4.8 Article

Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras

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SCIENCE ADVANCES
卷 8, 期 50, 页码 -

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AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abq2216

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资金

  1. Ministry of Education, Singapore (MOE) [RG6/20]
  2. Agency for Science, Technology and Research (A*STAR) [A1883c0011, A20E5c0090]
  3. National Natural Science Foundation of China (NSFC) [51929201]
  4. National Medical Research Council Singapore Large Collaborative Grant DYNAMO [NMRC/OFLCG/001/2017]
  5. National Medical Research Council Singapore Large Collaborative Grant TAAP [NMRC/OFLCG/004/2018]

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ENCTACs, by specifically degrading BET protein BRD4 and modulating hypoxic signaling, provide a precise treatment approach for cancer.
Epigenetic mediation through bromodomain and extraterminal (BET) proteins have progressively translated protein imbalance into effective cancer treatment. Perturbation of druggable BET proteins through proteolysis-targeting chimeras (PROTACs) has recently contributed to the discovery of effective therapeutics. Unfortunately, precise and microenvironment- activatable BET protein degradation content with promising tumor selectivity and pharmacological suitability remains elusive. Here, we present an enzyme-derived clicking PROTACs (ENCTACs) capable of orthogonally cross-linking two disparate small-molecule warhead ligands that recognize BET bromodomain-containing protein 4 (BRD4) protein and E3 ligase within tumors only upon hypoxia-induced activation of nitroreductase enzyme. This localized formation of heterobifunctional degraders promotes specific down-regulation of BRD4, which subsequently alters expression of epigenetic targets and, therefore, allows precise modulation of hypoxic signaling in live cells, zebrafish, and living mice with solid tumors. Our activation-feedback system demonstrates compelling superiorities and may enable the PROTAC technology with more flexible practicality and druggable potency for precision medicine in the near future.

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