spacer The 1.9A crystal structure of humanized Xenopus Mdm2 with nutlin-3a
Primary citation
Title Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development
Authors Vu,; Wovkulich,; Pizzolato,; Lovey,; Ding,; Jiang,; Liu,; Zhao,; Glenn,; Wen,; Tovar,; Packman,; Vassilev,; Graves,
Journal ACS (2013) DOI (10.1021/ml4000657)
Secondary citations
Title MDM2 Small-Molecule Antagonist RG7112 Activates p53 Signaling and Regresses Human Tumors in Preclinical Cancer Models.
Authors Tovar,; Graves,; Packman,; Filipovic,; Xia,; Tardell,; Garrido,; Lee,; Kolinsky,; To,; Linn,; Podlaski,; Wovkulich,; Vu,; Vassilev,
Journal CANCER vol:73, pag:2587-2597 (2013), Identifiers: PubMed ID (23400593)search DOI (10.1158/0008-5472.CAN-12-2807)
Abstract MDM2 negatively regulates p53 stability and many human tumors overproduce MDM2 as a mechanism to restrict p53 function. Thus, inhibitors of p53-MDM2 binding that can reactivate p53 in cancer cells may offer an effective approach for cancer therapy. RG7112 is a potent and selective member of the Nutlin family of MDM2 antagonists currently in Phase I clinical studies. RG7112 binds MDM2 with high affinity (KD ~11 nM), blocking its interactions with p53 in vitro. A crystal structure of the RG7112-MDM2 complex revealed that the small molecule binds in the p53 pocket of MDM2 mimicking the interactions of critical p53 amino acid residues. Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell cycle arrest and apoptosis. RG7112 showed potent antitumor activity against a panel of solid tumor cell lines. However, its apoptotic activity varied widely with the best response observed in osteosarcoma cells with MDM2 gene amplification. Interestingly, inhibition of caspase activity did not change the kinetics of p53-induced cell death. Oral administration of RG7112 to human xenograft-bearing mice at non-toxic concentrations caused dosedependent changes in proliferation/apoptosis biomarkers as well as tumor inhibition and regression. Notably, RG7112 was highly synergistic with androgen deprivation in LNCaP xenograft tumors. Our findings offer a preclinical proof-of-concept that RG7112 is effective in treatment of solid tumors expressing wild-type p53.
MeSH terms
Title In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.
Authors Vassilev,; Vu,; Graves,; Carvajal,; Podlaski,; Filipovic,; Kong,; Kammlott,; Lukacs,; Klein,; Fotouhi,; Liu,
Journal SCIENCEsearch vol:303, pag:844-848 (2004), Identifiers: PubMed ID (14704432)search DOI (10.1126/science.1092472)
Abstract MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice.
MeSH terms Animalssearch, Apoptosissearch, Binding Sitessearch, Cell Cyclesearch, Cell Divisionsearch, Cell Linesearch, Cell Linesearch, Tumorsearch, Cell Survivalsearch, Crystallizationsearch, Crystallographysearch, X-Raysearch, Cyclin-Dependent Kinase Inhibitor p21search, Cyclinssearch, Dose-Response Relationshipsearch, Drugsearch, Gene Expressionsearch, Genessearch, p53search, Humanssearch, Hydrophobic and Hydrophilic Interactionssearch, Imidazolessearch, Micesearch, Micesearch, Nudesearch, Modelssearch, Molecularsearch, Molecular Weightsearch, NIH 3T3 Cellssearch, Neoplasm Transplantationsearch, Neoplasmssearch, Experimentalsearch, Nuclear Proteinssearch, Phosphorylationsearch, Piperazinessearch, Protein Conformationsearch, Proto-Oncogene Proteinssearch, Proto-Oncogene Proteins c-mdm2search, Stereoisomerismsearch, Transplantationsearch, Heterologoussearch, Tumor Suppressor Protein p53search