Discovery of pyrimidine-2,4-diamine analogues as efficiency anticancer drug by targeting GTSE1.
Bioorg Chem
; 151: 107700, 2024 Oct.
Article
in En
| MEDLINE
| ID: mdl-39128245
ABSTRACT
A series of pyrimidine-2,4-diamine analogues were designed and synthesized. Their anticancer activity and the underlying mechanism against colorectal cancer (CRC) HCT116 cells and non-small cell lung cancer (NSCLC) A549 cells were investigated. The results demonstrated that the active compound Y18 significantly inhibited cancer cell proliferation by inducing robust cell cycle arrest and cell senescence through the persistence of DNA damage. Additionally, Y18 exhibited significant inhibitory effects on the adhesion, migration and invasion of cancer cells in vitro. Mechanistically, Y18 achieved these anticancer activities by suppressing GTSE1 transcription and expression. Y18 also effectively inhibited tumor growth in vivo with minimal side effects. Furthermore, Y18 exhibited a suitable half-life and oral bioavailability (16.27%), with limited inhibitory activity on CYP isoforms. Taken together, these results suggested that Y18 could be a potential chemotherapeutic drug for cancer treatment, particularly in cases of GTSE1 overexpressed cancers.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrimidines
/
Drug Screening Assays, Antitumor
/
Cell Proliferation
/
Dose-Response Relationship, Drug
/
Antineoplastic Agents
Limits:
Animals
/
Humans
Language:
En
Journal:
Bioorg Chem
/
Bioorganic chem
/
Bioorganic chemistry
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
Estados Unidos