We recently reported the crystal structure of tubulin in complex with a colchicine binding site inhibitor (CBSI), ABI-231, having 2-aryl-4-benzoyl-imidazole (ABI). Based on this and additional crystal structures, here we report the structure-activity relationship study of a novel series of pyridine analogues of ABI-231, with compound 4v being the most potent one (average IC50 ∼ 1.8 nM) against a panel of cancer cell lines. We determined the crystal structures of another potent CBSI ABI-274 and 4v in complex with tubulin and confirmed their direct binding at the colchicine site. 4v inhibited tubulin polymerization, strongly suppressed A375 melanoma tumor growth, induced tumor necrosis, disrupted tumor angiogenesis, and led to tumor cell apoptosis in vivo. Collectively, these studies suggest that 4v represents a promising new generation of tubulin inhibitors.

中文翻译：

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新型6-芳基-2-苯甲酰基-吡啶类具有微弱抗增殖特性的微管蛋白聚合抑制剂的结构-活性关系研究。

我们最近报道了微管蛋白的晶体结构与秋水仙碱结合位点抑制剂（CBSI），ABI-231，具有2-芳基-4-苯甲酰基-咪唑（ABI）的复合物。基于此和其他晶体结构，在此我们报道了一系列新颖的ABI-231吡啶类似物的结构-活性关系研究，其中化合物4v对一组癌细胞最有效（平均IC50〜1.8 nM）线。我们确定了另一种有效的CBSI ABI-274和4v与微管蛋白复合的晶体结构，并确认了它们在秋水仙碱位点的直接结合。4v抑制微管蛋白聚合，强烈抑制A375黑色素瘤肿瘤生长，诱导肿瘤坏死，破坏肿瘤血管生成，并导致体内肿瘤细胞凋亡。总的来说，