Discovery of new thieno[3,2-d]pyrimidine derivatives targeting EGFRL858R/T790M NSCLCs by the conformation constrained strategy.

Abstract

Studies on the third-generation of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFRL858R/T790M mutant remain hotspots, specifically for non-small cell lung cancer (NSCLC). In the current study, a new series of EGFR-TKIs with thieno[3,2-d]pyrimidine derivatives(6a-6r) bearing quinolin-2(1H)-ones were designed and synthesized, through conformational constrained strategy from the third generation of EGFR-TKI olmutinib. In vitro structure-activity relationship (SAR) studies indicated that compounds 6a, 6l, 6m, 6n and 6o exhibited good selective inhibition to EGFRL858R/T790M (IC50 ≤ 250 nM) over wild type EGFR (IC50 > 10000 nM). The observed selectivity of compounds 6l and 6o was also proved by the computational molecular docking and the cellular thermal shift assay. These compounds had good growth inhibitory effect on the four tested cancer cell lines. Specifically, 6o could significantly inhibit the colony formation, wound healing and the expression of p-EGFR and its downstream p-ERK in EGFRL858R/T790M H1975 lung cancer cells. Our findings suggest that the thieno[3,2-d]pyrimidine compounds, especially 6l and 6o, can selectively target the mutant EGFRL858R/T790M in vitro and at cellular level and may serve as the lead compounds for generating new series of the third-generation EGFR-TKIs.

• Authors: Yang Chen, Linlin Yang, Hui Qiao, Zhongyu Cheng, Jiahao Xie, Wenjuan Zhou, Xin Huang, Yaoxuan Jiang, Bin Yu, Wen Zhao
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 199 Pg. 112388 (Aug 01 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 32402937 (Publication Type: Journal Article)
• Copyright: Copyright © 2020. Published by Elsevier Masson SAS.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Pyrimidines
• thieno(2,3-d)pyrimidine
• EGFR protein, human
• ErbB Receptors

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Drug Discovery
• Drug Screening Assays, Antitumor
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Molecular Conformation
• Molecular Docking Simulation
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship