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==Discovery of NVP-CGM097 - a highly potent and selective MDM2 inhibitor undergoing phase 1 clinical trials in p53wt tumors: Hdm2 (MDM2) complexed with NVP-CGM097==
==Discovery of NVP-CGM097 - a highly potent and selective MDM2 inhibitor undergoing phase 1 clinical trials in p53wt tumors: Hdm2 (MDM2) complexed with NVP-CGM097==
<StructureSection load='4zyf' size='340' side='right' caption='[[4zyf]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
<StructureSection load='4zyf' size='340' side='right' caption='[[4zyf]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4zyf]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZYF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZYF FirstGlance]. <br>
<table><tr><td colspan='2'>[[4zyf]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZYF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZYF FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4T4:(S)-1-(4-CHLOROPHENYL)-7-ISOPROPOXY-6-METHOXY-2-(4-(METHYL(((1R,4S)-4-(4-METHYL-3-OXOPIPERAZIN-1-YL)CYCLOHEXYL)METHYL)AMINO)PHENYL)-1,2-DIHYDROISOQUINOLIN-3(4H)-ONE'>4T4</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4T4:(S)-1-(4-CHLOROPHENYL)-7-ISOPROPOXY-6-METHOXY-2-(4-(METHYL(((1R,4S)-4-(4-METHYL-3-OXOPIPERAZIN-1-YL)CYCLOHEXYL)METHYL)AMINO)PHENYL)-1,2-DIHYDROISOQUINOLIN-3(4H)-ONE'>4T4</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zyc|4zyc]], [[4dij|4dij]], [[4oq3|4oq3]]</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zyc|4zyc]], [[4dij|4dij]], [[4oq3|4oq3]]</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4zyf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zyf OCA], [http://pdbe.org/4zyf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zyf RCSB], [http://www.ebi.ac.uk/pdbsum/4zyf PDBsum]</span></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MDM2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4zyf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zyf OCA], [http://pdbe.org/4zyf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zyf RCSB], [http://www.ebi.ac.uk/pdbsum/4zyf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zyf ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Kallen, J]]
[[Category: Kallen, J]]
[[Category: Cell cycle]]
[[Category: Cell cycle]]
[[Category: Inhibitor complex]]
[[Category: Inhibitor complex]]
[[Category: Ppi with p53]]
[[Category: Ppi with p53]]

Revision as of 19:23, 16 November 2017

Discovery of NVP-CGM097 - a highly potent and selective MDM2 inhibitor undergoing phase 1 clinical trials in p53wt tumors: Hdm2 (MDM2) complexed with NVP-CGM097Discovery of NVP-CGM097 - a highly potent and selective MDM2 inhibitor undergoing phase 1 clinical trials in p53wt tumors: Hdm2 (MDM2) complexed with NVP-CGM097

Structural highlights

4zyf is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:MDM2 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

As a result of our efforts to discover novel p53-MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53-MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties and in vivo pharmacology/toxicology in preclinical species.

Discovery of a dihydroisoquinolinone derivative (NVP-CGM097) - a highly potent and selective MDM2 inhibitor undergoing phase 1 clinical trials in p53wt tumors.,Holzer P, Masuya K, Furet P, Kallen J, Valat-Stachyra T, Ferretti S, Berghausen J, Bouisset-Leonard M, Buschmann N, Pissot-Soldermann C, Rynn C, Ruetz S, Stutz S, Chene P, Jeay S, Gessier F J Med Chem. 2015 Jul 16. PMID:26181851[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ Holzer P, Masuya K, Furet P, Kallen J, Valat-Stachyra T, Ferretti S, Berghausen J, Bouisset-Leonard M, Buschmann N, Pissot-Soldermann C, Rynn C, Ruetz S, Stutz S, Chene P, Jeay S, Gessier F. Discovery of a dihydroisoquinolinone derivative (NVP-CGM097) - a highly potent and selective MDM2 inhibitor undergoing phase 1 clinical trials in p53wt tumors. J Med Chem. 2015 Jul 16. PMID:26181851 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00810

4zyf, resolution 1.80Å

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