CS-1248

CS-1248 - Names and Identifiers

Name	(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
Synonyms	CGM097 CS-1248 CS-2423 CGM 097 CGM-097 NVP-CGM097 NVPCGM097 NVPCGM 097 NVPCGM-097 NVP-CGM097 (CGM097) (S)-1-(4-Chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-[methyl[4-(4-methyl-3-oxopiperazin-1-yl)-trans-cyclohexylmethyl]amino]phenyl)-1,4-dihydro-2H-isoquinolin-3-one (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 (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
CAS	1313363-54-0

CS-1248 - Physico-chemical Properties

Molecular Formula	C38H47ClN4O4
Molar Mass	659.26
Density	1.210±0.06 g/cm3(Predicted)
Boling Point	830.1±65.0 °C(Predicted)
Solubility	DMSO
pKa	8.31±0.20(Predicted)
Storage Condition	-20℃
Use	CGM097 is an orally bioavailable HDM2 (human homolog of double minute 2) antagonist with potential antineoplastic activity. Upon oral administration, p53/HDM2 interaction inhibitor CGM097 inhibits the binding of the HDM2 protein to the transcriptional activation domain of the tumor suppressor protein p53. By preventing this HDM2-p53 interaction, the proteosome-mediated enzymatic degradation of p53 is inhibited, which may result in the restoration of p53 signaling and, thus, the p53-mediated induction of tumor cell apoptosis. HDM2, a zinc finger nuclear phosphoprotein, is a negative regulator of the p53 pathway, often overexpressed in cancer cells and has been implicated in cancer cell proliferation and survival.
In vitro study	The binding ability of NVP-CGM097 to MDM2 varied among different species. NVP-CGM097 was 1176-fold more selective for the p53:MDM2 interaction than for the p53:MDM4 interaction and 3000-fold more selective for the Ras:Raf interaction than for the Bcl-2:Bak, Bcl-2: the interaction of Bad, Mcl-1:Bak, Mcl-1:NOXA, XIAP:BIR3, c-IAP:BIR3 is not active and, therefore, NVP-CGM097 has high selectivity for p53:MDM2. NVP-CGM097 can significantly promote the wild type p53 into the nucleus, IC50 is 0.224 μm, indicating that it can inhibit the interaction of p53:MDM2 in living cells. NVP-CGM097 promotes p53 as the nucleus, leading to p53-dependent growth inhibition of the cell.
In vivo study	After intravenous injection, the serum clearance of NVP-CGM097 was 5 ml/min/kg in mice, 7 mL/min/kg in rats and 3 mL/min/kg in dogs, 4 mL/min/kg in monkeys. Compared to hepatic blood flow, NVP-CGM097 serum clearance in all species is low (typically 5-10% hepatic blood flow). The half-life of NVP-CGM097 in rodents and monkeys is 6-12 hours; The half-life in dogs is 20 hours, which is relatively longer. After oral administration, NVP-CGM097 can be well absorbed, reaching the highest concentration in vivo within 1-4.5 hours after administration. Its oral bioavailability is relatively high in mice, rats and dogs and relatively low in monkeys. In a SJSA-1 human tumor model with in vivo MDM2 amplification, NVP-CGM097 were able to inhibit the interaction between p53 and MDM2 and reactivate the p53 pathway. mRNA levels of p21 were elevated in tumor-bearing mice dosed with 30 mg/kg. Daily administration to mice significantly inhibited tumor growth by SJSA-1 in a dose-dependent manner.

CS-1248 - Reference

Reference

1: Jeay S, Gaulis S, Ferretti S, Bitter H, Ito M, Valat T, Murakami M, Ruetz S, Guthy DA, Rynn C, Jensen MR, Wiesmann M, Kallen J, Furet P, Gessier F, Holzer P, Masuya K, Würthner J, Halilovic E, Hofmann F, Sellers WR, Graus Porta D. A distinct p53 target gene set predicts for response to the selective p53-HDM2 inhibitor NVP-CGM097. Elife. 2015 May 12;4. doi: 10.7554/eLife.06498. PubMed PMID: 25965177; PubMed Central PMCID: PMC4468608.

