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X-ray Crystal Structure-Guided Discovery of Novel Indole Analogues as Colchicine-Binding Site Tubulin Inhibitors with Immune-Potentiating and Antitumor Effects against Melanoma
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-05-05 , DOI: 10.1021/acs.jmedchem.3c00011 Yichang Ren 1 , Yuxi Wang 2 , Jin Liu 1, 3 , Ting Liu 1 , Lin Yuan 1 , Chengyong Wu 2 , Zichao Yang 1 , Jianjun Chen 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-05-05 , DOI: 10.1021/acs.jmedchem.3c00011 Yichang Ren 1 , Yuxi Wang 2 , Jin Liu 1, 3 , Ting Liu 1 , Lin Yuan 1 , Chengyong Wu 2 , Zichao Yang 1 , Jianjun Chen 1
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A series of novel indole analogues were discovered as colchicine-binding site inhibitors of tubulin. Among them, 3a exhibited the highest antiproliferative activity (average IC50 = 4.5 nM), better than colchicine (IC50 = 65.3 nM). The crystal structure of 3a in complex with tubulin was solved by X-ray crystallography, which explained the improved binding affinity of 3a to tubulin and thus its higher anticancer activity (IC50 = 4.5 nM) than the lead compound 12b (IC50 = 32.5 nM). In vivo, 3a (5 mg/kg) displayed significant antitumor efficacy against B16-F10 melanoma with a TGI of 62.96% and enhanced the antitumor efficacy of a small-molecule PD-1/PD-L1 inhibitor NP19 (TGI = 77.85%). Moreover, 3a potentiated the antitumor immunity of NP19 by activating the tumor immune microenvironment, as demonstrated by the increased tumor-infiltrating lymphocytes (TIL). Collectively, this work shows a successful example of crystal structure-guided discovery of a novel tubulin inhibitor 3a as a potential anticancer and immune-potentiating agent.
中文翻译：
X 射线晶体结构引导发现新型吲哚类似物作为秋水仙碱结合位点微管蛋白抑制剂，具有针对黑色素瘤的免疫增强和抗肿瘤作用
一系列新型吲哚类似物被发现作为微管蛋白秋水仙碱结合位点抑制剂。其中，3a表现出最高的抗增殖活性（平均IC 50 = 4.5 nM），优于秋水仙碱（IC 50 = 65.3 nM）。通过 X 射线晶体学解析了3a与微管蛋白复合物的晶体结构，这解释了3a与微管蛋白的结合亲和力提高，因此其抗癌活性 (IC 50 = 4.5 nM) 高于先导化合物12b (IC 50 = 32.5)纳米）。体内, 3a(5 mg/kg) 对 B16-F10 黑色素瘤显示出显着的抗肿瘤功效，TGI 为 62.96%，并增强了小分子 PD-1/PD-L1 抑制剂 NP19 的抗肿瘤功效 (TGI = 77.85%)。此外，3a通过激活肿瘤免疫微环境来增强 NP19 的抗肿瘤免疫力，肿瘤浸润淋巴细胞 (TIL) 的增加证明了这一点。总的来说，这项工作展示了以晶体结构为指导发现新型微管蛋白抑制剂3a作为潜在抗癌和免疫增强剂的成功范例。
更新日期：2023-05-05
中文翻译：
X 射线晶体结构引导发现新型吲哚类似物作为秋水仙碱结合位点微管蛋白抑制剂，具有针对黑色素瘤的免疫增强和抗肿瘤作用
一系列新型吲哚类似物被发现作为微管蛋白秋水仙碱结合位点抑制剂。其中，3a表现出最高的抗增殖活性（平均IC 50 = 4.5 nM），优于秋水仙碱（IC 50 = 65.3 nM）。通过 X 射线晶体学解析了3a与微管蛋白复合物的晶体结构，这解释了3a与微管蛋白的结合亲和力提高，因此其抗癌活性 (IC 50 = 4.5 nM) 高于先导化合物12b (IC 50 = 32.5)纳米）。体内, 3a(5 mg/kg) 对 B16-F10 黑色素瘤显示出显着的抗肿瘤功效，TGI 为 62.96%，并增强了小分子 PD-1/PD-L1 抑制剂 NP19 的抗肿瘤功效 (TGI = 77.85%)。此外，3a通过激活肿瘤免疫微环境来增强 NP19 的抗肿瘤免疫力，肿瘤浸润淋巴细胞 (TIL) 的增加证明了这一点。总的来说，这项工作展示了以晶体结构为指导发现新型微管蛋白抑制剂3a作为潜在抗癌和免疫增强剂的成功范例。
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