Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction.
Potent, specific, non-peptide small-molecule inhibitors of the MDM2-p53 interaction were successfully designed. The most potent inhibitor (MI-63) has a K(i) value of 3 nM binding to MDM2 and greater than 10,000-fold selectivity over Bcl-2/Bcl-xL proteins. MI-63 is highly effective in activation of p53 function and in inhibition of cell growth in cancer cells with wild-type p53 status. MI-63 has excellent specificity over cancer cells with deleted p53 and shows a minimal toxicity to normal cells.
Ding
Ke
K
Department of Internal Medicine, Comprehensive Cancer Center, Life Sciences Institute, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, 48109, USA.
Lu
Yipin
Y
Nikolovska-Coleska
Zaneta
Z
Wang
Guoping
G
Qiu
Su
S
Shangary
Sanjeev
S
Gao
Wei
W
Qin
Dongguang
D
Stuckey
Jeanne
J
Krajewski
Krzysztof
K
Roller
Peter P
PP
Wang
Shaomeng
S
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D007211:Indoles; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2