State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.
Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.
Biochem Biophys Res Commun. 2021 Mar 19;545:125-131. doi: 10.1016/j.bbrc.2021.01.067. Epub 2021 Feb 3.
Bromodomain and PHD finger containing transcription factor (BPTF) is a multidomain protein that regulates the transcription of chromatin and is related to many cancers. Herein, we report the screening-based discovery of Cpd1, a compound with micromolar affinity to the BPTF bromodomain. Through structure-guided optimization, we synthesized a variety of new inhibitors. Among these compounds, Cpd8 and Cpd10 were highly potent and selective inhibitors, with K values of 428 nM and 655 nM in ITC assays, respectively. The high activity was explained by the cocrystal structure of Cpd8 in complex with the BPTF bromodomain protein. Cpd8 and Cpd10 were able to stabilize the BPTF bromodomain protein in cells in a cellular thermal shift assay (CETSA). Cpd8 downregulated c-MYC expression in A549 cells. All experiments prove that these two compounds are potential BPTF inhibitors.
溴结构域和 PH 结构域包含转录因子（Bromodomain and PHD finger containing transcription factor，BPTF）是一种具有多个结构域的蛋白质，可调节染色质的转录，与多种癌症有关。在此，我们报告了基于筛选的 Cpd1 的发现，这是一种对 BPTF 溴结构域具有微摩尔亲和力的化合物。通过结构导向优化，我们合成了多种新型抑制剂。在这些化合物中，Cpdl0 和 Cpd10 是高活性和选择性的抑制剂，在 ITC 测定中，它们的 K 值分别为 428 nM 和 655 nM。Cpdl0 的高活性可由其与 BPTF 溴结构域蛋白复合物的共晶结构解释。Cpdl0 和 Cpd10 能够在细胞热转移测定（CETSA）中稳定细胞中的 BPTF 溴结构域蛋白。Cpdl0 下调了 A549 细胞中的 c-MYC 表达。所有实验均证明这两种化合物是潜在的 BPTF 抑制剂。
