2. Academic Validation
  3. Design, synthesis and antitumor activity of novel thiophene-pyrimidine derivatives as EGFR inhibitors overcoming T790M and L858R/T790M mutations

Design, synthesis and antitumor activity of novel thiophene-pyrimidine derivatives as EGFR inhibitors overcoming T790M and L858R/T790M mutations

  • Eur J Med Chem. 2020 Oct 1;203:112511. doi: 10.1016/j.ejmech.2020.112511.
Zhen Xiao 1,  Zhihui Zhou 1,  Cilong Chu 1,  Qian Zhang 1,  Lingjia Zhou 1,  Zunhua Yang 2,  Xin Li 1,  Liying Yu 1,  Pengwu Zheng 1,  Shan Xu 3,  Wufu Zhu 4
Affiliations

Affiliations

  • 1 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China.
  • 2 College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China.
  • 3 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China. Electronic address: shanxu9891@126.com.
  • 4 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China. Electronic address: zhuwufu-1122@163.com.
PMID: 32679450 DOI: 10.1016/j.ejmech.2020.112511
Abstract

Five series of novel thiophene-pyrimidine derivatives (9a-h, 10a-f, 11a-f, 12a-f, 13a-f) have been synthesized and tested for their anti-proliferative activity against several Cancer cell lines in which EGF is highly expressed. Most of the target compounds showed excellent activity against one or more Cancer cell lines. The most promising compound 13a, of which IC50 values on of cell lines A549 and A431 (4.34 ± 0.60 μM and 3.79 ± 0.57 μM) were similar to the lead compound Olmutinib, showed strong activity and selectivity to EGFRT790M and EGFRT790M/L858R. Inhibition data of human normal hepatoma cell line LO2 indicated that most target compounds were less toxic to normal cells and had selective inhibitory effects on Cancer cells. In addition, the structure-activity relationship was analyzed and the mechanism of Apoptosis induced by the 13a was studied. The results showed that compound 13a induced late Apoptosis of A431 Cancer cells in a dose-dependent manner.

Keywords

Anti-proliferation; EGFR inhibitor; Synthesis; Thiophene-pyrimidine.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-146782
    EGFR抑制剂
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