Targeted protein degradation has garnered increasing attention by industry and academia alike in recent years as a modality to address challenges in both drug discovery and chemical biology. In order to efficiently translate the opportunities offered by Proteolysis Targeting Chimeras within this sphere, hurdles must be overcome to rationalise what has to date been a largely empirical design process. A PROTAC drug discovery collaboration between the University of Dundee and Boehringer Ingelheim is seeking to address this <i>via</i> structure based PROTAC design and the use of novel biophysical approaches recently disclosed. We detail how prioritizing and designing degraders based on their ability to induce stable complexes between the E3 ligase and the target is broadly applicable. We exemplify this with a case study detailing the targeted degradation of SMARCA2 and SMARCA4. These BAF complex ATPases are high profile, undrugged proteins that represent a synthetic lethality based therapeutic strategy for treating cancer.

Structure-based approaches to enable PROTAC drug discovery

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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