2. Academic Validation
  3. Discovery and biological evaluation of 4,6-pyrimidine analogues with potential anticancer agents as novel colchicine binding site inhibitors

Discovery and biological evaluation of 4,6-pyrimidine analogues with potential anticancer agents as novel colchicine binding site inhibitors

  • Eur J Med Chem. 2023 Feb 15:248:115085. doi: 10.1016/j.ejmech.2022.115085.
Jifa Zhang 1,  Lun Tan 2,  Chengyong Wu 1,  Yuyan Li 2,  Hao Chen 3,  Yinghuan Liu 4,  Yuxi Wang 5
Affiliations

Affiliations

  • 1 Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Tianfu Jincheng Laboratory, Chengdu, 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
  • 2 Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
  • 3 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, 38163, Tennessee, United States.
  • 4 Tianfu Jincheng Laboratory, Chengdu, 610041, Sichuan, China.
  • 5 Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Tianfu Jincheng Laboratory, Chengdu, 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: [email protected].
PMID: 36621138 DOI: 10.1016/j.ejmech.2022.115085
Abstract

Novel 4,6-pyrimidine analogues were designed and synthesized as colchicine binding site inhibitors (CBSIs) with potent antiproliferative activities. Among them, compound 17j has the most potent activities against 6 human Cancer cell lines with IC50 values from 1.1 nM to 4.4 nM, which was 76 times higher than the lead compound 3 in A549 cells. The co-crystal structure of 17j in complex with tubulin confirms the key binding mode at the colchicine binding site. Moreover, 17j inhibited the tubulin polymerization in biochemical assays, depolymerized cellular microtubules, induced the G2/M arrest, inhibited the cell migration, and promoted the initiation of Apoptosis. In vivo, 17j effectively inhibits primary tumor growth with tumor growth inhibition rates of 42.51% (5 mg/kg) and 65.42% (10 mg/kg) in A549 xenograft model. Taken together, 17j represents a promising new generation of CBSIs.

Keywords

Anti-tumor; CBSIs; Crystal structure; Inhibitors; Microtubules.

Figures