| 產(chǎn)品描述： | NVP-CGM097 sulfate is a potent and selective MDM2 inhibitor with IC50 of 1.7±0.1 nM for hMDM2. |
| 靶點(diǎn)： |
IC50 & Target: IC50: 1.7±0.1 nM (hMDM2);Others |
| 體外研究： |
NVP-CGM097 binds to human MDM2 with an IC50 of 1.7 nM and shows high selectivity over MDM4 (IC50=2000 nM). NVP-CGM097 is about four times more potent than Nutlin-3a (IC50=8 nM). In addition, NVP-CGM097 shows no significant activity against Bcl-2:Bak, Bcl-2:Bad, Mcl-1:Bak, Mcl-1:NOXA, XIAP:BIR3, and c-IAP:BIR3 protein-protein interactions. NVP-CGM097 significantly inhibits the proliferation of cells expressing wild-type p53, while sparing the p53 null cells with a 35-58-fold difference. NVP-CGM097 is able to significantly redistribute wild-type p53 into the cell nucleus with an IC50 of 0.224 μM, demonstrating its ability to inhibit the p53:MDM2 interaction in living cells. NVP-CGM097 significantly inhibits the proliferation of cells expressing wild-type p53, while sparing the p53 null cells with a 35-58-fold difference. NVP-CGM097 inhibtis HCT116 (p53WT/WT) with IC50 of 454±136 nM |
| 體內(nèi)研究： |
NVP-CGM097 is able to inhibit the interaction between p53 and MDM2 and reactivate the p53 pathway in a MDM2-amplified SJSA-1 human tumor model, as judged by elevation of p21 mRNA levels, a pharmacodynamic (PD) indicator for p53 activity. p21 mRNA levels are found to increase concomitantly with levels of NVP-CGM097 in tumor-bearing rats dosed at 30 mg/kg. The PD response is biphasic and prolonged up to 24 h. Additional p53 target genes such as MDM2 and PUMA mRNA levels are assessed in the tumor samples as well and showed a similar behavior. Daily treatment with NVP-CGM097 dose dependently and significantly inhibits SJSA-1 tumor growth in rats. It promotes stable disease at 20 mg/kg, which is associated with a plasma AUC0-24 of 163 μM?h. After iv administration, the total blood clearance (CL) of NVP-CGM097 is 5 mL/min per kg for mouse, 7 mL/min per kg for rat, 3 mL/min per kg for dog, and 4 mL/min per kg for monkey. The apparent terminal half-life (t1/2) is long in rodents and monkey (6-12 h) but is comparatively longer in dogs (20 h). After oral dosing, NVP-CGM097 is well absorbed with Tmax occurring between 1 and 4.5 h in all species tested |
| 參考文獻(xiàn)： |
1. Holzer P, et al. 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 Aug 27;58(16):6348-58. |
| 溶解性： |
Soluble in DMSO、H2O |
| 保存條件： |
-20℃ |
| 配置溶液濃度參考： |
|
1mg |
5mg |
10mg |
| 1 mM |
1.32 ml |
6.602 ml |
13.204 ml |
| 5 mM |
0.264 ml |
1.32 ml |
2.641 ml |
| 10 mM |
0.132 ml |
0.66 ml |
1.32 ml |
| 50 mM |
0.026 ml |
0.132 ml |
0.264 ml |
|
| 注意： |
部分產(chǎn)品我司僅能提供部分信息，我司不保證所提供信息的權(quán)威性，僅供客戶參考交流研究之用。 |
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