Radiotherapy-Triggered Proteolysis Targeting Chimera Prodrug Activation in Tumors.
Chunrong YangYuchen YangYujie LiQiankun NiJinghong LiPublished in: Journal of the American Chemical Society (2022)
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.
Keyphrases
- cancer therapy
- early stage
- radiation induced
- high resolution
- protein protein
- drug delivery
- amino acid
- clinical practice
- radiation therapy
- locally advanced
- squamous cell carcinoma
- binding protein
- oxidative stress
- small molecule
- drug release
- computed tomography
- magnetic resonance imaging
- magnetic resonance
- rectal cancer
- climate change
- human health