Identification of 2(1H)-pyrimidinones as potential EGFR T790M inhibitors for the treatment of gefitinib-resistant non-small cell lung cancer

Jianping Huang; Jiaxin Huang; Ning Wang; Luhong Wang; Lei Li; Changyuan Wang; Xiuli Sun; Yongming Li; Guoping Huang; Xiaodong Ma

doi:10.1016/j.bioorg.2019.102994

Identification of 2(1H)-pyrimidinones as potential EGFR T790M inhibitors for the treatment of gefitinib-resistant non-small cell lung cancer

Bioorg Chem. 2019 Aug:89:102994. doi: 10.1016/j.bioorg.2019.102994. Epub 2019 May 18.

Authors

Jianping Huang¹, Jiaxin Huang², Ning Wang², Luhong Wang², Lei Li², Changyuan Wang², Xiuli Sun³, Yongming Li⁴, Guoping Huang⁵, Xiaodong Ma⁶

Affiliations

¹ Institute of Functional Materials and Agricultural Applied Chemistry, College of Science, Jiangxi Agricultural University, Nanchang 330045, PR China; Nanchang Jiangteng Pharmaceutical Co., Ltd., Nanchang 330045, PR China.
² College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
³ Department of Hematology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China.
⁴ Institute of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, No. 138, Xianlin Avenue, Qixia District, Nanjing 210023, PR China.
⁵ Nanchang Jiangteng Pharmaceutical Co., Ltd., Nanchang 330045, PR China. Electronic address: [email protected].
⁶ College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: [email protected].

PMID: 31185393
DOI: 10.1016/j.bioorg.2019.102994

Abstract

A new class of 2(1H)-pyrimidinone derivatives was identified as potential EGFR T790M inhibitors against TKI-resistant NSCLC. These novel compounds inhibited the EGFR T790M kinase activity at concentrations in the range of 85.3 to 519.9 nM. In particular, compound 7e exhibited the strongest activity against both EGFR^WT (IC₅₀ = 96.9 nM) and EGFR^T790M (IC₅₀ = 85.3 nM) kinases in the cells. Compared with inhibitor 7e, compound 7b displayed enhanced antiproliferative activity against gefitinib-resistant H1975 cells harboring the EGFR T790M mutation. In addition, compound 7b also has low toxicity against the normal human liver cells LO2, with an IC₅₀ of 11.1 µM. Moreover, both the AO/EB and DAPI staining assays also demonstrated the inhibitory efficacy of 7b against the resistant H1975 cells. This contribution provides a new scaffold 2(1H)-pyrimidinone as potential EGFR T790M inhibitor against drug-resistant NSCLC.

Keywords: EGFR T790M; Inhibitor; NSCLC; Pyrimidinone; Resistant.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Binding Sites
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line
Cell Movement / drug effects
Cell Proliferation / drug effects
Drug Design
Drug Resistance, Neoplasm / drug effects*
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / genetics
ErbB Receptors / metabolism
Gefitinib / pharmacology
Humans
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Molecular Docking Simulation
Mutation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Protein Structure, Tertiary
Pyrimidinones / chemistry*
Pyrimidinones / metabolism
Pyrimidinones / pharmacology

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidinones
ErbB Receptors
Gefitinib