C-2 (E)-4-(Styryl)aniline Substituted Diphenylpyrimidine Derivatives (Sty-DPPYs) as Specific Kinase Inhibitors Targeting Clinical Resistance related EGFRT790M Mutant

Publication date: Available online 18 March 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Anran Song, Jianbin Zhang, Yang Ge, Changyuan Wang, Qiang Meng, Zeyao Tang, Jinyong Peng, Kexin Liu, Yanxia Li, Xiaodong Ma
With the aim to overcome the drug resistance induced by the EGFR T790M mutation (EGFR^T790M), herein, a family of diphenylpyrimidine derivatives (Sty-DPPYs) bearing a C-2 (E)-4-(styryl)aniline functionality were designed and synthesized as potential EGFR^T790M inhibitors. Among them, the compound 10e displayed strong potency against the EGFR^T790M enzyme, with the IC50 of 11.0 nM. Compound 10e also showed a higher SI value (SI = 49.0) than rociletinib (SI = 21.4), indicating its less side effect. In addition, compound 10e could effectively inhibit the proliferation of H1975 cells harboring the EGFR^T790M mutation, within the concentration of 2.91 μM. Significantly, compound 10e has low toxicity against the normal HBE cell (IC50 = 22.48 μM). This work provided new insights into the discovery of potent and selective inhibitor against EGFR^T790M over wild-type (EGFR^WT)

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