title: The MDM2 Inhibitor AMG 232 Demonstrates Robust Antitumor Efficacy and Potentiates the Activity of p53-Inducing Cytotoxic Agents.
abstract: p53 is a critical tumor suppressor and is the most frequently inactivated gene in human cancer. Inhibition of the interaction of p53 with its negative regulator MDM2 represents a promising clinical strategy to treat p53 wild-type tumors. AMG 232 is a potential best-in-class inhibitor of the MDM2-p53 interaction and is currently in clinical trials. We characterized the activity of AMG 232 and its effect on p53 signaling in several preclinical tumor models. AMG 232 binds the MDM2 protein with picomolar affinity and robustly induces p53 activity, leading to cell-cycle arrest and inhibition of tumor cell proliferation. AMG 232 treatment inhibited the in vivo growth of several tumor xenografts and led to complete and durable regression of MDM2-amplified SJSA-1 tumors via growth arrest and induction of apoptosis. Therapeutic combination studies of AMG 232 with chemotherapies that induce DNA damage and p53 activity resulted in significantly superior antitumor efficacy and regression, and markedly increased activation of p53 signaling in tumors. These preclinical data support the further evaluation of AMG 232 in clinical trials as both a monotherapy and in combination with standard-of-care cytotoxics.
authors.affiliation: Department of Oncology Research, Amgen Inc., Thousand Oaks, California. jcanon@amgen.com.
authors.forename: Jude
authors.initials: J
authors.lastname: Canon
authors.affiliation: Department of Oncology Research, Amgen Inc., Thousand Oaks, California.
authors.forename: Tao
authors.initials: T
authors.lastname: Osgood
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., San Francisco, California.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Olson
authors.affiliation: Department of Oncology Research, Amgen Inc., Thousand Oaks, California.
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Saiki
authors.affiliation: Department of Oncology Research, Amgen Inc., Thousand Oaks, California.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Robertson
authors.affiliation: Department of Oncology Research, Amgen Inc., Thousand Oaks, California.
authors.forename: Dongyin
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of Molecular Structure, Amgen Inc., San Francisco, California.
authors.forename: John
authors.initials: J
authors.lastname: Eksterowicz
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., San Francisco, California.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., San Francisco, California.
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Molecular Structure, Amgen Inc., San Francisco, California.
authors.forename: Ada
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of Molecular Structure, Amgen Inc., San Francisco, California.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pathology, Amgen Inc., Thousand Oaks, California.
authors.forename: David
authors.initials: D
authors.lastname: Cordover
authors.affiliation: Department of Pathology, Amgen Inc., Thousand Oaks, California.
authors.forename: Stephen
authors.initials: S
authors.lastname: Kaufman
authors.affiliation: Department of Oncology Research, Amgen Inc., Thousand Oaks, California.
authors.forename: Richard
authors.initials: R
authors.lastname: Kendall
authors.affiliation: Department of Oncology Research, Amgen Inc., Thousand Oaks, California.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Oliner
authors.affiliation: Department of Oncology Research, Amgen Inc., Thousand Oaks, California.
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
authors.affiliation: Department of Oncology Research, Amgen Inc., Thousand Oaks, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Radinsky
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003603:Cytotoxins / Q000494:pharmacology*; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D010881:Piperidones / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C588087:2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; D000085:Acetates; D000970:Antineoplastic Agents; D003603:Cytotoxins; D010881:Piperidones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2