Will and Manfred’s review on the present and future of PROTACs for cancer therapy is now out in Current Opinion in Pharmacology
Authors: William Farnaby*, Manfred Koegl*, Darryl B. McConnell, Alessio Ciulli
Title: Transforming targeted cancer therapy with PROTACs: A forward-looking perspective
Highlights:
- Targeted protein degradation approaches can address key cancer therapy challenges.
- Previously undrugged, genetically validated targets can be prosecuted with PROTACs.
- PROTACs can address some known drug resistance mechanisms but may have their own.
- Target selectivity well beyond that achievable with inhibitors is possible.
- Tissue specificity due to differential E3 ligase activity holds much promise.
Abstract
Small-molecule targeted protein degraders have in recent years made a great impact on the strategies of many industry and academic cancer research endeavours. We seek here to provide a concise perspective on the opportunities and challenges that lie ahead for bifunctional degrader molecules, so-called ‘Proteolysis Targeting Chimeras (PROTACs),’ in the context of cancer therapy. We highlight high-profile studies that support the potential for PROTAC approaches to broaden drug target scope, address drug resistance, enhance target selectivity and provide tissue specificity, but also assess where the modality is yet to fully deliver in these contexts. Future opportunities presented by the unique bifunctional nature of these molecules are also discussed.