title: Structure-based design of potent non-peptide MDM2 inhibitors.
abstract: 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.
authors: 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.
authors: Ke
authors: K
authors: Ding
authors: Yipin
authors: Y
authors: Lu
authors: Zaneta
authors: Z
authors: Nikolovska-Coleska
authors: Su
authors: S
authors: Qiu
authors: Yousong
authors: Y
authors: Ding
authors: Wei
authors: W
authors: Gao
authors: Jeanne
authors: J
authors: Stuckey
authors: Krzysztof
authors: K
authors: Krajewski
authors: Peter P
authors: PP
authors: Roller
authors: York
authors: Y
authors: Tomita
authors: Damon A
authors: DA
authors: Parrish
authors: Jeffrey R
authors: JR
authors: Deschamps
authors: Shaomeng
authors: S
authors: Wang
mesh_terms: 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
chemical_list: D026121:Indole Alkaloids; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2