Colchicine binding site inhibitors (CBSIs) hold great potential in developing new generations of antimitotic drugs. Unlike existing tubulin inhibitors such as paclitaxel, they are generally much less susceptible to resistance caused by the overexpression of drug efflux pumps. The 3,4,5-trimethoxyphenyl (TMP) moiety is a critical component present in many CBSIs, playing an important role in maintaining suitable molecular conformations of CBSIs and contributing to their high binding affinities to tubulin. Previously reported modifications to the TMP moiety in a variety of scaffolds of CBSIs have usually resulted in reduced antiproliferative potency. We previously reported a potent CBSI, VERU-111, that also contains the TMP moiety. Herein, we report the discovery of a VERU-111 analogue 13f that is significantly more potent than VERU-111. The X-ray crystal structure of 13f in complex with tubulin confirms its direct binding to the colchicine site. In addition, 13f exhibited a strong inhibitory effect on tumor growth in vivo.

中文翻译：

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微管蛋白抑制剂VERU-111中的3,4,5-三甲氧基苯基部分的结构修饰导致改善的抗增殖活性

秋水仙碱结合位点抑制剂（CBSI）在开发新一代抗有丝分裂药物方面具有巨大潜力。与现有的微管蛋白抑制剂（例如紫杉醇）不同，它们通常不易受到药物外排泵过表达引起的耐药性的影响。3,4,5-三甲氧基苯基（TMP）部分是许多CBSI中存在的关键组分，在维持CBSI的合适分子构象并促进其与微管蛋白的高结合亲和力中起重要作用。先前报道的各种CBSI支架中TMP部分的修饰通常导致抗增殖能力降低。我们之前曾报道过一种有效的CBSI，即VERU-111，它也含有TMP部分。在此，我们报告发现VERU-111类似物13f比VERU-111更有力。与微管蛋白复合的13f的X射线晶体结构证实了其与秋水仙碱位点的直接结合。另外，13f在体内对肿瘤生长表现出强烈的抑制作用。