2. Academic Validation
  3. Discovery of Novel Benzimidazole and Indazole Analogues as Tubulin Polymerization Inhibitors with Potent Anticancer Activities

Discovery of Novel Benzimidazole and Indazole Analogues as Tubulin Polymerization Inhibitors with Potent Anticancer Activities

  • J Med Chem. 2021 Apr 22;64(8):4498-4515. doi: 10.1021/acs.jmedchem.0c01837.
Yichang Ren 1,  Yuxi Wang 2,  Gang Li 3,  Zherong Zhang 4,  Lingling Ma 2,  Binbin Cheng 1,  Jianjun Chen 1
Affiliations

Affiliations

  • 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.
  • 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.
PMID: 33788562 DOI: 10.1021/acs.jmedchem.0c01837
Abstract

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.

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