Design, synthesis and biological evaluation of the tumor hypoxia-activated PROTACs bearing caged CRBN E3 ligase ligands

Weiyan Cheng; Shasha Li; Siyuan Han; Ruoyang Miao; Suhua Wang; Chunxia Liu; Han Wei; Xin Tian; Xiaojian Zhang

doi:10.1016/j.bmc.2023.117237

Design, synthesis and biological evaluation of the tumor hypoxia-activated PROTACs bearing caged CRBN E3 ligase ligands

Bioorg Med Chem. 2023 Mar 15:82:117237. doi: 10.1016/j.bmc.2023.117237. Epub 2023 Mar 8.

Authors

Weiyan Cheng¹, Shasha Li², Siyuan Han², Ruoyang Miao², Suhua Wang², Chunxia Liu², Han Wei², Xin Tian³, Xiaojian Zhang⁴

Affiliations

¹ Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China; Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. Electronic address: chengweiyancwy@126.com.
² Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China; Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
³ Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China; Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. Electronic address: tianx@zzu.edu.cn.
⁴ Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China; Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. Electronic address: firstpha@163.com.

PMID: 36906965
DOI: 10.1016/j.bmc.2023.117237

Abstract

Tumor hypoxia-activated proteolysis targeting chimeras (ha-PROTACs) 9 and 10 were designed and synthesized by incorporating the hypoxia-activated leaving group (1-methyl-2-nitro-1H-imidazol-5-yl)methyl or 4‑nitrobenzyl into the structure of the cereblon (CRBN) E3 ligand of an epidermal growth factor receptor 19 deletions (EGFR^Del19-based PROTAC 8. The in vitro protein degradation assay demonstrated that 9 and 10 could effectively and selectively degrade EGFR^Del19 in tumor hypoxia. Meanwhile, these two compounds showed higher potency in inhibiting cell viability and migration, as well as in promoting cells apoptosis in tumor hypoxia. Moreover, nitroreductase reductive activation assay indicated that prodrugs 9 and 10 could successfully release the active compound 8. This study confirmed the feasibility to develop ha-PROTACs to enhance the selectivity of PROTACs by caging CRBN E3 ligase ligand.

Keywords: Anticancer; CRBN E3 ligase ligand; EGFR; Hypoxia; PROTAC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ligands
Proteolysis
Proteolysis Targeting Chimera*
Tumor Hypoxia
Ubiquitin-Protein Ligases* / metabolism

Substances

Ubiquitin-Protein Ligases
Ligands
Proteolysis Targeting Chimera