Conditional PROTAC: Recent Strategies for Modulating Targeted Protein Degradation

Abstract

Proteolysis-targeting chimeras (PROTACs) have emerged as a promising technology for inducing targeted protein degradation by leveraging the intrinsic ubiquitin-proteasome system (UPS). While the potential druggability of PROTACs toward undruggable proteins has accelerated their rapid development and the wide-range of applications across diverse disease contexts, off-tissue effects and side-effects of PROTACs have recently received attentions to improve their efficacy. To address these issues, spatial or temporal target protein degradation by PROTACs has been spotlighted. In this review, we explore chemical strategies for modulating protein degradation in a cell type-specific (spatio-) and time-specific (temporal-) manner, thereby offering insights for expanding PROTAC applications to overcome the current limitations of target protein degradation strategy.

Keywords: PROTAC; Spatial PROTAC; Spatiotemporal PROTAC; Targeted Protein Degradation (TPD); Temporal PROTAC.

Figure 1

Conditional PROTACs. Overview of recent strategies for modulating targeted protein degradation. Conditional PROTACs are categorized into three parts. Spatial PROTACs utilize cellular abundant components or cell‐specific membrane receptors to induce cell type‐specific target protein degradation. Temporal PROTACs facilitate click chemistry to activate or quench the TPD at time‐specific manner. Spatiotemporal PROTACs is based on optical or sonodynamic control for precise degradation of target protein both spatial and temporal manners.

Figure 2

Spatial PROTACs. Overview of the mechanism of action for Spatial PROTACs and their applications. These applications include the modification of ligands by conjugating them with small molecules, monoclonal antibodies (mABs), and aptamers that target cancer‐associated membrane proteins. Spatial PROTACs can form nano‐spherical assemblies via specific assembly motifs, such as lipids or peptides conjugated to either the ligand for the POI or the E3 ligase ligand of the PROTAC. Tumor‐targeting motifs, such as folate, facilitate cell‐specific target degradation. Furthermore, various caging groups can be incorporated to conditionally activate the PROTACs in cells exhibiting elevated levels of reactive oxygen species (ROS) or glutathione (GSH), as well as in hypoxic states. Finally, tumor‐selective click reactions can be utilized, taking advantage of either elevated copper (Cu) levels or the overexpression of integrin within tumor tissues.

Figure 3

Temporal PROTACs. Overview of the mechanism of Temporal PROTACs. PROTACs can be conditionally activated through a linker connection via a click reaction between tetrazine and TCO. In contrast, PROTACs can be conditionally deactivated by the addition of a poly(amidoamine) dendrimer that contains a TCO motif, which can scavenge the PROTACs with a tetrazine motif.

Figure 4

Spatiotemporal PROTACs. Overview of the mechanism of Spatiotemporal PROTACs. The active form of PROTACs can be conditionally released from nanoparticles or caging groups upon exposure to external stimuli such as light, radiation, or ultrasound. Additionally, diazo bridges can be employed to reversibly activate or inactivate PROTAC function with different light sources.