Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction.
We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a K(i) of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model.
Yu
Shanghai
S
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Qin
Dongguang
D
Shangary
Sanjeev
S
Chen
Jianyong
J
Wang
Guoping
G
Ding
Ke
K
McEachern
Donna
D
Qiu
Su
S
Nikolovska-Coleska
Zaneta
Z
Miller
Rebecca
R
Kang
Sanmao
S
Yang
Dajun
D
Wang
Shaomeng
S
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D015195:Drug Design; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D009025:Morpholines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013141:Spiro Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D007211:Indoles; C543589:MI-63 compound; D009025:Morpholines; D010879:Piperazines; D013141:Spiro Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2