Design and synthesis of proteolysis-targeting chimeras (PROTACs) as degraders of glutathione peroxidase 4.

Autor: Cai M; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China., Ma F; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China., Hu C; Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China., Li H; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China., Cao F; College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, China., Li Y; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China., Dong J; Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China. Electronic address: dongjy@ibmc.ac.cn., Qin JJ; Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China. Electronic address: jqin@ucas.ac.cn.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2023 Jul 15; Vol. 90, pp. 117352. Date of Electronic Publication: 2023 May 26.
DOI: 10.1016/j.bmc.2023.117352
Abstrakt: Ferroptosis is a new type of regulated, non-apoptotic cell death driven by iron-dependent phospholipid peroxidation. Inducing cell ferroptosis by inactivating glutathione peroxidase 4 (GPX4) has been considered as an effective cancer treatment strategy, but only few GPX4 inhibitors have been reported to date. Targeted protein degradation is receiving increasing attention in the discovery and development of therapeutic modality, particularly proteolysis targeting chimeras (PROTACs). Herein, we reported the design, synthesis, and evaluation of different types of GPX4-targeting PROTACs using ML162 derivatives and ligands for CRBN/VHL E3 ligases. Among them, CRBN-based PROTAC GDC-11 showed a relatively balanced biological profile in GPX4 degradation (degradation rate of 33% at 10 μM), cytotoxicity (IC 50  = 11.69 μM), and lipid peroxides accumulation (2-foldincreaserelatedtoDMSO), suggesting a typical characteristic of ferroptosis. In silico docking and quantum chemistry theoretical calculations provided a plausible explanation for the moderate degrading effect of these synthesized PROTACs. Overall, this work lays the foundation for subsequent studies of GPX4-targeting PROTACs, and further design and synthesis of GPX4-targeting degrader are currently in progress in our group, which will be reported in due course.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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