机构：[1]School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China[2]Targeted Tracer Research and Development Laboratory, Precision Medicine Research Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China四川大学华西医院[3]Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou 510260, China[4]Department of Psychological and Brain Sciences, Dartmouth College, Hanover, New Hampshire 03755, United States[5]Targeted Tracer Research and Development Laboratory, Precision Medicine Research Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China四川大学华西医院[6]School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China[7]School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China
Novel indazole and benzimidazole analogues were designed and synthesized as tubulin inhibitors with potent antiproliferative activities. Among them, compound 12b exhibited the strongest inhibitory effects on the growth of cancer cells with an average IC50 value of 50 nM, slightly better than colchicine. 12b exhibited nearly equal potency against both, a paclitaxel-resistant cancer cell line (A2780/T, IC50 = 9.7 nM) and the corresponding parental cell line (A2780S, IC50 = 6.2 nM), thus effectively overcoming paclitaxel resistance in vitro. The crystal structure of 12b in complex with tubulin was solved to 2.45 Å resolution by X-ray crystallography, and its direct binding was confirmed to the colchicine site. Furthermore, 12b displayed significant in vivo antitumor efficacy in a melanoma tumor model with tumor growth inhibition rates of 78.70% (15 mg/kg) and 84.32% (30 mg/kg). Collectively, this work shows that 12b is a promising lead compound deserving further investigation as a potential anticancer agent.
基金：
This work was supported by the scientific research project of
high-level talents (no. G618319142) in Southern Medical
University of China; International Science and Technology
Cooperation Projects of Guangdong Province (no.
G819310411); Thousand Youth Talents Program (no.
C1080092) from the Organization Department of the CPC
Central Committee, China; GDAS Special Project of Science
and Technology Development (2016GDASRC-0104 and
2018GDASCX-0107); and Guangdong Basic Research Foundation
(no. 2019A1515110616). The X-ray work was
supported by the National Major Scientific and Technological
Special Project for “Significant New Drugs Development” (no.
2018ZX09201018-021), National Natural Science Foundation
of China (no. 81703553), China Postdoctoral Science
Foundation (nos. 2017M610607 and 2018T110984), and
Sichuan Science and Technology Program (no.
2019YFS0003).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2021]版：
大类|1 区医学
小类|1 区药物化学
最新[2023]版：
大类|1 区医学
小类|1 区药物化学
第一作者：
第一作者机构：[1]School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China
共同第一作者：
通讯作者：
通讯机构：[7]School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China[*1]School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China
推荐引用方式(GB/T 7714)：
Yichang Ren,Yuxi Wang,Gang Li,et al.Discovery of Novel Benzimidazole and Indazole Analogues as Tubulin Polymerization Inhibitors with Potent Anticancer Activities.[J].Journal of medicinal chemistry.2021,64(8):4498-4515.doi:10.1021/acs.jmedchem.0c01837.
APA：
Yichang Ren,Yuxi Wang,Gang Li,Zherong Zhang,Lingling Ma...&Jianjun Chen.(2021).Discovery of Novel Benzimidazole and Indazole Analogues as Tubulin Polymerization Inhibitors with Potent Anticancer Activities..Journal of medicinal chemistry,64,(8)
MLA：
Yichang Ren,et al."Discovery of Novel Benzimidazole and Indazole Analogues as Tubulin Polymerization Inhibitors with Potent Anticancer Activities.".Journal of medicinal chemistry 64..8(2021):4498-4515
医学