Exploring Degradation of Mutant and Wild-Type Epidermal Growth Factor Receptors Induced by Proteolysis-Targeting Chimeras

Xufen Yu, Meng Cheng, Kaylene Lu, Yudao Shen, Yue Zhong, Jing Liu, Yue Xiong, Jian Jin

Research output: Contribution to journalArticlepeer-review

Abstract

Several epidermal growth factor receptor (EGFR) proteolysis-targeting chimeras (PROTACs), including MS39 and MS154 developed by us, have been reported to effectively degrade the mutant but not the wild-type (WT) EGFR. However, the mechanism underlying the selectivity in degrading the mutant over the WT EGFR has not been elucidated. Here, we report comprehensive structure-activity relationship studies that led to the discovery of two novel EGFR degraders, 31 (MS9449) and 72 (MS9427), and mechanistic studies of these EGFR degraders. Compounds 31 and 72 selectively degraded the mutant but not the WT EGFR through both ubiquitination/proteasome and autophagy/lysosome pathways. Interestingly, we found that the mutant but not the WT EGFR can effectively form EGFR-PROTAC-E3 ligase ternary complexes. Furthermore, we found that PI3K inhibition sensitized WT EGFR to PROTAC-induced degradation and combination treatment with a PI3K inhibitor enhanced antiproliferation activities of EGFR degraders in cancer cells harboring WT EGFR, providing a potential therapeutic strategy for patients with WT EGFR overexpression.

Original languageEnglish
Pages (from-to)8416-8443
Number of pages28
JournalJournal of Medicinal Chemistry
Volume65
Issue number12
DOIs
StatePublished - 23 Jun 2022

Fingerprint

Dive into the research topics of 'Exploring Degradation of Mutant and Wild-Type Epidermal Growth Factor Receptors Induced by Proteolysis-Targeting Chimeras'. Together they form a unique fingerprint.

Cite this