Conformational Dynamics and Binding Kinetics Drive Mutant Selective Degradation of EGFR

Targeted degradation of proteins by chimeric chemical inducers of degradation (CIDEs) has emerged as a major drug discovery paradigm. Despite the increased interest in this approach, the criteria dictating target protein degradation by a CIDE remain poorly understood, and potent target engagement by a CIDE does not strongly correlate with target degradation. In this study, we present the biochemical characterization of an EGFR mutant-selective degrader that potently binds to wildtype and mutant EGFR but only degrades EGFR mutant variants. Mechanistic studies reveal that ternary complex half-life is the primary determinant driving mutant-selective degradation. We present a cryo-EM structure of a CRL2VHL:CIDE:EGFR complex and show that potent target degradation can be achieved in the absence of CIDE-induced protein-protein interactions. These results highlight the importance of considering target conformation during CIDE development as well as leveraging ligand binding kinetics to achieve robust target degradation.