PUBLICATION

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

Authors
Do, T.C., Lau, J.W., Sun, C., Liu, S., Kha, K.T., Lim, S.T., Oon, Y.Y., Kwan, Y.P., Ma, J.J., Mu, Y., Liu, X., Carney, T.J., Wang, X., Xing, B.
ID
ZDB-PUB-221216-13
Date
2022
Source
Science advances   8: eabq2216eabq2216 (Journal)
Registered Authors
Keywords
none
MeSH Terms
none
PubMed
36516252 Full text @ Sci Adv
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.
Genes / Markers
Marker Marker Type Name
vhlGENEvon Hippel-Lindau tumor suppressor
1 - 1 of 1
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Figures
Figure Gallery (8 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hu2117
    		Point Mutation
    y1TgTransgenic Insertion
      1 - 2 of 2
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      Human Disease / Model
      No data available
      Sequence Targeting Reagents
      No data available
      Fish
      No data available
      Antibodies
      Name Type Antigen Genes Isotypes Host Organism
      Ab3-hif1apolyclonal
        		IgGRabbit
        1 - 1 of 1
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        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        EGFPEFGEGFP
        1 - 1 of 1
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        Mapping
        No data available
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        Citation
        Do, T.C., Lau, J.W., Sun, C., Liu, S., Kha, K.T., Lim, S.T., Oon, Y.Y., Kwan, Y.P., Ma, J.J., Mu, Y., Liu, X., Carney, T.J., Wang, X., Xing, B. (2022) Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras. Science advances. 8:eabq2216eabq2216.