Background
NVP-CGM097 is a potent and selective MDM2 inhibitor with IC50 of 1.7±0.1 nM for hMDM2.
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. In addition, NVP-CGM097 activity against the p53:MDM2 interaction is assessed in proliferation assays using either wild-type p53 or p53 null 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[1].
NVP-CGM097 is able to inhibit the interaction between p53 and MDM2 and reactivate the p53 pathway in vivo 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[1].
参考文献:
[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
Protocol
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Cell experiment [1,2]:
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Cell lines
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Neuroblastoma cell lines, HCT116 cells
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Preparation method
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Soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reacting condition
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24 h
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Applications
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The combination of NVP-CGM097 with NVP-LDK378 promoted apoptosis in ALK mutant and p53 WT neuroblastoma cell lines. NVP-LDK378 inhibited ALK phosphorylation and NVP-CGM097 caused induction of p53 and its downstream target genes in these cell lines. NVP-CGM097 significantly inhibited the proliferation of cells expressing wild-type p53, while sparing the p53 null cells with a 35-58-fold difference. NVP-CGM097 significantly redistributed wild-type p53 into the cell nucleus with an IC50 of 0.224 μM. NVP-CGM097 inhibited HCT116 (p53WT/WT) with IC50 of 454 ± 136 nM.
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Animal experiment [1,3]:
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Animal models
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NOD.SCID.IL2R-/- (NSG) mice engraftmented with hCD45+/hCD19+ cells, ALK mutant neuroblastoma models, MDM2-amplified SJSA-1 human tumor model
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Dosage form
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Intravenous injection, 30 mg/kg, Daily
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Application
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In NOD.SCID.IL2R-/- (NSG) mice engraftmented with hCD45+/hCD19+ cells, CGM097 ultimately became moribund from progressive leukemia. CGM097 significantly upregulated the expression of 11 genes at the 26 hour timepoint, including the canonical p53 targets BBC3, CDKN1A and MDM2. CGM097 markedly improved overall survival. NVP-LDK378 and NVP-CGM097 combination resulted in complete tumor regression and markedly prolonged survival in neuroblastoma xenograft models. NVP-CGM097 inhibited the interaction between p53 and MDM2 and reactivated the p53 pathway in a MDM2-amplified SJSA-1 human tumor model. NVP-CGM097 (30 mg/kg) increased p21 mRNA levels in tumor-bearing rats. Daily treatment with NVP-CGM097 dose-dependently inhibited SJSA-1 tumor growth in rats.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1]. Wang H Q, Battalagine L, Liang J, et al. The Mdm2 inhibitor NVP-CGM097 enhances the anti-tumor activity of NVP-LDK378 in ALK mutant neuroblastoma models[J]. 2014.
[2]. 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.
[3]. Townsend E C, DeSouza T, Murakami M A, et al. The MDM2 Inhibitor NVP-CGM097 Is highly active in a randomized preclinical trial of B-cell acute lymphoblastic leukemia patient derived xenografts[J]. 2015.
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