title: A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice.
abstract: We previously reported the discovery of a class of spirooxindoles as potent and selective small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors). We report herein our efforts to improve their pharmacokinetic properties and in vivo antitumor activity. Our efforts led to the identification of 9 (MI-888) as a potent MDM2 inhibitor (Ki = 0.44 nM) with a superior pharmacokinetic profile and enhanced in vivo efficacy. Compound 9 is capable of achieving rapid, complete, and durable tumor regression in two types of xenograft models of human cancer with oral administration and represents the most potent and efficacious MDM2 inhibitor reported to date.
authors.affiliation: Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Shanghai
authors.initials: S
authors.lastname: Yu
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Lu
authors.forename: Donna
authors.initials: D
authors.lastname: McEachern
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Shargary
authors.forename: Denzil
authors.initials: D
authors.lastname: Bernard
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Li
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.forename: Peng
authors.initials: P
authors.lastname: Zou
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D019540:Area Under Curve; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000078183:Oxindoles; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; C586852:MI-888; D000078183:Oxindoles; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; C022960:2-oxindole; D051736:Proto-Oncogene Proteins c-mdm2