Discovery of novel EGFR-PROTACs capable of degradation of multiple EGFR-mutated proteins.

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  • Additional Information
    • Source:
      Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
    • Publication Information:
      Publication: Paris : Editions Scientifiques Elsevier
      Original Publication: Paris, S.E.C.T. [etc.]
    • Subject Terms:
      ErbB Receptors*/metabolism ; ErbB Receptors*/antagonists & inhibitors ; ErbB Receptors*/genetics ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/chemistry ; Antineoplastic Agents*/chemical synthesis ; Cell Proliferation*/drug effects ; Proteolysis*/drug effects ; Mutation*; Humans ; Animals ; Structure-Activity Relationship ; Drug Discovery ; Mice ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/chemical synthesis ; Drug Screening Assays, Antitumor ; Molecular Structure ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Lung Neoplasms/drug therapy ; Lung Neoplasms/pathology ; Lung Neoplasms/metabolism ; Mice, Nude ; Proteolysis Targeting Chimera
    • Abstract:
      Although three generations of Epidermal growth factor receptor (EGFR) - TK inhibitors have been approved for the treatment of Non-small-cell lung cancers (NSCLC), their clinical application is still largely hindered by acquired drug resistance mediated new EGFR mutations and side effects. The Proteolysis targeting chimera (PROTAC) technology has the potential to overcome acquired resistance from mutant EGFR through a novel mechanism of action. In this study, we developed the candidate degrader IV-3 by structural modifications of the lead compound 13, which exhibited limited antiproliferative activity against HCC-827 cells. Compared to compound 13, IV-3 exhibited remarkable anti-proliferative activity against HCC-827 cells, NCI-H1975 cells, and NCI-H1975-TM cells (IC 50  = 0.009 μM, 0.49 μM and 3.24 μM, respectively), as well as significantly inducing degradation of EGFR protein in these cell lines (DC 50  = 17.93 nM, 0.25 μM and 0.63 μM, respectively). Further investigations confirmed that IV-3 exhibited superior anti-tumor activity in all xenograft tumor models through the degradation of mutant EGFR protein. Moreover, IV-3 showed no inhibitory activity against A431 and A549 cells expressing wild-type EGFR, thereby eliminating potential toxic side effects emerging from wild-type EGFR inhibition. Overall, our study provides promising insights into EGFR-PROTACs as a potential therapeutic strategy against EGFR-acquired mutation.
      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.
      (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
    • Contributed Indexing:
      Keywords: EGFR; In vivo efficacy; PROTAC; Xenograft tumors
    • Accession Number:
      EC 2.7.10.1 (ErbB Receptors)
      0 (Antineoplastic Agents)
      EC 2.7.10.1 (EGFR protein, human)
      0 (Protein Kinase Inhibitors)
      0 (Proteolysis Targeting Chimera)
    • Publication Date:
      Date Created: 20240517 Date Completed: 20240525 Latest Revision: 20240531
    • Publication Date:
      20240531
    • Accession Number:
      10.1016/j.ejmech.2024.116489
    • Accession Number:
      38759458