Design Synthesis and Biological Evaluation of NovelConformationally Constrained Inhibitors Targeting EGFR

摘要

This letter describes the construction of conformationally constrained quinazoline analogues. Structure–activity relationship studies led to the identification of the lead compound >9n. Compound >9n exhibits effective in vitro activity against A431^{WT,overexpression} and H1975^{[L858R/T790M]} cancer cell lines but is significantly less effective against EGFR negative cancer cell lines (SW620, A549, and K562). Compound >9n was also assessed for potency in enzymatic assays and in vivo antitumor studies. The results indicated that >9n is a potent kinase inhibitor against both wild-type and T790M mutant EGFR kinase. Meanwhile, an oral administration of >9n at a dose of 200 mg/kg produced a considerable antitumor effect in a A431 xenograft model, as compared to gefitinib. A preliminary pharmacokinetic study of >9n also indicates it has good pharmacokinetic properties, and therefore, it is a good starting point for further development.