4IPF

The 1.7A crystal structure of humanized Xenopus MDM2 with RO5045337

Summary for 4IPF

• Entry DOI: 10.2210/pdb4ipf/pdb
• Related: 1RV1
• Descriptor: E3 ubiquitin-protein ligase Mdm2, [(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]{4-[3-(methylsulfonyl)propyl]piperazin-1-yl}methanone, SULFATE ION, ... (4 entities in total)
• Functional Keywords: mdm2, p53, protein-protein interaction, imidazoline, e3 ubiquitin ligase, nucleus, ligase-antagonist complex, ligase/antagonist
• Biological source: Xenopus laevis (clawed frog,common platanna,platanna)
• Cellular location: Nucleus, nucleoplasm (By similarity): P56273
• Total number of polymer chains: 1
• Total formula weight: 10751.33

Authors

Graves, B.J.,Lukacs, C.,Kammlott, R.U.,Crowther, R. (deposition date: 2013-01-09, release date: 2013-02-20, Last modification date: 2024-02-28)

Primary citation

Tovar, C.,Graves, B.,Packman, K.,Filipovic, Z.,Xia, B.H.,Tardell, C.,Garrido, R.,Lee, E.,Kolinsky, K.,To, K.H.,Linn, M.,Podlaski, F.,Wovkulich, P.,Vu, B.,Vassilev, L.T.
MDM2 Small-Molecule Antagonist RG7112 Activates p53 Signaling and Regresses Human Tumors in Preclinical Cancer Models.
Cancer Res., 73:2587-2597, 2013

PubMed 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 (K(D) ~ 11 nmol/L), 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 nontoxic concentrations caused dose-dependent 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.

PubMed: 23400593
DOI: 10.1158/0008-5472.CAN-12-2807

Experimental method

X-RAY DIFFRACTION (1.7 Å)