Structure-based design of potent non-peptide MDM2 inhibitors.
A successful structure-based design of a class of non-peptide small-molecule MDM2 inhibitors targeting the p53-MDM2 protein-protein interaction is reported. The most potent compound 1d binds to MDM2 protein with a Ki value of 86 nM and is 18 times more potent than a natural p53 peptide (residues 16-27). Compound 1d is potent in inhibition of cell growth in LNCaP prostate cancer cells with wild-type p53 and shows only a weak activity in PC-3 prostate cancer cells with a deleted p53. Importantly, 1d has a minimal toxicity to normal prostate epithelial cells. Our studies provide a convincing example that structure-based strategy can be employed to design highly potent, non-peptide, cell-permeable, small-molecule inhibitors to target protein-protein interaction, which remains a very challenging area in chemical biology and drug design.
Ding
Ke
K
Departments of Internal Medicine and Medicinal Chemistry and Comprehensive Cancer Center, and Life Sciences Institute, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA.
Lu
Yipin
Y
Nikolovska-Coleska
Zaneta
Z
Qiu
Su
S
Ding
Yousong
Y
Gao
Wei
W
Stuckey
Jeanne
J
Krajewski
Krzysztof
K
Roller
Peter P
PP
Tomita
York
Y
Parrish
Damon A
DA
Deschamps
Jeffrey R
JR
Wang
Shaomeng
S
D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D026121:Indole Alkaloids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism
D026121:Indole Alkaloids; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2