Center for Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China.
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
Bioorg Med Chem. 2021 Jun 1;39:116133. doi: 10.1016/j.bmc.2021.116133. Epub 2021 Apr 3.
Bromodomain and extra-terminal (BET) is a promising therapeutic target for various hematologic cancers. We used the BRD4 inhibitor compound 13 as a lead compound to develop a variety of compounds, and we introduced diverse groups into the position of the compound 13 orienting toward the ZA channel. A series of compounds (14-23, 38-41, 43, 47-49) bearing triazolopyridazine motif exhibited remarkable BRD4 protein inhibitory activities. Among them, compound 39 inhibited BRD4(BD1) protein with an IC of 0.003 μM was superior to lead compound 13. Meanwhile, compound 39 possess activity, IC = 2.1 μM, in antiproliferation activity against U266 cancer cells. On the other hand, compound 39 could arrest tumor cells into the G0/G1 phase and induce apoptosis, which was consistent with its results in inhibiting cell proliferation. Biological and biochemical data suggest that BRD4 protein might be a therapeutic target and that compound 39 is an excellent lead compound for further development.
溴结构域和末端结构域（BET）是治疗各种血液系统癌症的一个很有前途的治疗靶点。我们使用 BRD4 抑制剂化合物 13 作为先导化合物，开发了多种化合物，并在化合物 13 朝向 ZA 通道的位置引入了各种基团。一系列含有三唑并嘧啶基序的化合物（14-23、38-41、43、47-49）表现出显著的 BRD4 蛋白抑制活性。其中，化合物 39 对 BRD4（BD1）蛋白的抑制活性 IC50 为 0.003 μM，优于先导化合物 13。同时，化合物 39 对 U266 癌细胞的增殖具有活性，IC50 = 2.1 μM。另一方面，化合物 39 可以将肿瘤细胞阻滞在 G0/G1 期并诱导细胞凋亡，这与其抑制细胞增殖的结果一致。生物学和生化数据表明，BRD4 蛋白可能是一个治疗靶点，化合物 39 是进一步开发的一个极好的先导化合物。
