Radiotherapy-Triggered Proteolysis Targeting Chimera Prodrug Activation in Tumors

Abstract

Proteolysis targeting chimera (PROTAC) is an emerging protein degradation strategy, which shows excellent advantages in targeting those so-called “undruggable” proteins. However, the potential systemic toxicity of PROTACs caused by undesired off-tissue protein degradation may limit the application of PROTACs in clinical practice. Here we reported a radiotherapy-triggered PROTAC prodrug (RT-PROTAC) activation strategy to precisely and spatiotemporally control protein degradation through X-ray radiation. We demonstrated this concept by incorporating an X-ray inducible phenyl azide-cage to a bromodomain (BRD)-targeting PROTAC to form the first RT-PROTAC. The RT-PROTAC prodrug exhibits little activity but can be activated by X-ray radiation in vitro and in vivo. Activated RT-PROTAC degrades BRD4 and BRD2 with a comparable effect to the PROTAC degrader and shows a synergistic antitumor potency with radiotherapy in the MCF-7 xenograft model. Our work provides an alternative strategy to spatiotemporally control protein degradation in vivo and points to an avenue for reducing the undesired systemic toxicity of PROTACs.

Recent Advances in Pro-PROTAC Development to Address On-Target Off-Tumor Toxicity

“…In a proof-of-concept study, Yang et al developed a radiotherapy-triggered PROTAC (RT-PROTAC). 50 Replacement of the hydroxyl group in the VHL moiety of active PROTAC with an X-ray-inducible phenyl azide cage masked protein degradation. Upon X-ray radiation, the phenyl azide group on RT-PROTAC 31 (Figure 7A) was reduced to aniline, triggering subsequent 1,6-benzyl elimination and decarboxylation.…”

Emerging TACnology: Heterobifunctional Small Molecule Inducers of Targeted Posttranslational Protein Modifications

“…These general limitations could be overcome by improving the spectral properties of photo-responsive groups to absorb in the near-IR region. In a very recent study, a caged BET-PROTAC was developed to be responsive to X-ray radiation [ 34 ], which has a high precision and deep tissue penetration. In a xenograft mouse model, X-ray radiation not only served as a stimulus to release the active PROTAC and control BET degradation spatiotemporally but also synergistically suppressed tumor growth [ 34 ].…”

“…In a very recent study, a caged BET-PROTAC was developed to be responsive to X-ray radiation [ 34 ], which has a high precision and deep tissue penetration. In a xenograft mouse model, X-ray radiation not only served as a stimulus to release the active PROTAC and control BET degradation spatiotemporally but also synergistically suppressed tumor growth [ 34 ]. However, it has yet to be demonstrated in vivo that such radiotherapy-triggered PROTACs can avoid systemic toxicity caused by off-tissue POI degradation.…”

Self-Assembled Nano-PROTAC Enables Near-Infrared Photodynamic Proteolysis for Cancer Therapy

“…To reduce off-tumor side effects, tumor-targeted PROTACs have been developed through the integration of tumor-homing moieties. − Alternatively, stimuli-activatable PROTAC, which remains inactive until exposure to a certain trigger at tumor sites to regain its proteolytic activity, offers a practical way to manipulate the degradation process. ,, Apart from endogenous biomarker stimuli such as tumor-localized reductive species − and enzymes − or the external X-ray stimulus, light is particularly attractive for PROTAC regulation because of its safety and high spatiotemporal resolution. , Photo-caged − and photo-switchable − PROTACs that, respectively, employ photocleavable and photoisomerization groups to temporarily mask the proteolytic activity have recently been developed. These photoactivatable PROTACs show enormous promises in optical control of targeted protein degradation in living cells.…”