2. Academic Validation
  3. Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras

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

  • Sci Adv. 2022 Dec 14;8(50):eabq2216. doi: 10.1126/sciadv.abq2216.
Thang Cong Do 1,  Jun Wei Lau 1 2,  Caixia Sun 1,  Songhan Liu 1,  Khoa Tuan Kha 1,  Seok Ting Lim 3 4,  Yu Yang Oon 5,  Yuet Ping Kwan 3 4,  Jia Jia Ma 6,  Yuguang Mu 5,  Xiaogang Liu 2,  Thomas James Carney 6,  Xiaomeng Wang 3 4 7,  Bengang Xing 1 8
Affiliations

Affiliations

  • 1 Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore.
  • 2 Department of Chemistry, National University of Singapore, Singapore 117543, Singapore.
  • 3 Duke-NUS Medical School, Singapore 169857, Singapore.
  • 4 Singapore Eye Research Institute, Singapore 169856, Singapore.
  • 5 School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
  • 6 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore.
  • 7 Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore.
  • 8 School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 637371, Singapore.
PMID: 36516252 DOI: 10.1126/sciadv.abq2216
Abstract

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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