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.

Lixue Chen ¹, Fuyun Chi ², Tong Wang ¹, Ning Wang ², Wei Li ¹, Kexin Liu ², Xiaohong Shu ², Xiaodong Ma ³, Youjun Xu ⁴

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.

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