XHL11, a novel selective EGFR inhibitor, overcomes EGFR T790M -mediated resistance in non-small cell lung cancer

The first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib significantly improved the therapeutic effect in non-small cell lung cancer (NSCLC) patients with EGFR mutation. However, the EGFR mutation occurs and results in acquired resistanc...

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Published inEuropean journal of pharmacology Vol. 907; p. 174297
Main Authors Li, Yi, Yu, Qing-Long, Li, Tong-Fang, Xiao, Ya-Ni, Zhang, Li, Zhang, Qiu-Yan, Ren, Chun-Guang, Xie, Hong-Lei
Format Journal Article
LanguageEnglish
Published Netherlands 15.09.2021
Subjects
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Humans
Lung Neoplasms
Mutation
Protein Kinase Inhibitors - pharmacology
EGFR TKI
Non-small cell lung cancer
EGFR(T790M)
Apoptosis
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Summary:The first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib significantly improved the therapeutic effect in non-small cell lung cancer (NSCLC) patients with EGFR mutation. However, the EGFR mutation occurs and results in acquired resistance. Consequently, mutant selective third-generation EGFR TKIs represented by AZD9291 (Osimertinib) have been developed to offer more effective therapeutic treatment, but the clinical application is limited by the acquired resistance and the high costs. A series of 5-chloropyrimidine-2,4-diamine derivatives were synthesized and screened for in vitro antitumor activity on H1975 and A431 cells. XHL11 showed the strongest antineoplastic activity. Compared to AZD9291, XHL11 suppressed cellular proliferation and colony formation and induced apoptosis in H1975 cells with EGFR mutation. In addition, XHL11 caused expression changes in EGFR and apoptosis-related pathways. Moreover, oral administration of XHL11 suppressed tumor progression in vivo in a H1975 subcutaneous xenograft model. These data demonstrated that XHL11 might be developed as a promising EGFR TKI for the therapeutic use of NSCLC patients.
ISSN:1879-0712