Article ; Online: Targeting EGFR degradation by autophagosome degraders.
European journal of medicinal chemistry
2024 Volume 270, Page(s) 116345
Abstract: Several generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been developed for the treatment of non-small cell lung cancer (NSCLC) in clinic. However, emerging drug resistance mediated by new EGFR mutations or ... ...
| Abstract | Several generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been developed for the treatment of non-small cell lung cancer (NSCLC) in clinic. However, emerging drug resistance mediated by new EGFR mutations or activations by pass, leads to malignant progression of NSCLC. Proteolysis targeting chimeras (PROTACs) have been utilized to overcome the drug resistance acquired by mutant EGFR, newly potent and selective degraders are still need to be developed for clinical applications. Herein, we developed autophagosome-tethering compounds (ATTECs) in which EGFR can be anchored to microtubule-associated protein-1 light chain-3B (LC3B) on the autophagosome with the assistance of the LC3 ligand GW5074. A series of EGFR-ATTECs have been designed and synthesized. Biological evaluations showed that these compounds could degrade EGFR and exhibited moderate inhibitory effects on certain NSCLC cell lines. The ATTEC 12c potently induced the degradation of EGFR with a DC |
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| MeSH term(s) | Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/pathology ; Lung Neoplasms/pathology ; Cell Proliferation ; Autophagosomes/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Cell Line, Tumor ; ErbB Receptors ; Mutation ; Drug Resistance, Neoplasm |
| Chemical Substances | Protein Kinase Inhibitors ; ErbB Receptors (EC 2.7.10.1) ; EGFR protein, human (EC 2.7.10.1) |
| Language | English |
| Publishing date | 2024-03-26 |
| Publishing country | France |
| Document type | Journal Article |
| ZDB-ID | 188597-2 |
| ISSN | 1768-3254 ; 0009-4374 ; 0223-5234 |
| ISSN (online) | 1768-3254 |
| ISSN | 0009-4374 ; 0223-5234 |
| DOI | 10.1016/j.ejmech.2024.116345 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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