2. Academic Validation
  3. Discovery of novel quinazoline analogs as tubulin inhibitors targeting the colchicine binding site for potent antitumor therapy in combination with PD-L1 inhibitors

Discovery of novel quinazoline analogs as tubulin inhibitors targeting the colchicine binding site for potent antitumor therapy in combination with PD-L1 inhibitors

  • Bioorg Chem. 2026 Jan:168:109301. doi: 10.1016/j.bioorg.2025.109301.
Yichang Ren 1,  Songwen Zhou 1,  Chenglong Xu 1,  Jiamin Tan 1,  Xixiang Yang 1,  Zichao Yang 1,  Xiaopeng Peng 2,  Jin Liu 3,  Jianjun Chen 4
Affiliations

Affiliations

  • 1 NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2 Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Jiangxi Provincial Key Laboratory of Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou 341000, China.. Electronic address: [email protected].
  • 3 Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.. Electronic address: [email protected].
  • 4 NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; The Seventh Affiliated Hospital, Southern Medical University, Foshan 528244, PR China.. Electronic address: [email protected].
PMID: 41349359 DOI: 10.1016/j.bioorg.2025.109301
Abstract

A new class of quinazoline analogues were rationally designed and synthesized as colchicine binding site inhibitors, demonstrating powerful Anticancer activities. Compound 4a stood out as the most effective across four Cancer cell, affording a mean IC50 value of 52 nM marginally superior to that of colchicine (IC50 = 59 nM), possessing the capacity to circumvent paclitaxel-associated drug resistance. Moreover, treatment with 4a led to a pronounced impairment of clonogenic survival in HepG-2 cells. Mechanistic investigations demonstrated that tubulin polymerization was robustly suppressed by 4ain vitro, concomitant with a marked perturbation of microtubule dynamics. Molecular docking analyses suggested a high affinity binding mode between 4a and the colchicine site on tubulin. Additionally, exposure to 4a evoked a pronounced G2/M arrest and was accompanied by robust activation of Apoptosis. Moreover, 4a exposure curbed cancer-cell motility in a concentration-dependent fashion. In vivo, 4a (10 mg/kg) showed significant tumor suppression, achieving a TGI value of 69.25 %. Co-administration of 4a and NP19 (a PD-L1 blockade) led to a pronounced synergistic antitumor effect (TGI 85.20 %). In summary, 4a represents a candidate CBSIs for deeper study.

Keywords

Antitumor; Colchicine binding site; Drug resistance; Quinazoline analogs; Tubulin.

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