2. Academic Validation
  3. Noncovalent EGFR T790M/L858R inhibitors based on diphenylpyrimidine scaffold: Design, synthesis, and bioactivity evaluation for the treatment of NSCLC

Noncovalent EGFR T790M/L858R inhibitors based on diphenylpyrimidine scaffold: Design, synthesis, and bioactivity evaluation for the treatment of NSCLC

  • Eur J Med Chem. 2021 Nov 5:223:113626. doi: 10.1016/j.ejmech.2021.113626.
Lixue Chen 1,  Yunhao Zhang 1,  Liangliang Tian 2,  Changyuan Wang 1,  Tuo Deng 2,  Xu Zheng 1,  Tong Wang 2,  Zhen Li 1,  Zeyao Tang 1,  Qiang Meng 1,  Huijun Sun 1,  Lei Li 3,  Xiaodong Ma 4,  Youjun Xu 5
Affiliations

Affiliations

  • 1 College of Pharmacy, Dalian Medical University, Dalian, 116044, PR China.
  • 2 School of Pharmaceutical Engineering, Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
  • 3 College of Pharmacy, Dalian Medical University, Dalian, 116044, PR China. Electronic address: lilei0332@126.com.
  • 4 College of Pharmacy, Dalian Medical University, Dalian, 116044, PR China. Electronic address: xiaodong.ma@139.com.
  • 5 School of Pharmaceutical Engineering, 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: 34218082 DOI: 10.1016/j.ejmech.2021.113626
Abstract

A series of diphenylpyrimidine derivatives bearing a hydroxamic acid group was designed and synthesized as noncovalent EGFRT790M/L858R inhibitors to improve the biological activity and selectivity. One of the most promising compound 9d effectively interfered EGFRT790M/L858R binding with ATP and suppressed the proliferation of H1975 cells with IC50 values of 1.097 nM and 0.09777 μM, respectively. Moreover, compound 9d also not only exhibited a high selective index of 43.4 for EGFRT790M/L858R over the wild-type and 10.9 for H1975 cells over A431, but also exhibited low toxicity against the normal HBE cells (IC50 > 20 μΜ). In addition, the action mechanism validated that compound 9d effectively inhibited cell migration and promoted cell Apoptosis by blocking cell cycle at G2/M stage. Furthermore, the target dose-dependently downregulated the expression of p-EGFR and arrested the activation of downstream Akt and ERK in H1975. All these studies provide important clues for the discovery of potent noncovalent EGFRT790M/L858R inhibitors.

Keywords

EGFR T790M/L858R; NSCLC; Noncovalent inhibitors; Resistance.

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