| Structural highlights
Disease
[MDM2_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.
Function
[MDM2_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 PubMed
Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.
Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein-Protein Interaction.,Chessari G, Hardcastle IR, Ahn JS, Anil B, Anscombe E, Bawn RH, Bevan LD, Blackburn TJ, Buck I, Cano C, Carbain B, Castro J, Cons B, Cully SJ, Endicott JA, Fazal L, Golding BT, Griffin RJ, Haggerty K, Harnor SJ, Hearn K, Hobson S, Holvey RS, Howard S, Jennings CE, Johnson CN, Lunec J, Miller DC, Newell DR, Noble MEM, Reeks J, Revill CH, Riedinger C, St Denis JD, Tamanini E, Thomas H, Thompson NT, Vinkovic M, Wedge SR, Williams PA, Wilsher NE, Zhang B, Zhao Y J Med Chem. 2021 Mar 24. doi: 10.1021/acs.jmedchem.0c02188. PMID:33761253[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Girnita L, Girnita A, Larsson O. Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8247-52. Epub 2003 Jun 23. PMID:12821780 doi:10.1073/pnas.1431613100
- ↑ Li M, Brooks CL, Kon N, Gu W. A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol Cell. 2004 Mar 26;13(6):879-86. PMID:15053880
- ↑ Bernardi R, Scaglioni PP, Bergmann S, Horn HF, Vousden KH, Pandolfi PP. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat Cell Biol. 2004 Jul;6(7):665-72. Epub 2004 Jun 13. PMID:15195100 doi:10.1038/ncb1147
- ↑ Sdek P, Ying H, Chang DL, Qiu W, Zheng H, Touitou R, Allday MJ, Xiao ZX. MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein. Mol Cell. 2005 Dec 9;20(5):699-708. PMID:16337594 doi:10.1016/j.molcel.2005.10.017
- ↑ Brady M, Vlatkovic N, Boyd MT. Regulation of p53 and MDM2 activity by MTBP. Mol Cell Biol. 2005 Jan;25(2):545-53. PMID:15632057 doi:25/2/545
- ↑ Stevenson LF, Sparks A, Allende-Vega N, Xirodimas DP, Lane DP, Saville MK. The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J. 2007 Feb 21;26(4):976-86. Epub 2007 Feb 8. PMID:17290220 doi:10.1038/sj.emboj.7601567
- ↑ Chen D, Zhang J, Li M, Rayburn ER, Wang H, Zhang R. RYBP stabilizes p53 by modulating MDM2. EMBO Rep. 2009 Feb;10(2):166-72. doi: 10.1038/embor.2008.231. Epub 2008 Dec 19. PMID:19098711 doi:10.1038/embor.2008.231
- ↑ Busso CS, Iwakuma T, Izumi T. Ubiquitination of mammalian AP endonuclease (APE1) regulated by the p53-MDM2 signaling pathway. Oncogene. 2009 Apr 2;28(13):1616-25. doi: 10.1038/onc.2009.5. Epub 2009 Feb 16. PMID:19219073 doi:10.1038/onc.2009.5
- ↑ Taira N, Yamamoto H, Yamaguchi T, Miki Y, Yoshida K. ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage. J Biol Chem. 2010 Feb 12;285(7):4909-19. doi: 10.1074/jbc.M109.042341. Epub 2009 , Dec 4. PMID:19965871 doi:10.1074/jbc.M109.042341
- ↑ Gilmore-Hebert M, Ramabhadran R, Stern DF. Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways. Mol Cancer Res. 2010 Oct;8(10):1388-98. doi: 10.1158/1541-7786.MCR-10-0042. Epub , 2010 Sep 21. PMID:20858735 doi:10.1158/1541-7786.MCR-10-0042
- ↑ Fu X, Yucer N, Liu S, Li M, Yi P, Mu JJ, Yang T, Chu J, Jung SY, O'Malley BW, Gu W, Qin J, Wang Y. RFWD3-Mdm2 ubiquitin ligase complex positively regulates p53 stability in response to DNA damage. Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4579-84. doi:, 10.1073/pnas.0912094107. Epub 2010 Feb 19. PMID:20173098 doi:10.1073/pnas.0912094107
- ↑ Chessari G, Hardcastle IR, Ahn JS, Anil B, Anscombe E, Bawn RH, Bevan LD, Blackburn TJ, Buck I, Cano C, Carbain B, Castro J, Cons B, Cully SJ, Endicott JA, Fazal L, Golding BT, Griffin RJ, Haggerty K, Harnor SJ, Hearn K, Hobson S, Holvey RS, Howard S, Jennings CE, Johnson CN, Lunec J, Miller DC, Newell DR, Noble MEM, Reeks J, Revill CH, Riedinger C, St Denis JD, Tamanini E, Thomas H, Thompson NT, Vinkovic M, Wedge SR, Williams PA, Wilsher NE, Zhang B, Zhao Y. Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein-Protein Interaction. J Med Chem. 2021 Mar 24. doi: 10.1021/acs.jmedchem.0c02188. PMID:33761253 doi:https://dx.doi.org/10.1021/acs.jmedchem.0c02188
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