title: Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors.
abstract: Small-molecule inhibitors that block the MDM2-p53 protein-protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring-opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereochemistry in this class of compounds has a major effect on their binding affinities to MDM2, with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a Ki value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer.
authors: Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA.
authors: Yujun
authors: Y
authors: Zhao
authors: Liu
authors: L
authors: Liu
authors: Wei
authors: W
authors: Sun
authors: Jianfeng
authors: J
authors: Lu
authors: Donna
authors: D
authors: McEachern
authors: Xiaoqin
authors: X
authors: Li
authors: Shanghai
authors: S
authors: Yu
authors: Denzil
authors: D
authors: Bernard
authors: Philippe
authors: P
authors: Ochsenbein
authors: Vincent
authors: V
authors: Ferey
authors: Jean-Christophe
authors: JC
authors: Carry
authors: Jeffrey R
authors: JR
authors: Deschamps
authors: Duxin
authors: D
authors: Sun
authors: Shaomeng
authors: S
authors: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003500:Cyclization; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016513:Mice, SCID; D008958:Models, Molecular; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000078183:Oxindoles; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D013141:Spiro Compounds; C022960:2-oxindole; D051736:Proto-Oncogene Proteins c-mdm2
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