School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
Targeted Tracer Research and Development Laboratory, Precision Medicine Research Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
J Med Chem. 2021 Apr 22;64(8):4498-4515. doi: 10.1021/acs.jmedchem.0c01837. Epub 2021 Mar 31.
Novel indazole and benzimidazole analogues were designed and synthesized as tubulin inhibitors with potent antiproliferative activities. Among them, compound exhibited the strongest inhibitory effects on the growth of cancer cells with an average IC value of 50 nM, slightly better than colchicine. exhibited nearly equal potency against both, a paclitaxel-resistant cancer cell line (A2780/T, IC = 9.7 nM) and the corresponding parental cell line (A2780S, IC = 6.2 nM), thus effectively overcoming paclitaxel resistance . The crystal structure of in complex with tubulin was solved to 2.45 Å resolution by X-ray crystallography, and its direct binding was confirmed to the colchicine site. Furthermore, displayed significant antitumor efficacy in a melanoma tumor model with tumor growth inhibition rates of 78.70% (15 mg/kg) and 84.32% (30 mg/kg). Collectively, this work shows that is a promising lead compound deserving further investigation as a potential anticancer agent.
新型吲唑和苯并咪唑类似物被设计并合成，作为具有强效抗增殖活性的微管蛋白抑制剂。其中，化合物 对癌细胞的生长表现出最强的抑制作用，平均 IC 值为 50 nM，略优于秋水仙碱。 对紫杉醇耐药的癌细胞系（A2780/T，IC = 9.7 nM）和相应的亲本细胞系（A2780S，IC = 6.2 nM）均具有几乎相等的效力，因此有效克服了紫杉醇耐药性。 通过 X 射线晶体学解析了 与微管蛋白复合物的晶体结构，分辨率为 2.45 Å，并证实其直接结合秋水仙碱结合位点。此外， 在黑色素瘤肿瘤模型中显示出显著的抗肿瘤疗效，肿瘤生长抑制率分别为 78.70%（15 mg/kg）和 84.32%（30 mg/kg）。综上所述，这项工作表明 是一种很有前途的先导化合物，值得进一步研究作为潜在的抗癌药物。
