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

Zijun Tang; Mingxing Hu; Ye Gan; Lin Wen; Yijie Wang; Yongmei Xie; Mingqing Yuan

doi:10.1016/j.bmcl.2025.130315

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

Bioorg Med Chem Lett. 2025 Jun 22:127:130315. doi: 10.1016/j.bmcl.2025.130315. Online ahead of print.

Authors

Zijun Tang¹, Mingxing Hu², Ye Gan³, Lin Wen⁴, Yijie Wang², Yongmei Xie⁵, Mingqing Yuan⁶

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 EGFR^T790M 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 EGFR^L858R/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 EGFR^L858R/T790M mutation.

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