Abstract
The epidermal growth factor receptor (EGFR) tertiary C797S mutation is an important cause of resistance to Osimertinib, which seriously hinders the clinical application of Osimertinib. Developing proteolysis-targeting chimeras (PROTACs) targeting EGFR mutants can offer a promising strategy to overcome drug resistance. In this study, some novel PROTACs targeting C797S mutation were designed and synthesized based on a new EGFR inhibitor and displayed a potent degradation effect in H1975-TM cells harboring EGFRL858R/T790M/C797S. The representative compound C6 exhibited a DC50 of 10.2 nM against EGFRL858R/T790M/C797S and an IC50 of 10.3 nM against H1975-TM. Furthermore, C6 also showed potent degradation activity against various main EGFR mutants, including EGFRDel19/T790M/C797S. Mechanistic studies revealed that the protein degradation was achieved through the ubiquitin-proteasome system. Finally, C6 inhibited tumor growth in the H1975-TM xenograft tumor model effectively and safely. This study identifies a novel and potent EGFR PROTAC to overcome Osimertinib resistance mediated by C797S mutation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylamides / chemical synthesis
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Acrylamides / chemistry
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Acrylamides / pharmacology
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Aniline Compounds / chemical synthesis
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Aniline Compounds / chemistry
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Aniline Compounds / pharmacology
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Animals
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Antineoplastic Agents* / chemical synthesis
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Antineoplastic Agents* / chemistry
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Antineoplastic Agents* / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Design*
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Drug Resistance, Neoplasm / drug effects
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ErbB Receptors* / antagonists & inhibitors
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ErbB Receptors* / genetics
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ErbB Receptors* / metabolism
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Humans
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Indoles
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mutation*
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Protein Kinase Inhibitors* / chemical synthesis
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Protein Kinase Inhibitors* / chemistry
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Protein Kinase Inhibitors* / pharmacology
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Proteolysis Targeting Chimera
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Proteolysis* / drug effects
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Pyrimidines
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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ErbB Receptors
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EGFR protein, human
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Acrylamides
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osimertinib
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Aniline Compounds
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Proteolysis Targeting Chimera
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Indoles
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Pyrimidines