EGFR L858R (including T790M/C797S resistant mutants)

Class

Targeted protein degrader (BiDAC bifunctional degrader)

Pathway

TORPEDO platform-designed degrader that induces ubiquitin-proteasome degradation of mutant EGFR L858R while sparing wild-type EGFR

EGFR (epidermal growth factor receptor) is a receptor tyrosine kinase that, upon growth-factor binding, dimerizes and activates downstream RAS-MAPK and PI3K-AKT signaling that drives cell proliferation and survival. Certain mutations found in non-small cell lung cancer, such as L858R, lock the kinase into a constitutively active state independent of ligand, making the receptor an oncogenic driver. Small-molecule kinase inhibitors have long targeted its ATP-binding pocket, but tumors often acquire secondary mutations, such as T790M or C797S, that reshape this pocket and disrupt inhibitor binding, particularly for covalent inhibitors that depend on a specific cysteine residue, restoring signaling and driving relapse. An alternative strategy is targeted protein degradation, using bifunctional degrader molecules that link a mutant-EGFR-binding moiety to a segment recruiting a cellular E3 ubiquitin ligase, marking the mutant receptor for destruction through the ubiquitin-proteasome system. Because this approach removes the receptor entirely rather than only blocking its catalytic activity, it can act even against mutants that evade conventional inhibitor binding. Designing selectivity for mutant over wild-type EGFR is important, since wild-type EGFR performs essential physiological roles in tissues such as skin and gut, and its unwanted degradation could produce on-target toxicity.