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<p>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 (&gt;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.</p>

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Spatiotemporally controlled protein degradation via NIR-activatable PROTAC platform

  • 期刊论文

  • 发表日期：

    2025年11月13日

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  • Nan Wang,
  • Wei Cong,
  • Yurui Zhu,
  • Huaxing Shen,
  • Chao Liu,
  • Honggang Hu,
  • Man Pan

摘要

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.