Proteolysis-targeting chimeras(PROTACs) achieve therapeutic effects by degrading disease-related proteins but face limitations due to off-target toxicity caused by poor spatial control.To address this,we developed a n...Proteolysis-targeting chimeras(PROTACs) achieve therapeutic effects by degrading disease-related proteins but face limitations due to off-target toxicity caused by poor spatial control.To address this,we developed a near-infrared(NIR)-activated photocaged PROTAC platform that enables precise molecular spatiotemporal control over protein degradation.Two degraders targeting oncology-relevant proteins,breakpoint cluster region gene-abelson gene(BCR-ABL) and bromodomain-containing protein 4(BRD4),showed light-dependent activation.NIR irradiation induced efficient target degradation(>70%) in cancer models,considerably improving therapeutic outcomes and reducing metastatic behavior.In animal studies,NIR-activated degraders demonstrated strong tumor suppression without detectable toxicity,outperforming light-restricted controls.Overall,this platform provides spatiotemporally controlled protein degradation with enhanced tissue penetration,offering a promising approach to reduce off-target effects in precision oncology.展开更多
基金supported by the National Key R&D Program of China (2023YFA0915300)the National Natural Science Foundation of China (22277073,22077078,22477075)+3 种基金the Shanghai Pilot Program for Basic Research,Shanghai Jiao Tong University (21TQ1400224)Foundation of Muyuan Laboratory (118602240)Fundamental Research Funds for the Central University UniversitiesShanghai Jiao Tong University 2030 Initiative (WH510363003/003)。
文摘Proteolysis-targeting chimeras(PROTACs) achieve therapeutic effects by degrading disease-related proteins but face limitations due to off-target toxicity caused by poor spatial control.To address this,we developed a near-infrared(NIR)-activated photocaged PROTAC platform that enables precise molecular spatiotemporal control over protein degradation.Two degraders targeting oncology-relevant proteins,breakpoint cluster region gene-abelson gene(BCR-ABL) and bromodomain-containing protein 4(BRD4),showed light-dependent activation.NIR irradiation induced efficient target degradation(>70%) in cancer models,considerably improving therapeutic outcomes and reducing metastatic behavior.In animal studies,NIR-activated degraders demonstrated strong tumor suppression without detectable toxicity,outperforming light-restricted controls.Overall,this platform provides spatiotemporally controlled protein degradation with enhanced tissue penetration,offering a promising approach to reduce off-target effects in precision oncology.
