Photopharmacology of Proteolysis-Targeting Chimeras: A New Frontier for Drug Discovery

Abstract

Photopharmacology is an emerging field that uses light to precisely control drug activity. This strategy promises to improve drug specificity for reducing off-target effects. Proteolysis-targeting chimeras (PROTACs) are an advanced technology engineered to degrade pathogenic proteins through the ubiquitin-proteasome system for disease treatment. This approach has the potential to target the undruggable proteome via event-driven pharmacology. Recently, the combination strategy of photopharmacology and PROTACs has gained tremendous momentum for its use in the discovery and development of new therapies. This review systematically focuses on PROTAC-based photopharmacology. Herein, we provide an overview of the new and vibrant research on photoPROTACs, discuss the advantages and disadvantages of this approach as a biological tool, and outline the challenges it faces in a clinical setting.

Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy

“…Furthermore, opto-PROTACs were developed for ultraviolet light-inducible protein degradation 23 , 24 . These photoactivatable PROTACs have been demonstrated to spatiotemporally control protein degradation in vitro 25 – 27 . However, clinical translation of opto-PROTACs is restricted by the poor tissue penetration profile of ultraviolet light with short wavelength (e.g., 360 nm).…”

Target and tissue selectivity of PROTAC degraders

“…However, due to the light-dependent conversion of the photoswitchable linker as the key to ps-PROTAC activity, efficient light-delivery to cells and tissues will be an important consideration. 112 Expanding the repertoire of photosensitive moieties for both pc-PROTACs and ps-PROTACs may improve this technology to further drug development.…”

Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies

“…There is a need for the discovery of new PROTAC E3 ligases with a specific expression profile, based on targeted protein expression depending on the tumor type, cellular compartment, or current cell condition. Moreover, newer generations of PROTACs might even be activated by light (photoPROTACs, PHOTACs) [ 118 ]. Other PROTACs act on the activation of the tyrosine kinase receptors and their subsequent phosphorylation (phosphoPROTACs) [ 119 ].…”

“…Protein degradation can be prompted by an unfolded protein response via the UPS. One of the reasons might be the hydrophobicity of the protein surface, and hydrophobic tagging of proteins is another strategy used for targeted protein degradation [ 118 ]. Ma et al used this approach to target and deplete EZH2 histone methyltransferase [ 143 ].…”