6-Regioisomeric 5,8-quinolinediones as potent CDC25 inhibitors against colorectal cancers.
Eur J Med Chem
; 258: 115505, 2023 Oct 05.
Article
em En
| MEDLINE
| ID: mdl-37302341
ABSTRACT
Precise and accurate control of cell cycle progression is required to maintain cell identity and proliferation. Failing to keep it will lead to genome instability and tumorigenesis. Cell Division Cycle 25 (CDC25) phosphatases are the key to regulating the activity of the master cell cycle controller, cyclin-dependent kinases (CDKs). Dysregulation of CDC25 has been shown to associate with several human malignancies. Here, we reported a series of derivatives of the CDC25 inhibitor, NSC663284, bearing quinones as core scaffolds and morpholin alkylamino side chains. Among these derivatives, the cytotoxic activity of the 6-isomer of 5,8-quinolinedione derivatives (6b, 16b, 17b, and 18b) displayed higher potency against colorectal cancer (CRC) cells. Compound 6b possessed the most antiproliferative activity, with IC50 values of 0.59 µM (DLD1) and 0.44 µM (HCT116). The treatment of compound 6b resulted in a remarkable effect on cell cycle progression, blocking S-phase progression in DLD1 cells straight away while slowing S-phase progression and accumulated cells in the G2/M phase in HCT116 cells. Furthermore, we showed that compound 6b inhibited CDK1 dephosphorylation and H4K20 methylation in cells. The treatment with compound 6b induced DNA damage and triggered apoptosis. Our study identifies compound 6b as a potent CDC25 inhibitor that induces genome instability and kills cancer cells through an apoptotic pathway, deserving further investigation to fulfill its candidacy as an anti-CRC agent.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
/
Fosfatases cdc25
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article