title: Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition.
abstract: We have designed MI-219 as a potent, highly selective and orally active small-molecule inhibitor of the MDM2-p53 interaction. MI-219 binds to human MDM2 with a K(i) value of 5 nM and is 10,000-fold selective for MDM2 over MDMX. It disrupts the MDM2-p53 interaction and activates the p53 pathway in cells with wild-type p53, which leads to induction of cell cycle arrest in all cells and selective apoptosis in tumor cells. MI-219 stimulates rapid but transient p53 activation in established tumor xenograft tissues, resulting in inhibition of cell proliferation, induction of apoptosis, and complete tumor growth inhibition. MI-219 activates p53 in normal tissues with minimal p53 accumulation and is not toxic to animals. MI-219 warrants clinical investigation as a new agent for cancer treatment.
authors.affiliation: Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Shangary
authors.forename: Dongguang
authors.initials: D
authors.lastname: Qin
authors.forename: Donna
authors.initials: D
authors.lastname: McEachern
authors.forename: Meilan
authors.initials: M
authors.lastname: Liu
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Miller
authors.forename: Su
authors.initials: S
authors.lastname: Qiu
authors.forename: Zaneta
authors.initials: Z
authors.lastname: Nikolovska-Coleska
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.forename: Guoping
authors.initials: G
authors.lastname: Wang
authors.forename: Jianyong
authors.initials: J
authors.lastname: Chen
authors.forename: Denzil
authors.initials: D
authors.lastname: Bernard
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Yipin
authors.initials: Y
authors.lastname: Lu
authors.forename: Qingyang
authors.initials: Q
authors.lastname: Gu
authors.forename: Rajal B
authors.initials: RB
authors.lastname: Shah
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Ling
authors.forename: Sanmao
authors.initials: S
authors.lastname: Kang
authors.forename: Ming
authors.initials: M
authors.lastname: Guo
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.forename: Dajun
authors.initials: D
authors.lastname: Yang
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C574930:MI-219; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2