4jve
From Proteopedia
Co-crystal structure of MDM2 with inhibitor (2R,3E)-2-[(2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5-oxomorpholin-4-yl]pent-3-enoic acid
Structural highlights
DiseaseMDM2_HUMAN Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding. FunctionMDM2_HUMAN E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] Publication Abstract from PubMedStructural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 muM. The co-crystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogs were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 muM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21 induction (2-fold over vehicle) upon oral dosing of 27 at 300 mg/kg. Rational Design and Binding Mode Duality of MDM2-p53 Inhibitors.,Gonzalez-Lopez de Turiso F, Sun D, Rew Y, Bartberger MD, Beck HP, Canon J, Chen A, Chow D, Correll TL, Huang X, Julian LD, Kayser F, Lo MC, Long AM, McMinn D, Oliner JD, Osgood T, Powers JP, Saiki AY, Schneider S, Shaffer P, Xiao SH, Yakowec P, Yan X, Ye Q, Yu D, Zhao X, Zhou J, Medina JC, Olson SH J Med Chem. 2013 Apr 18. PMID:23597064[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Bartberger MD | Beck HP | Cannon J | Gonzalez-Lopez de Turiso F | Huang X | Medina JC | Oliner JD | Olson SH | Shaffer P | Sun D | Yosup R