CS-1248 - Preparation solution concentration reference

	1mg	5mg	10mg
1 mM	1.517 ml	7.584 ml	15.169 ml
5 mM	0.303 ml	1.517 ml	3.034 ml
10 mM	0.152 ml	0.758 ml	1.517 ml
5 mM	0.03 ml	0.152 ml	0.303 ml

Last Update：2024-01-02 23:10:35

CS-1248 - Cell Experiment

Two pairs of cell lines are used to assess NVP-CGM097 p53-dependent antiproliferative effects: (1) an isogenic pair of HCT116 cell lines either expressing wild-type p53 or knocked-out for the p53 gene and (2) a nonisogenic pair of osteosarcoma cell lines either endogenously expressing wild-type p53 and amplified for MDM2 (SJSA-1 cells) or null for p53 (SAOS-2 cells)

Last Update：2023-08-16 21:32:38

CS-1248 - Animal Experiment

Female athymic rats bearing subcutaneous xenotransplants of SJSA-1 tumors (n=5-12) are treated at 5, 10, 20, or 30 mg/kg or three times a week on Monday, Wednesday, and Friday (3qw M, W, F) at 30 or 70 mg/kg p.o for 14 days. Plasma AUCs are determined at the end of the study. Positive numbers indicate the percentage of tumor growth inhibition (T/C); negative numbers indicate the percentage of tumor regression.

Last Update：2023-08-16 21:32:38

CS-1248 - Reference Information

biological activity	NVP-CGM097 is a highly effective and selective MDM2 inhibitor with a Ki value of 1.3 nM. It binds to the p53 binding site of MDM2 protein, disrupts its protein-protein interaction, and leads to the activation of p53 pathway.
target	TargetValue hMDM2 (Cell-free say) 1.7 nM
Target	Value
hMDM2 (Cell-free assay)	1.7 nM
In vitro study	The binding ability of NVP-CGM097 and MDM2 is different among different species. The selectivity of the NVP-CGM097 for the p53:MDM2 interaction was 1176 times higher than for the p53:MDM4 interaction and 3000 times higher than for the Ras:Raf interaction, whereas for the Bcl-2:Bak, Bcl-2:Bad, Mcl-1:Bak, Mcl-1:NOXA, XIAP:BIR3, c-IAP:BIR3 interactions were inactive and, therefore, NVP-CGM097 had a high selectivity for p53:MDM2. NVP-CGM097 can significantly promote wild-type p53 to enter the nucleus with IC50 of 0.224 μM, indicating that it can inhibit the interaction of p53:MDM2 in living cells. NVP-CGM097 promotes p53, such as nuclei, resulting in cell p53-dependent growth inhibition.
in vivo study	after intravenous injection, the serum clearance rate of NVP-CGM097 was 5 mL/min/kg in mice, 7 mL/min/kg in rats, 3 mL/min/kg in dogs and 4 mL/min/kg in monkeys. Compared with liver blood flow, the serum clearance rate of NVP-CGM097 is relatively low in all species (usually 5-10% liver blood flow). The half-life of NVP-CGM097 in rodents and monkeys is 6-12 hours; while the half-life in dogs is 20 hours, which is relatively longer. After oral administration, the NVP-CGM097 can be well absorbed and reach the highest concentration in the body 1-4.5 hours after administration. The utilization rate of oral bioactivity is relatively high in mice, rats and dogs, but relatively low in monkeys. In SJSA-1 human tumor models with MDM2 amplification in vivo, NVP-CGM097 can inhibit the interaction between p53 and MDM2 and reactivate p53 pathway. The mRNA level of p21 was elevated in tumor-carrying mice administered 30 mg/kg. Daily administration to mice will significantly inhibit the growth of SJSA-1 tumors in a dose-dependent manner.

Last Update：2024-04-09 21:54:55