2. Academic Validation
  3. Design, synthesis, and evaluation of 1,3,4-oxadiazole-based EGFR inhibitors

Design, synthesis, and evaluation of 1,3,4-oxadiazole-based EGFR inhibitors

  • Bioorg Med Chem Lett. 2025 Nov 1:127:130315. doi: 10.1016/j.bmcl.2025.130315.
Zijun Tang 1,  Mingxing Hu 2,  Ye Gan 3,  Lin Wen 4,  Yijie Wang 2,  Yongmei Xie 5,  Mingqing Yuan 6
Affiliations

Affiliations

  • 1 Guangxi Key Laboratory of Special Biomedicine; School of Medicine, Guangxi University, Nanning, 530004, PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, PR China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, PR China.
  • 3 Guangxi Key Laboratory of Special Biomedicine; School of Medicine, Guangxi University, Nanning, 530004, PR China.
  • 4 Guangxi University Hospital, Nanning, 530004, PR China.
  • 5 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, PR China. Electronic address: xieym@scu.edu.cn.
  • 6 Guangxi Key Laboratory of Special Biomedicine; School of Medicine, Guangxi University, Nanning, 530004, PR China. Electronic address: yuanmingqing@gxu.edu.cn.
PMID: 40555282 DOI: 10.1016/j.bmcl.2025.130315
Abstract

The epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase (RTK) family, serves as a validated and significant therapeutic target in various cancers. EGFR inhibitors have substantially improved the treatment outcomes for patients with EGFR-positive tumors. The EGFRT790M mutation has emerged as a leading cause of clinically acquired resistance to both first- and second-generation EGFR inhibitors. In this study, we integrated azoles, particularly 1,3,4-oxadiazoles, into a preferred quinazoline scaffold to design novel EGFR inhibitors. Compound 4b, a new 1,3,4-oxadiazole-based EGFR Inhibitor, demonstrated superior potency against the EGFRL858R/T790M mutant (IC50 = 17.18 nM compared to 733.20 nM for Erlotinib) and in NCI-H1975 cells (IC50 = 2.17 ± 0.20 μM compared to 11.01 ± 0.05 μM for Erlotinib). Furthermore, 4b significantly inhibited the migration of both A431 and NCI-H1975 cells and induced G1 phase cell cycle arrest in NCI-H1975 cells. In conclusion, these findings suggest that 4b is a promising lead compound for the development of inhibitors targeting the EGFRL858R/T790M mutation.

Keywords

1,3,4-oxadiazole; Activity evaluation; Cancer; EGFR; Inhibitor.

Figures
Products