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NVP-CGM097 sulfate ( also known as CGM097; NVP-CGM-097; NVPCGM097), the sulfate salt of NVP-CGM097 or CGM-097, is a novel, orally bioavailable and selective inhibitor of MDM2 (human homolog of double minute 2)-p53 interaction with antitumor activity. With an IC50 of 1.7±0. nM, it blocks inhibits MDM2-p53.
NVP-CGM097 (also known as CGM-097) is a potent, highly selective, and orally bioavailable small-molecule inhibitor of the Mouse Double Minute 2 (MDM2) protein. Developed by Novartis, it is designed to antagonize the interaction between MDM2 and the tumor suppressor protein p53. By blocking this interaction, NVP-CGM097 activates the p53 pathway, leading to cell cycle arrest and apoptosis in cancer cells that retain wild-type p53. It is a dihydroisoquinolinone derivative and has been evaluated in Phase I clinical trials for the treatment of p53 wild-type malignancies .| Targets |
hMDM2 (IC50 = 1.7±0.1 nM); NVP-CGM097 specifically targets the human homolog of Mouse Double Minute 2 (HDM2 or MDM2). It binds to the p53-binding pocket on the surface of the MDM2 protein. The binding affinity (IC50) of NVP-CGM097 for MDM2 is approximately 1.7 ± 0.1 nM, demonstrating high potency. It shows significant selectivity for the p53-MDM2 interaction over other protein-protein interactions, such as p53-MDM4 (1176-fold selectivity) .
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| ln Vitro |
In vitro, NVP-CGM097 effectively inhibits the proliferation of cancer cells harboring wild-type p53 (p53wt) in a p53-dependent manner. For instance, in p53wt neuroendocrine tumor cells (GOT1), treatment with 2,500 nM NVP-CGM097 for 96 hours resulted in a significant reduction in cell viability to 47.7%. In ER-positive breast cancer cell lines (MCF-7, ZR75-1), sub-micromolar IC50 values (approx. 0.2 μM) were observed, while p53-mutant cells (T-47D) were resistant (IC50 ~7.2 μM). Mechanistically, it induces nuclear translocation of p53, increases the expression of p53 target proteins like p21 and PUMA, and leads to G1 and G2/M cell cycle arrest followed by apoptosis .
NVP-CGM097 sulfate binds to human MDM2 with an IC50 of 1.7 nM and demonstrates strong selectivity for MDM4 (IC50=2000 nM). NVP-CGM097 sulfate is roughly four times more powerful than Nutlin-3a (IC50=8 nM). In addition, NVP-CGM097 sulfate showed no significant action on Bcl-2:Bak, Bcl-2:Bad, Mcl-1:Bak, Mcl-1:NOXA, XIAP:BIR3 and c-IAP:BIR3 protein-protein responses. CGM097 sulfate effectively reduced the growth of cells expressing wild-type p53 while sparing p53-null cells with a 35-58-fold differential. NVP-CGM097 sulfate may dramatically relocate wild-type p53 into the nucleus, with an IC50 of 0.224 μM, indicating that it can suppress NVP-CGM097 sulfate significantly reduces the proliferation of cells expressing wild-type p53, at a 35-58-fold rate. Differential retention of p53 null cells. NVP-CGM097 sulfate inhibits HCT116 (p53WT/WT) with an IC50 of 454±136nM[1]. |
| ln Vivo |
In vivo, NVP-CGM097 demonstrates potent antitumor activity in mouse xenograft models. In the MDM2-amplified, p53wt SJSA-1 osteosarcoma model, oral administration of NVP-CGM097 at well-tolerated doses (e.g., 25, 50, 100 mg/kg daily) led to significant tumor growth inhibition and even regression. Efficacy was observed across various dosing schedules (from daily to twice per week). Furthermore, it showed efficacy in other p53wt models, including patient-derived xenografts (PDX) of liposarcoma, AML, and endocrine-resistant breast cancer, particularly in combination with other agents like fulvestrant or CDK4/6 inhibitors .
