PROTACs are small molecules that facilitate targeted protein degradation by binding to two proteins simultaneously, one of them being an E3 ubiquitin ligase. In contrast with molecular glues like Thalidomide (not all of which facilitate protein degradation), these consist of discrete small molecular binders connected by a linker.
Details
- The most common E3 ligases are Cereblon, followed by DCAF15 and 14-3-3.
- The first Clinical trials started in 2019 against the estrogen receptor (ARV-471) and androgen receptor (ARV-110).
- Other variations
- AUTACs: autophagy-targeting chimeras, use a guanine derivative, recruit autophagy machinery
- ATTECs: Autophagosome-tethering compounds, links warhead to autophagy protein LC3
- LYTACs: lysosome-targeting chimeras, binds membrane-bound protein and extracellular domain of lysosome-shuttling receptor
- AbTACs: Antibody-based PROTACs, bispecific antibodies that also use lysosomal degradation pathway
This extensively cites Békés et al. (1)
1.
Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue. Nature Reviews Drug Discovery. 2022;21(3):181–200. Available from: https://doi.org/10.1038/s41573-021-00371-6