Discovery of novel indolin-2-one compounds as potent inhibitors of HsClpP for cancer treatment.

Abstract

Human caseinolytic protease proteolytic subunit (HsClpP) is a highly conserved serine protease that plays an essential role in cell homeostasis through removal of the damaged and/or misfolded proteins. Recently, due to its critical role in cancer proliferation and metastasis, HsClpP has been considered as a promising target for the cancer treatment. In this paper, through a random screening toward a library of 2086 bioactive chemicals, a novel compound I, 3-(3,5-dibromo-4-hydroxybenzylidene) -5-iodoindolin-2-one, was identified as a potent suppressor of HsClpP. Herein, a series of compound I derivatives were synthesized, and evaluated for their anti-cancer activities on a variety of cancers cells. Through the preliminary biological assay in vitro, including MTT assay and proteolytic activity assay, compound I was identified as the most potent inhibitor. Treatment with compound I impaired the migration of Hela cells. In addition, compound I disrupted the mitochondrial function, and reduced the level of the SDHB and induced the production of the ATF4. In general, compound I is a promising probe of HsClpP for cancer treatment, and is a good lead compound for the development of novel anti-cancer agent.

• Authors: Rao Song, Yang Yang, Jiasheng Huang, Wenliang Qiao, Baozhu Luo, Yuan Ju, Tao Yang, Youfu Luo
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 110 Pg. 104820 (05 2021) ISSN: 1090-2120 [Electronic] United States
• PMID: 33773224 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Indoles
• Protease Inhibitors
• indolin-2-one
• Peptide Hydrolases

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Discovery
• Drug Screening Assays, Antitumor
• Humans
• Indoles (chemical synthesis, chemistry, pharmacology)
• Molecular Docking Simulation
• Molecular Structure
• Peptide Hydrolases (metabolism)
• Protease Inhibitors (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured