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7401749 
Journal Article 
Targeted protein degradation: expanding the toolbox 
Schapira, M; Calabrese, MF; Bullock, AN; Crews, CM 
2019 
1 
Nature Reviews. Drug Discovery
ISSN: 1474-1776
EISSN: 1474-1784 
18 
12 
949-963 
English 
31666732 
WOS:000499643000015 
Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin-proteasome system represent a new therapeutic modality and are the focus of great interest, owing to potential advantages over traditional occupancy-based inhibitors with respect to dosing, side effects, drug resistance and modulating 'undruggable' targets. However, the technology is still maturing, and the design elements for successful PROTAC-based drugs are currently being elucidated. Importantly, fewer than 10 of the more than 600 E3 ubiquitin ligases have so far been exploited for targeted protein degradation, and expansion of knowledge in this area is a key opportunity. Here, we briefly discuss lessons learned about targeted protein degradation in chemical biology and drug discovery and systematically review the expression profile, domain architecture and chemical tractability of human E3 ligases that could expand the toolbox for PROTAC discovery.