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Discovery of novel indolin-2-one compounds as potent inhibitors of HsClpP for cancer treatment
- Source :
- Bioorganic Chemistry. 110:104820
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
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.
- Subjects :
- Indoles
medicine.medical_treatment
Antineoplastic Agents
01 natural sciences
Biochemistry
Metastasis
HeLa
Structure-Activity Relationship
chemistry.chemical_compound
Cell Movement
Drug Discovery
Tumor Cells, Cultured
medicine
Humans
Protease Inhibitors
MTT assay
Molecular Biology
Cell Proliferation
Serine protease
Protease
Dose-Response Relationship, Drug
Molecular Structure
biology
010405 organic chemistry
Organic Chemistry
Cancer
medicine.disease
biology.organism_classification
In vitro
0104 chemical sciences
Molecular Docking Simulation
010404 medicinal & biomolecular chemistry
chemistry
biology.protein
Drug Screening Assays, Antitumor
Lead compound
Peptide Hydrolases
Subjects
Details
- ISSN :
- 00452068
- Volume :
- 110
- Database :
- OpenAIRE
- Journal :
- Bioorganic Chemistry
- Accession number :
- edsair.doi.dedup.....6d74bd183cbafa852d792569e13f4e64