The nucleosome remodeling factor (NURF) alters chromatin accessibility through interactions with its largest subunit,the bromodomain PHD finger transcription factor BPTF. BPTF is overexpressed in several cancers and is an emerging anticancer target. Targeting the BPTF bromodomain presents a potential strategy for its inhibition and the evaluation of its functional significance; however, inhibitor development for BPTF has lagged behind those of other bromodomains. Here we describe the development of pyridazinone-based BPTF inhibitors. The lead compound, BZ1, possesses a high potency (K_d = 6.3 nM) and >350-fold selectivity over BET bromodomains. We identify an acidic triad in the binding pocket to guide future designs. We show that our inhibitors sensitize 4T1 breast cancer cells to doxorubicin but not BPTF knockdown cells, suggesting a specificity to BPTF. Given the high potency and good physicochemical properties of these inhibitors, we anticipate that they will be useful starting points for chemical tool development to explore the biological roles of BPTF.

中文翻译：

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通过 BPTF 溴结构域抑制开发有效的核小体重塑因子 (NURF) 细胞活性抑制剂的新设计规则

核小体重塑因子 (NURF) 通过与其最大的亚基溴结构域 PHD 指转录因子 BPTF 相互作用来改变染色质的可及性。BPTF 在几种癌症中过度表达，是一种新兴的抗癌靶点。靶向 BPTF 溴结构域为其抑制和评估其功能意义提供了一种潜在的策略；然而，BPTF 抑制剂的开发落后于其他溴结构域。在这里，我们描述了基于哒嗪酮的 BPTF 抑制剂的开发。先导化合物BZ1具有高效力 ( K _d= 6.3 nM) 和 > 350 倍于 BET 溴结构域的选择性。我们在结合口袋中确定了一个酸性三元组，以指导未来的设计。我们表明，我们的抑制剂使 4T1 乳腺癌细胞对阿霉素敏感，但对 BPTF 敲低细胞不敏感，这表明对 BPTF 具有特异性。鉴于这些抑制剂的高效力和良好的物理化学特性，我们预计它们将成为开发化学工具以探索 BPTF 生物学作用的有用起点。