Discovery of estrogen receptor α targeting caged hypoxia-responsive PROTACs with an inherent bicyclic skeleton for breast cancer treatment.

Abstract

In view of the potential off-target effects of antitumor drugs, including proteolysis targeting chimera (PROTAC), certain toxic effects may be caused in normal tissues. Herein, based on the characteristics of the tumor microenvironment, we reported the first estrogen receptor α (ERα) targeting hypoxia-responsive PROTACs in order to improve their safety in breast cancer treatment by introducing two hypoxia-activated groups, nitroimidazole and nitrobenzene, into the ER ligand or E3 ligand of an active PROTAC, which has certain cytotoxicity in normal cells. Bioactivity studies showed that these hypoxia-responsive PROTACs exhibited excellent hypoxic responsiveness and ERα degradation activity under hypoxic conditions, and thus improved the toxic effects of the active PROTAC in normal cells. It is expected that our caged compounds provide a new strategy for precise functional control of PROTAC drugs for breast cancer treatment.

• Authors: Baohua Xie, Bin Xu, Lilan Xin, Yizhou Wei, Xinyi Guo, Chune Dong
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 137 Pg. 106590 (08 2023) ISSN: 1090-2120 [Electronic] United States
• PMID: 37163809 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• Estrogen Receptor alpha
• Proteolysis Targeting Chimera
• Ligands

Topics

• Humans
• Female
• Breast Neoplasms (pathology)
• Estrogen Receptor alpha (metabolism)
• Proteolysis Targeting Chimera
• Ligands
• Hypoxia (drug therapy, metabolism)
• Skeleton (metabolism, pathology)
• Proteolysis
• Tumor Microenvironment