Exploration of novel four-membered-heterocycle constructed peptidyl proteasome inhibitors with improved metabolic stability for cancer treatment

Hanlin Wang; Zhaoxiao Wu; Yu Cao; Lixin Gao; Jiaan Shao; Yanmei Zhao; Jiankang Zhang; Yubo Zhou; Gang Wei; Jia Li; Huajian Zhu

doi:10.1016/j.bioorg.2023.106626

Exploration of novel four-membered-heterocycle constructed peptidyl proteasome inhibitors with improved metabolic stability for cancer treatment

Bioorg Chem. 2023 Sep:138:106626. doi: 10.1016/j.bioorg.2023.106626. Epub 2023 May 27.

Authors

Hanlin Wang¹, Zhaoxiao Wu², Yu Cao³, Lixin Gao⁴, Jiaan Shao², Yanmei Zhao³, Jiankang Zhang², Yubo Zhou⁵, Gang Wei⁶, Jia Li⁷, Huajian Zhu⁸

Affiliations

¹ School of Pharmacy, Fudan University, Shanghai 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
³ Department of pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science, Jiangnan University, Wuxi 214122, China.
⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁶ School of Pharmacy, Fudan University, Shanghai 210023, China. Electronic address: weigang@shmu.edu.cn.
⁷ School of Pharmacy, Fudan University, Shanghai 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: jli@simm.ac.cn.
⁸ Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: zhuhj@zucc.edu.cn.

PMID: 37295239
DOI: 10.1016/j.bioorg.2023.106626

Abstract

Peptides have limitations as active pharmaceutical agents due to rapid hydrolysis by proteases and poor cell permeability. To overcome these limitations, a series of peptidyl proteasome inhibitors embedded with four-membered heterocycles were designed to enhance their metabolic stabilities. All synthesized compounds were screened for their inhibitory activities against human 20S proteasome, and 12 target compounds displayed potent efficacy with IC₅₀ values lower than 20 nM. Additionally, these compounds exhibited strong anti-proliferative activities against multiple myeloma (MM) cell lines (MM1S: 72, IC₅₀ = 4.86 ± 1.34 nM; RPMI-8226: 67, IC₅₀ = 12.32 ± 1.44). Metabolic stability assessments of SGF, SIF, plasma and blood were conducted, and the representative compound 73 revealed long half-lives (Plasma: T_1/2 = 533 min; Blood: T_1/2 > 1000 min) and good proteasome inhibitory activity in vivo. These results suggest that compound 73 serve as a lead compound for the development of more novel proteasome inhibitors.

Keywords: Four-memberedheterocycles; Metabolic stability; Multiple myeloma; Proteasome inhibitors.

Publication types

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

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cell Proliferation
Drug Design
Humans
Neoplasms*
Proteasome Endopeptidase Complex / metabolism
Proteasome Inhibitors / chemistry
Proteasome Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Proteasome Inhibitors
Antineoplastic Agents
Proteasome Endopeptidase Complex