The Discovery of Potential MDM2 Inhibitors: A Combination of Pharmacophore Modeling, Virtual Screening, Molecular Docking Studies, and inâ
vitro/inâ
vivo Biological Evaluation.
ChemMedChem
; 17(4): e202100517, 2022 02 16.
Article
in En
| MEDLINE
| ID: mdl-34806333
ABSTRACT
Small-molecule inhibitors of MDM2 that block the MDM2-p53 protein-protein interaction have been considered as potential therapeutic agents for the treatment of cancer. Here, we identify five highly potent inhibitors of MDM2 (termed as WY 1-5) that display significant inhibitory effects on MDM2-p53 interaction by using a combined strategy of pharmacophore modeling, virtual screening, and molecular docking studies. Among them, WY-5 is the most active MDM2 inhibitor with an IC50 value of 14.1±2.8â
nM. Moreover, WY-5 significantly up-regulate the protein level of p53 in SK-Hep-1 cells harboring wild-type p53. In vitro anticancer study reveals that WY-5 markedly inhibits the survival of SK-Hep-1 cells. In vivo anticancer study suggests that WY-5 significantly inhibits the growth of SK-Hep-1 cells-derived xenograft in nude mice, with no observable toxicity. Our results demonstrate that WY-5 may be a promising candidate for the treatment of cancer harboring wild-type p53.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Proto-Oncogene Proteins c-mdm2
/
Drug Discovery
/
Antineoplastic Agents
Type of study:
Diagnostic_studies
/
Screening_studies
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
ChemMedChem
Journal subject:
FARMACOLOGIA
/
QUIMICA
Year:
2022
Document type:
Article
Affiliation country: