The synthesis of 4-arylamido-2-arylaminoprimidines as potent EGFR T790M/L858R inhibitors for NSCLC

Lixue Chen; Fuyun Chi; Tong Wang; Ning Wang; Wei Li; Kexin Liu; Xiaohong Shu; Xiaodong Ma; Youjun Xu

doi:10.1016/j.bmc.2018.11.009

The synthesis of 4-arylamido-2-arylaminoprimidines as potent EGFR T790M/L858R inhibitors for NSCLC

Bioorg Med Chem. 2018 Dec 15;26(23-24):6087-6095. doi: 10.1016/j.bmc.2018.11.009. Epub 2018 Nov 10.

Authors

Lixue Chen¹, Fuyun Chi², Tong Wang¹, Ning Wang², Wei Li¹, Kexin Liu², Xiaohong Shu², Xiaodong Ma³, Youjun Xu⁴

Affiliations

¹ School of Pharmaceutical Engineering, and Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, PR China.
² College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
³ College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: xiaodong.ma@139.com.
⁴ School of Pharmaceutical Engineering, and Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: xuyoujun@syphu.edu.cn.

PMID: 30471829
DOI: 10.1016/j.bmc.2018.11.009

Abstract

A series of 4-arylamido-2-arylaminoprimidines bearing acrylamide pharmacophore were synthesized as potent EGFR^T790M/L858R inhibitors among which 9c (IC₅₀ = 0.5872 nM), 9d (IC₅₀ = 2.213 nM), or 9h (IC₅₀ = 12.57 nM) showed more potent anti-EGFR^T790M/L858R activity compared with AZD-9291 (IC₅₀ = 20.80 nM) and possessed high SI displaying 307.6, 56.5, or 12.5 for EGFR^T790M/L858R over the wild-type respectively. 9h also showed pretty good activity against H 1975 cells with an IC₅₀ of 1.664 μM and exhibited low toxicity against the normal HBE cells (IC₅₀ > 20 μΜ). 9h had moderate selectivity for H 1975 over A 431 (SI = 7.0) and the other selected cell lines. Morphological staining results further indicated that 9h could promote apoptosis. Hence, 9h was a promising compound for further investigation as a potential EGFR^T790M/L858R inhibitor for the treatment of NSCLC.

Keywords: EGFR T790M/L858R; Inhibitors; NSCLC; Resistance.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship
Wound Healing / drug effects

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
EGFR protein, human
ErbB Receptors