2. Academic Validation
  3. Structure-based design and synthesis of 3-substituted-1,2,4-triazolo[1,5-a]pyrimidines as dual vinca/gatorbulin-site ligands for cancer treatment

Structure-based design and synthesis of 3-substituted-1,2,4-triazolo[1,5-a]pyrimidines as dual vinca/gatorbulin-site ligands for cancer treatment

  • Eur J Med Chem. 2026 Jan 5:301:118245. doi: 10.1016/j.ejmech.2025.118245.
Chufeng Zhang 1,  Wei Yan 2,  Hongxiu Chen 1,  Maoru Sun 1,  Fang Wang 1,  Yilin Wang 1,  Shuai Zhang 1,  Li Liu 1,  Qingqing Li 1,  Xiuying Hu 1,  Zhuang Yang 3,  Jianhong Yang 4,  Yong Li 5
Affiliations

Affiliations

  • 1 Innovation Center of Nursing Research and Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, 610041, Sichuan, China.
  • 2 Department of Neurology, Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
  • 3 Laboratory of Natural and Targeted Small Molecule Drugs, Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: young9008@126.com.
  • 4 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: yjh1988@scu.edu.cn.
  • 5 Innovation Center of Nursing Research and Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: liyong562@126.com.
PMID: 41106064 DOI: 10.1016/j.ejmech.2025.118245
Abstract

Our preliminary studies indicate that cevipabulin concurrently binds to both the vinca site and the gatorbulin site, and promotes tubulin degradation. To improve its antiproliferative activity and investigate the structure-activity relationships (SARs), thirty-eight cevipabulin derivatives were designed and synthesized based on the cevipabulin-tubulin cocrystal structure. Among them, compound 8g exerted optimal antiproliferative activity, with IC50 values ranging from 0.016 to 0.035 μM against three tested tumor cell lines. The cocrystal structure of the 8g-tubulin complex revealed that it simultaneously occupies both the vinca site and the gatorbulin site, while maintaining a binding mode similar to that of cevipabulin. Furthermore, 8g promoted αβ-tubulin degradation and displayed good oral bioavailability. In an HT29 xenograft model, oral administration of 8g at doses of 20 and 40 mg/kg every 3 days resulted in potent in vivo antitumor activity, with tumor growth inhibition (TGI) rates of 41.0 % and 49.5 %, respectively. Moreover, 8g exhibited significantly reduced toxicity and fewer adverse effects compared to cevipabulin, supporting its potential as a promising therapeutic agent for Cancer treatment.

Keywords

Cevipabulin; Gatorbulin site; Microtubule degradation; Vinca site.

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