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Title | Ternary complex dissociation kinetics contribute to mutant-selective EGFR degradation. |
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Journal, issue, pages | Cell Chem Biol, Year 2023 |
Publish date | Feb 8, 2023 |
Authors | Scott C Rosenberg / Frances Shanahan / Sayumi Yamazoe / Marc Kschonsak / Yi J Zeng / James Lee / Emile Plise / Ivana Yen / Christopher M Rose / John G Quinn / Lewis J Gazzard / Benjamin T Walters / Donald S Kirkpatrick / Steven T Staben / Scott A Foster / Shiva Malek / |
PubMed 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 ...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. |
External links | Cell Chem Biol / PubMed:36773603 |
Methods | EM (single particle) |
Resolution | 6.2 Å |
Structure data | EMDB-29101: EGFR:Degrader:VHL:Elongin-B/C:Cul2 |
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