| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T00176 | ||||
| Target Name | Ubiquitin-protein ligase E3 Mdm2 | ||||
| Target Type | Clinical Trial |
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| Action against Disease Model | RG7112 | Targeted inhibition of the p53-MDM2 interaction by nutlin-3 decreased the viability of UKF-NB-3 cells in a dose- and time-dependent manner, with IC50 values in the low micromolar range (2.03 uM ~ 3.62 uM). | [552999] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | Here we report that Mdm2 haplo-insufficiency profoundly suppresses lymphomagenesis in E micro -myc transgenic mice. Mdm2(+/-)E micro -myc transgenics had greatly protracted rates of B cell lymphoma development with life spans twice that of wild-type transgenic littermates. Im paired lymphoma development was associated with drastic reductions in peripheral B cell n uMbers in Mdm2(+/-)E micro -myc transgenics, and primary pre-B cells from Mdm2(+/-)E micro -myc transgenics and Mdm2(+/-) littermates were extremely susceptible to spontaneous apoptosis. Loss of p53 rescued allof the effects of Mdm2 haplo-insufficiency, indicating they were p53 dependent. Furthermore, half of the lymphomas that ultimately emerged in Mdm2(+/-)E micro -myc transgenics harbored inactivating mutations in p53, and the majority overcame haplo-insufficiency by overexpressing Mdm2. These results support the concept that Mdm2 functions are rate limiting in lymphomagenesis and that targeting Mdm2 will enhance p53-mediated apoptosis, compromising t uMor development and/or maintenance. | [552999] | |||
| References | |||||
| Ref 552999 | Antitumor activity of the selective MDM2 antagonist nutlin-3 against chemoresistant neuroblastoma with wild-type p53. J Natl Cancer Inst. 2009 Nov 18;101(22):1562-74. doi: 10.1093/jnci/djp355. Epub 2009 Nov 10. | ||||
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