X-ray Crystal Structure-Guided Discovery of Novel Indole Analogues as Colchicine-Binding Site Tubulin Inhibitors with Immun Potentiating and Antitumor Effects against Melanoma

作者：Ren, Yichang; Wang, Yuxi; Liu, Jin; Liu, Ting; Yuan, Lin; Wu, Chengyong; Yang, Zichao; Chen, Jianjun^*

来源：Journal of Medicinal Chemistry, 2023, 66(10): 6697-6714.

DOI：10.1021/acs.jmedchem.3c00011

• MICROTUBULES
• LAULIMALIDE
• COMPLEX
• TARGETS
• DESIGN
• AGENTS
• CELLS

A series of novel indole analogues were discovered as colchicinebinding 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.

• 单位
  海南大学; 1; 四川大学; 南方医科大学