这些衍生物中，化合物18对BRPF1B表现出有效的选择性抑制活性（IC50=102nM），并对破骨细胞生成（73.8％@1μM）和分化（IC50=0.19μM）具有出色的抑制活性，且无细胞毒性。此外，细胞机制分析表明，化合物18通过调节RANKL/RANK/NFATc1通路表现出强大的骨吸收作用。 BRPF1 抑制剂的结构和功能研究有助于进一步了解骨细胞发育的表观遗传机制，并创造治疗实体瘤骨转移和其他骨侵蚀性疾病的创新疗法。版权所有 © 2023 Elsevier Ltd。保留所有权利。
Bromodomain and PHD finger-containing (BRPF) proteins function as epigenetic readers that specifically recognize acetylated lysine residues on histone tails. The acetyl-lysine binding pocket of BRPF has emerged as an attractive target for the development of protein interaction inhibitors owing to its potential druggability. In this study, we identified 3-acetylindoles as bone antiresorptive agents with a novel scaffold by performing structure-based virtual screening and hit optimization. Among those derivatives, compound 18 exhibited potent and selective inhibitory activities against BRPF1B (IC50 = 102 nM) as well as outstanding inhibitory activity against osteoclastogenesis (73.8% @ 1 μM) and differentiation (IC50 = 0.19 μM) without cytotoxicity. Besides, cellular mechanism assays demonstrated that compound 18 exhibited a strong bone antiresorptive effect by modulating the RANKL/RANK/NFATc1 pathway. Structural and functional studies on BRPF1 inhibitors aid in making advances to understand the epigenetic mechanisms of bone cell development and create innovative therapeutics for treating bone metastases from solid tumors and other bone erosive diseases.Copyright © 2023 Elsevier Ltd. All rights reserved.