Design, synthesis and biological evaluation of aminopyrimidine derivatives bearing a 4,5,6,7-tetrahydrothieno [3,2-c]pyridine as potent EGFR inhibitors

Yingxue Li; Yaoyao Chang; Jianfang Fu; Rongcai Ding; Lingyun Zhang; Tian Liang; Yajing Liu; Yue Liu; Jinxing Hu

doi:10.1016/j.ejmech.2021.113845

Design, synthesis and biological evaluation of aminopyrimidine derivatives bearing a 4,5,6,7-tetrahydrothieno [3,2-c]pyridine as potent EGFR inhibitors

Eur J Med Chem. 2021 Dec 15:226:113845. doi: 10.1016/j.ejmech.2021.113845. Epub 2021 Sep 11.

Authors

Yingxue Li¹, Yaoyao Chang¹, Jianfang Fu¹, Rongcai Ding¹, Lingyun Zhang¹, Tian Liang¹, Yajing Liu², Yue Liu³, Jinxing Hu⁴

Affiliations

¹ Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China.
² Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
³ Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China. Electronic address: liuyue@wfmc.edu.cn.
⁴ Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China. Electronic address: jinxinghu2013@wfmc.edu.cn.

PMID: 34534838
DOI: 10.1016/j.ejmech.2021.113845

Abstract

To resolve the problem of drug resistance caused by epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer, we used the principle of collocation to design and synthesize a series of aminopyrimidine derivatives with 4,5,6,7-tetrahydrothieno [3,2-c]pyridine side chains (according to the binding mode of AZD9291 to EGFR^T790M) for use as EGFR^L858R/T790M kinase inhibitors. The most promising compound A12, a non-covalently bound reversible inhibitor, showed excellent kinase inhibitory activity against EGFR^L858R/T790M, with an IC₅₀ value of 4.0 nM and more than 42-fold selectivity for EGFR^WT (IC₅₀ = 170.0 nM). Moreover, compound A12 showed strong anti-proliferative activity against H1975 cells, with IC₅₀ value of 0.086 μΜ. Additionally, the effective inhibition of cell migration and the promotion of apoptosis by A12 verified its mechanism of action, as a selective inhibitor of EGFR^L858R/T790M.

Keywords: Antitumor; EGFR mutations; EGFR(L858R/T790M); NSCLC; Reversible inhibitor.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

4,5,6,7-tetrahydrothieno(3,2-c)pyridine
Antineoplastic Agents
Protein Kinase Inhibitors
Pyridines
Pyrimidines
2-aminopyrimidine
EGFR protein, human
ErbB Receptors