Shan Peipei, Liu Kai-Lu, Jiang Xiu, Zhou Guangzhao, Zhu Kongkai, Zhang Hua
Institute of Translational Medicine, the Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China.
School of Biological Science and Technology, University of Jinan, Jinan, China.
Cell Death Discov. 2025 Aug 19;11(1):392. doi: 10.1038/s41420-025-02679-3.
Microtubules, critical to diverse cellular processes, represent a clinically validated target for anticancer therapeutics. In this study, a virtual screening of the Specs library, consisting of 200,340 compounds, was conducted to target the taxane and colchicine binding sites on tubulin, resulting in the identification of 93 promising candidates for further analysis. Subsequent characterization revealed a nicotinic acid derivative (compound 89) as a potent tubulin inhibitor, demonstrating significant anti-tumor efficacy in vitro and in vivo, with no observable toxicity at therapeutic doses in mice. Notably, compound 89 also exhibited robust antitumor activity in patient-derived organoids. Mechanistic studies, including EBI competitive binding assays and molecular docking, confirmed its inhibition toward tubulin polymerization via selective binding to the colchicine site. Furthermore, compound 89 disrupted tubulin assembly dynamics through modulation of the PI3K/Akt signaling pathway. This work presents a novel tubulin-inhibiting scaffold with potential for advancing next-generation microtubule-targeted chemotherapies.
微管对多种细胞过程至关重要，是经临床验证的抗癌治疗靶点。在本研究中，针对微管蛋白上的紫杉烷和秋水仙碱结合位点，对包含200,340种化合物的Specs库进行了虚拟筛选，从而鉴定出93种有前景的候选化合物以供进一步分析。随后的表征显示，一种烟酸衍生物（化合物89）是一种有效的微管蛋白抑制剂，在体外和体内均表现出显著的抗肿瘤功效，在小鼠治疗剂量下未观察到毒性。值得注意的是，化合物89在患者来源的类器官中也表现出强大的抗肿瘤活性。包括EBI竞争性结合试验和分子对接在内的机制研究证实，它通过选择性结合秋水仙碱位点抑制微管蛋白聚合。此外，化合物89通过调节PI3K/Akt信号通路破坏微管蛋白组装动力学。这项工作提出了一种新型的微管蛋白抑制支架，具有推进下一代微管靶向化疗的潜力。
