Discovery of a nanomolar inhibitor of the human murine double minute 2 (MDM2)-p53 interaction through an integrated, virtual database screening strategy.
An integrated, virtual database screening strategy has led to 7-[anilino(phenyl)methyl]-2-methyl-8-quinolinol (4, NSC 66811) as a novel inhibitor of the murine double minute 2 (MDM2)-p53 interaction. This quinolinol binds to MDM2 with a Ki of 120 nM and activates p53 in cancer cells with a mechanism of action consistent with targeting the MDM2-p53 interaction. It mimics three p53 residues critical in the binding to MDM2 and represents a promising new class of non-peptide inhibitors of the MDM2-p53 interaction.
Lu
Yipin
Y
Comprehensive Cancer Center and Department of Medicinal Chemistry, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109, USA.
Nikolovska-Coleska
Zaneta
Z
Fang
Xueliang
X
Gao
Wei
W
Shangary
Sanjeev
S
Qiu
Su
S
Qin
Dongguang
D
Wang
Shaomeng
S
D000814:Aniline Compounds / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D045325:HCT116 Cells; D006801:Humans; D006912:Hydroxyquinolines / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D018716:Molecular Mimicry; D009154:Mutation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C512434:7-(anilino(phenyl)methyl)-2-methyl-8-quinolinol; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D006912:Hydroxyquinolines; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2