Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.
J Med Chem. 2021 Sep 23;64(18):13902-13917. doi: 10.1021/acs.jmedchem.1c01294. Epub 2021 Sep 13.
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, , possesses a high potency ( = 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.
核小体重塑因子（NURF）通过与其最大亚基溴结构域 PH 结构域转录因子 BPTF 的相互作用改变染色质的可及性。BPTF 在多种癌症中过表达，是一个新兴的抗癌靶点。靶向 BPTF 的溴结构域为其抑制和功能意义的评估提供了一种潜在策略；然而，BPTF 的抑制剂开发落后于其他溴结构域。本文描述了基于哒嗪酮的 BPTF 抑制剂的开发。先导化合物 ，对 BET 溴结构域具有高活性（=6.3 nM）和 >350 倍的选择性。我们确定了结合口袋中的酸性三联体以指导未来的设计。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，这表明它们对 BPTF 具有特异性。鉴于这些抑制剂的高活性和良好的物理化学性质，我们预计它们将成为化学工具开发的有用起点，以探索 BPTF 的生物学作用。
