Chimeric protein degraders (ProDegs, PROTACs) exert their efficacy by simultaneously binding an E3 ligase and a protein target of interest. This necessary first step results in protein target polyubiquitination and subsequent proteasome-mediated degradation. Compound optimization typically involves identifying a target binder and an E3 ligase binder and connecting the two pieces by varying linkers. Potent and selective degradation of various proteins have been reported in the literature and demonstrated in vivo. Recent structural studies of ternary complexes attempt to provide a detailed understanding of the molecular mechanism of action. This presentation will introduce this novel modality, summarize the state of the art in the field, and identify challenges and opportunities for computational modeling in this space with some specific case studies.

Protein degradation: Hijacking the ubiquitin-proteasome system

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.