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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z