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  2. Design, synthesis, and evaluation of antitumor activity of Mobocertinib derivatives, a third-generation EGFR inhibitor

Design, synthesis, and evaluation of antitumor activity of Mobocertinib derivatives, a third-generation EGFR inhibitor

  • Bioorg Chem. 2024 Jun:147:107390. doi: 10.1016/j.bioorg.2024.107390.
Dang Fan 1 Han Zhang 1 Lei Duan 1 Li Long 1 Shan Xu 1 Yuanbiao Tu 2 Linxiao Wang 1 Pengwu Zheng 3 Wufu Zhu 4
Affiliations

Affiliations

  • 1 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang Jiangxi, 330013, China.
  • 2 Jiangxi Univ Tradit Chinese Med, Jiangzhong Canc Res Ctr, 1688 Meiling Rd, Nanchang Jiangxi, 330004, China.
  • 3 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang Jiangxi, 330013, China. Electronic address: zhengpw@126.com.
  • 4 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang Jiangxi, 330013, China. Electronic address: zhuwufu-1122@163.com.
Abstract

Mobocertinib, as a structural analog of the third generation TKI Osimertinib, can selectively act on the EGFRex20 mutation. We have structurally modified Mobocertinib to obtain new EGFR inhibitors. In this paper, we chose Mobocertinib as a lead compound for structural modification to investigate the effect of Mobocertinib derivatives on EGFRT790M mutation. We designed and synthesized 63 Mobocertinib derivatives by structural modification using the structural similarity strategy and the bioelectronic isoarrangement principle. Then, we evaluated the in vitro antitumor activity of the 63 Mobocertinib derivatives and found that the IC50 of compound H-13 against EGFRL858R/T790M mutated H1975 cells was 3.91 μM, and in further kinase activity evaluation, the IC50 of H-13 against EGFRL858R/T790M kinase was 395.2 nM. In addition, the preferred compound H-13 was able to promote Apoptosis of H1975 tumor cells and block the proliferation of H1975 cells in the G0/G1 phase; meanwhile, it was able to significantly inhibit the migratory ability of H1975 tumor cells and inhibit the growth of H1975 cells in a time-concentration-dependent manner. In the in vivo anti-tumor activity study, the preferred compound H-13 had no obvious toxicity to normal mice, and the tumor inhibition effect on H1975 cell-loaded nude mice was close to that of Mobocertinib. Finally, molecular dynamics simulations showed that the binding energy between compound H-13 and 3IKA protein was calculated to be -162.417 ± 14.559 kJ/mol. In summary, the preferred compound H-13 can be a potential third-generation EGFR inhibitor.

Keywords

Antitumor activity evaluation; Drug synthesis; EGFR inhibitor; Mobocertinib derivative; Non-small cell lung cancer; T790M mutation.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162602
    EGFR Inhibitor