C-2 (E)-4-(Styryl)aniline substituted diphenylpyrimidine derivatives (Sty-DPPYs) as specific kinase inhibitors targeting clinical resistance related EGFRT790M mutant

Anran Song; Jianbin Zhang; Yang Ge; Changyuan Wang; Qiang Meng; Zeyao Tang; Jinyong Peng; Kexin Liu; Yanxia Li; Xiaodong Ma

doi:10.1016/j.bmc.2017.03.032

C-2 (E)-4-(Styryl)aniline substituted diphenylpyrimidine derivatives (Sty-DPPYs) as specific kinase inhibitors targeting clinical resistance related EGFR^T790M mutant

Bioorg Med Chem. 2017 May 15;25(10):2724-2729. doi: 10.1016/j.bmc.2017.03.032. Epub 2017 Mar 18.

Authors

Affiliations

¹ College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
² Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China.
³ College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: xiaodong.ma@139.com.

PMID: 28385595
DOI: 10.1016/j.bmc.2017.03.032

Abstract

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 11.0nM. 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 2.91μM. Significantly, compound 10e has low toxicity against the normal HBE cell (IC₅₀=22.48μM). This work provided new insights into the discovery of potent and selective inhibitor against EGFR^T790M over wild-type (EGFR^WT).

Keywords: Diphenylpyrimidine; EGFR(T790M); Inhibitor; NSCLC; Resistance.

MeSH terms

Aniline Compounds / chemistry
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / toxicity
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Resistance, Neoplasm / drug effects
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / genetics
ErbB Receptors / metabolism
Humans
Molecular Docking Simulation
Mutation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / toxicity
Protein Structure, Tertiary
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / toxicity
Stereoisomerism
Structure-Activity Relationship

Substances

Aniline Compounds
Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
ErbB Receptors
aniline