Development of hypoxia-activated PROTAC exerting a more potent effect in tumor hypoxia than in normoxia.

Abstract

Hypoxia is a hallmark of many solid tumors, and it causes the overexpression of a variety of proteins including the epidermal growth factor receptor (EGFR). Many antitumor prodrugs have been designed to target hypoxia. Here we report the identification of a kind of hypoxia-activated proteolysis targeting chimera (ha-PROTAC) by introducing the hypoxia-activated leaving group (1-methyl-2-nitro-1H-imidazol-5-yl)methyl or 4-nitrobenzyl into the structure of an EGFRDel19-based PROTAC. Among the obtained molecules, ha-PROTAC 13 exhibits a more potent degradation activity for EGFRDel19 in hypoxia than in normoxia in HCC4006 cells. This is the first example of identifying a PROTAC to selectively act on tumors utilizing the characteristic of tumor hypoxia and provides a new approach for PROTAC development.

• Authors: Weiyan Cheng, Shasha Li, Xueqian Wen, Siyuan Han, Suhua Wang, Han Wei, Zhizhen Song, Yueqin Wang, Xin Tian, Xiaojian Zhang
• Journal: Chemical communications (Cambridge, England) (Chem Commun (Camb)) Vol. 57 Issue 95 Pg. 12852-12855 (Nov 30 2021) ISSN: 1364-548X [Electronic] England
• PMID: 34788776 (Publication Type: Journal Article)

Chemical References

• Imidazoles
• Nitrobenzenes
• EGFR protein, human
• ErbB Receptors

Topics

• Drug Development
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Humans
• Imidazoles (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Nitrobenzenes (chemical synthesis, chemistry, pharmacology)
• Proteolysis (drug effects)
• Tumor Hypoxia (drug effects)