Several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been developed and approved by Food and Drug Administration for the treatment of non-small-cell lung cancers, but their efficacy can be compromised by acquired drug resistance conferred by EGFR-mutant variants. Here, we described the discovery of a novel E3 ligase von Hippel-Lindau-recruiting EGFR degrader, MS39 (compound 6), and a first-in-class E3 ligase cereblon-recruiting EGFR degrader, MS154 (compound 10), using the proteolysis targeting chimera technology. These compounds potently induced the degradation of mutant but not wild-type EGFR in an E3 ligasedependent manner in cancer cell lines and effectively suppressed the growth of lung cancer cells
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.
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