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- W4319986536 abstract "Targeted degradation of proteins by chimeric heterobifunctional degraders has emerged as a major drug discovery paradigm. Despite the increased interest in this approach, the criteria dictating target protein degradation by a degrader remain poorly understood, and potent target engagement by a degrader does not strongly correlate with target degradation. In this study, we present the biochemical characterization of an epidermal growth factor receptor (EGFR) degrader that potently binds both wild-type and mutant EGFR, but only degrades EGFR mutant variants. Mechanistic studies reveal that ternary complex half-life strongly correlates with processive ubiquitination with purified components and mutant-selective degradation in cells. We present cryoelectron microscopy and hydrogen-deuterium exchange mass spectroscopy data on wild-type and mutant EGFR ternary complexes, which demonstrate that potent target degradation can be achieved in the absence of stable compound-induced protein-protein interactions. These results highlight the importance of considering target conformation during degrader development as well as leveraging heterobifunctional ligand binding kinetics to achieve robust target degradation." @default.
- W4319986536 created "2023-02-11" @default.
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- W4319986536 date "2023-02-01" @default.
- W4319986536 modified "2023-10-14" @default.
- W4319986536 title "Ternary complex dissociation kinetics contribute to mutant-selective EGFR degradation" @default.
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- W4319986536 doi "https://doi.org/10.1016/j.chembiol.2023.01.007" @default.
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