The tubulin colchicine binding site has been recognized as an attractive drug target to combat cancer, but none of the candidate drugs have been approved for medical treatment. We recently identified a structurally distinct small molecule S-40 as an oral potent tubulin destabilizing agent. Crystal structure analysis of S-40 in a complex with tubulin at a resolution of 2.4 Å indicated that S-40 occupies all 3 zones in the colchicine pocket with interactions different from known microtubule inhibitors, presenting unique effects on assembly and curvature of tubulin dimers. S-40 overcomes paclitaxel resistance and lacks neurotoxicity, which are the main obstacles limiting clinical applications of paclitaxel. Moreover, S-40 harbors the ability to inhibit growth of cancer cell lines as well as patient-derived organoids, induce mitotic arrest and cell apoptosis. Xenograft mouse models of human prostate cancer DU145, non-small cell lung cancer NCI–H1299 and paclitaxel-resistant A549 were strongly restrained without apparent side effects by S-40 oral administration once daily. These findings provide evidence for the development of S-40 as the next generation of orally effective microtubule inhibitors for cancer therapy.

微管蛋白秋水仙碱结合位点被认为是对抗癌症的有吸引力的药物靶标，但是没有候选药物被批准用于医学治疗。我们最近确定了一种结构独特的小分子S-40作为口服有效的微管蛋白去稳定剂。S-40与微管蛋白的复合物的晶体结构分析，分辨率为2.4，表明S-40占据了秋水仙碱口袋中的所有3个区域，其相互作用不同于已知的微管抑制剂，对微管蛋白二聚体的组装和曲率产生了独特的影响。S-40克服了紫杉醇的耐药性并且缺乏神经毒性，这是限制紫杉醇临床应用的主要障碍。此外，S-40具有抑制癌细胞系以及患者来源的类器官生长的能力，诱导有丝分裂阻滞和细胞凋亡。每天一次S-40口服给药可强烈抑制人前列腺癌DU145，非小细胞肺癌NCI-H1299和耐紫杉醇A549的异种移植小鼠模型，而无明显副作用。这些发现为S-40作为下一代口服有效的微管抑制剂在癌症治疗中的发展提供了证据。