Design, synthesis, and biological evaluation of Indazole-based CA-4 analogues as tubulin polymerization inhibitors
- Bioorg Chem. 2026 Aug 15:178:109943. doi: 10.1016/j.bioorg.2026.109943.
- 1. Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
- 2. Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
- 3. Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
- 4. Guangdong Provincial Key Laboratory of Chemical Measurement and Emergency Test Technology, Institute of Analysis, Guangdong Academy of Sciences (China National Analytical Center Guangzhou), Guangzhou 510070, PR China.
- 5. Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
Microtubules represent a clinically validated target for Anticancer therapy. However, the clinical utility of existing tubulin inhibitors is frequently compromised by the emergence of drug resistance and systemic toxicities. Herein, we designed and synthesized a series of indazole-based Combretastatin A-4 (CA-4) analogues as potent tubulin polymerization inhibitors. Among them, SMU-G4 potently inhibited the proliferation of B16-F10 Melanoma cells (IC50 = 4 nM). Moreover, SMU-G4 significantly induced G2/M phase cell cycle arrest and triggered Apoptosis, while effectively suppressing tumor cell migration in vitro. Most importantly, SMU-G4 demonstrated potent in vivo antitumor efficacy in a B16-F10 xenograft mouse model (TGI = 74.4%, 15 mg/kg) without inducing significant systemic toxicity or observable adverse effects. These findings suggest that SMU-G4, characterized by its novel scaffold and potent inhibitory profile, serves as a promising lead compound for the development of next-generation microtubule-targeting agents.