Liu Tingting, Wan Yichao, Liu Renshuai, Ma Lin, Li Minyong, Fang Hao
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Jinan, Shandong 250012, PR China.
Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, Ministry of Education, College of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201, PR China.
Bioorg Med Chem. 2017 Mar 15;25(6):1939-1948. doi: 10.1016/j.bmc.2017.02.014. Epub 2017 Feb 11.
The B-cell lymphoma-2 (Bcl-2) family proteins are attractive targets for cancer therapy. In our previous work, the structure-activity relationship of WL-276 was studied. According to the results, rhodanine derivatives show potent binding affinity for Bcl-2 and Mcl-1 protein and show weaker activity against Bcl-X protein. Based on the previous results, a new class of indole-3-carboxylic acid-based derivatives were designed and synthesized as Bcl-2/Mcl-1 dual inhibitors. Among them, compound 17 has a K value of 0.26μM for Bcl-2 protein and is better than WL-276. Furthermore, it inhibits the myeloid cell leukemia sequence 1 (Mcl-1) protein with a K value of 72nM. Especially, compound 31 can selectively acting on Bcl-2 and Mcl-1 protein but not Bcl-X protein, which has great significance for developing dual inhibitors targeting Bcl-2 and Mcl-1 protein, as well as specific antitumor abilities in cells.
B细胞淋巴瘤-2（Bcl-2）家族蛋白是癌症治疗中颇具吸引力的靶点。在我们之前的工作中，对WL-276的构效关系进行了研究。结果表明，罗丹宁衍生物对Bcl-2和Mcl-1蛋白具有较强的结合亲和力，而对Bcl-X蛋白的活性较弱。基于之前的结果，设计并合成了一类新型的基于吲哚-3-羧酸的衍生物作为Bcl-2/Mcl-1双重抑制剂。其中，化合物17对Bcl-2蛋白的K值为0.26μM，优于WL-276。此外，它对髓样细胞白血病序列1（Mcl-1）蛋白的抑制K值为72nM。特别地，化合物31可选择性作用于Bcl-2和Mcl-1蛋白，而不作用于Bcl-X蛋白，这对于开发靶向Bcl-2和Mcl-1蛋白的双重抑制剂以及细胞中的特异性抗肿瘤能力具有重要意义。
