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

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.

• Authors: Thang Cong Do, Jun Wei Lau, Caixia Sun, Songhan Liu, Khoa Tuan Kha, Seok Ting Lim, Yu Yang Oon, Yuet Ping Kwan, Jia Jia Ma, Yuguang Mu, Xiaogang Liu, Thomas James Carney, Xiaomeng Wang, Bengang Xing
• Journal: Science advances (Sci Adv) Vol. 8 Issue 50 Pg. eabq2216 (Dec 14 2022) ISSN: 2375-2548 [Electronic] United States
• PMID: 36516252 (Publication Type: Journal Article)