2. Academic Validation
  3. Design, synthesis, and antitumor evaluation of quinazoline-4-tetrahydroquinoline chemotypes as novel tubulin polymerization inhibitors targeting the colchicine site

Design, synthesis, and antitumor evaluation of quinazoline-4-tetrahydroquinoline chemotypes as novel tubulin polymerization inhibitors targeting the colchicine site

  • Eur J Med Chem. 2025 Feb 5:283:117139. doi: 10.1016/j.ejmech.2024.117139.
Qinhuai Lai 1,  Zhijia Wang 1,  Chengyong Wu 1,  Ruofei Zhang 1,  Leyan Li 2,  Yiran Tao 1,  Dan Mo 1,  Jifa Zhang 3,  Lantu Gou 4,  Yuxi Wang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, Chinese Evidence-based Medicine Center, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, Chinese Evidence-based Medicine Center, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, 610041, China; Course of Biological Sciences, Department of Life Science, Imperial College London, United Kingdom.
  • 3 State Key Laboratory of Biotherapy and Cancer Center, Chinese Evidence-based Medicine Center, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: zjf298257@163.com.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, Chinese Evidence-based Medicine Center, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: goulantu@scu.edu.cn.
  • 5 State Key Laboratory of Biotherapy and Cancer Center, Chinese Evidence-based Medicine Center, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, 610041, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China. Electronic address: yuxiwang@scu.edu.cn.
PMID: 39662284 DOI: 10.1016/j.ejmech.2024.117139
Abstract

We designed, synthesized, and evaluated the antitumor activity of a series of novel quinazoline-4-(6-methoxytetrahydroquinoline) analogues. Among the tested compounds, 4a4 exhibited the most potent antiproliferative activities across four human Cancer cell lines with half-maximal inhibitory concentration (IC50) values ranging from 0.4 to 2.7 nM, more potent than the lead compound. The 2.71 Å resolution co-crystal structure of 4a4 with tubulin (PDB code: 8YER) confirmed its critical binding at the colchicine site. Moreover, 4a4 inhibited the polymerization of tubulin, colony formation, and tumor cell migration, while inducing G2/M phase arrest and Apoptosis. In vivo, 4a4 significantly delayed primary tumor growth in the SKOV3 xenograft model without obvious side effect. Our research enhances the structure-activity relationships (SARs) understanding of the quinazoline-4-tetrahydroquinoline scaffold and provides new insights for potential structural optimization and the development of novel colchicine binding site inhibitors (CBSIs).

Keywords

Antitumor; Co-crystal structure; Colchicine binding site inhibitors (CBSIs); Quinazoline-4-tetrahydroquinoline; Structure-activity relationship (SAR); Tubulin.

Figures
Products