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Design, synthesis, and evaluation of antitumor activity of Mobocertinib derivatives, a third-generation EGFR inhibitor.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2024 Jun; Vol. 147, pp. 107390. Date of Electronic Publication: 2024 Apr 22. - Publication Year :
- 2024
-
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 EGFR <superscript>T790M</superscript> 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 IC <subscript>50</subscript> of compound H-13 against EGFR <superscript>L858R/T790M</superscript> mutated H1975 cells was 3.91 μM, and in further kinase activity evaluation, the IC <subscript>50</subscript> of H-13 against EGFR <superscript>L858R/T790M</superscript> 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.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Structure-Activity Relationship
Molecular Structure
Animals
Mice
Mice, Nude
Cell Line, Tumor
Neoplasms, Experimental drug therapy
Neoplasms, Experimental pathology
Neoplasms, Experimental metabolism
ErbB Receptors antagonists & inhibitors
ErbB Receptors metabolism
Antineoplastic Agents pharmacology
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Drug Design
Cell Proliferation drug effects
Drug Screening Assays, Antitumor
Apoptosis drug effects
Dose-Response Relationship, Drug
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 147
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38691904
- Full Text :
- https://doi.org/10.1016/j.bioorg.2024.107390