Light-mediated multi-target protein degradation using photoswitching

A collaborative project, led by Tate group, has combined PROTAC technology with light-activatable control to achieve protein degradation

PROteolysis-TArgeting Chimeras (PROTACs) are molecules which are able to bind to a protein of interest (POI) and lead to its degradation. By linking an E3 ligase ligand and a POI binder, PROTACs allow the formation of an E3 ligase/PROTAC/POI ternary complex which drives proximity-induced POI ubiquitination and subsequent degradation.

While many oncogenic protein targets have been successfully degraded by PROTACs, thereby showing their potential as a novel therapeutic modality for drug discovery, spatiotemporal control of protein degradation with light remains less explored, with only a few examples to date.

Our publication in Chem. Commun. reports a new class of photoswitchable PROTAC incorporating a novel arylazopyrazole photoswitch (AP-PROTACs) featuring differentiated photoswitching properties, and the first example of non-azobenzene PHOTAC technology. With a bromodomain (BRD) ligand (AP-PROTAC-1) or a multi-kinase inhibitor (AP-PROTAC-2) as the PROTAC warhead, light-switchable degradation of multiple proteins was achieved. In particular, it demonstrates the first example of light-tuneable degradation of multiple specific protein kinases using a broad-spectrum kinase inhibitor as the POI ligand.

A huge thanks to Prof. Matt Fuchter, Dr Dima Kozakov, GSK, and everyone in their teams for the valuable input and funding for this research project.