In the SJSA-1 human tumor model, NVP-CGM097 sulfate reactivates the p53 dye adjacent to MDM2 and suppresses the response between p53 and MDM2, as indicated by higher p21 mRNA levels, a measure of p53 activity according to pharmacodynamic (PD) indications. It was discovered that when NVP-CGM097 sulfate levels were raised to 30 mg/kg in the tumor-bearing state, p21 mRNA levels rose as well. The biphasic PD response lasts for a maximum of twenty-four hours. Comparable patterns were observed in the mRNA levels of other p53 target genes, including MDM2 and PUMA, which were assessed in concurrent samples. NVP-CGM097 sulfate administration on a daily basis dramatically and dose-dependently enhanced SJSA-1 tumor development. 20 mg/kg is a dose that can help stabilize the condition, and the antibiotic's AUC0–24 is 163 μM.h. The total blood clearance (CL) of NVP-CGM097 following intravenous injection is 5 mL/min/kg for mice, 7 mL/min/kg for rats, 3 mL/min/kg for dogs, and 4 mL/min/kg for monkeys. Dogs have a longer apparent terminal half-life (t1/2) than birds (20 hours), whereas rats and monkeys have a longer t1/2 (6–12 hours). NVP-CGM097 was well absorbed upon prototyping, with Tmax occurring in the range of 1 to 4.5 for all studied species [1]. |
| Enzyme Assay |
In vivo, NVP-CGM097 demonstrates potent antitumor activity in mouse xenograft models. In the MDM2-amplified, p53wt SJSA-1 osteosarcoma model, oral administration of NVP-CGM097 at well-tolerated doses (e.g., 25, 50, 100 mg/kg daily) led to significant tumor growth inhibition and even regression. Efficacy was observed across various dosing schedules (from daily to twice per week). Furthermore, it showed efficacy in other p53wt models, including patient-derived xenografts (PDX) of liposarcoma, AML, and endocrine-resistant breast cancer, particularly in combination with other agents like fulvestrant or CDK4/6 inhibitors .
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| Cell Assay |
: A standard in vitro cell viability assay for NVP-CGM097 is performed using the CellTiter 96 AQueous One Solution Cell Proliferation Assay (MTS). Cells (e.g., 50,000 GOT1 cells/well) are seeded in 96-well plates and allowed to adhere overnight. They are then treated with a range of concentrations of NVP-CGM097 (e.g., 0.1 nM to 2,500 nM) for a defined period, typically 72 to 96 hours. After treatment, the MTS reagent is added to each well and incubated for 1-4 hours. The absorbance is measured at 492 nm using an ELISA plate reader. The IC50 is calculated by comparing the absorbance of treated wells to vehicle-treated control wells .
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)[1]. |
| Animal Protocol |
A typical in vivo efficacy study involves female athymic nude mice bearing subcutaneous SJSA-1 xenografts. When tumors reach a certain size (e.g., ~200-300 mm³), mice are randomized into treatment groups (n=6-12 per group). NVP-CGM097 is formulated as an oral suspension and administered by oral gavage at various doses (e.g., 25, 50, 100 mg/kg) and schedules (e.g., daily for 14 days, or three times a week). Tumor volumes are measured twice weekly with calipers, and body weight is monitored as a proxy for toxicity. At the end of the study, tumors and plasma are collected for pharmacokinetic (PK) and pharmacodynamic (PD) analysis (e.g., measuring p21 mRNA levels) .
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| ADME/Pharmacokinetics |
NVP-CGM097 exhibits favorable pharmacokinetic properties in preclinical species. It is well absorbed after oral administration, with time to maximum concentration (Tmax) ranging from 1 to 4.5 hours across species. The oral bioavailability (%F) is high in mice, rats, and dogs, and moderate in monkeys. The total blood clearance (CL) is low, ranging from 3-7 mL/min/kg, which is 5-10% of hepatic blood flow. The terminal half-life (t1/2) is approximately 6-12 hours in rodents and monkeys, and longer (20 hours) in dogs. A good PK/PD relationship has been established, where plasma drug levels correlate with p53 target gene activation in tumors .
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| Toxicity/Toxicokinetics |
The primary dose-limiting toxicity identified for NVP-CGM097 in clinical studies (Phase I) is delayed thrombocytopenia (low platelet counts). This is an on-target, mechanism-based toxicity resulting from p53 activation in megakaryocytes, which impairs platelet production. Preclinical studies have shown that NVP-CGM097 is not classified as a hazardous substance in acute toxicity tests, and no significant body weight loss was observed in animal efficacy studies at therapeutic doses. However, like all p53-MDM2 inhibitors, careful monitoring of platelet counts is required. Long-term carcinogenicity and reproductive toxicity studies are standard for such investigational agents .
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| References |
| Molecular Formula |
C38H49CLN4O8S
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|---|---|
| Molecular Weight |
757.335668325424
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| Exact Mass |
756.296
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| Elemental Analysis |
C, 60.27; H, 6.52; Cl, 4.68; N, 7.40; O, 16.90; S, 4.23
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| CAS # |
1313367-56-4
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| Related CAS # |
NVP-CGM097;1313363-54-0;NVP-CGM097 (stereoisomer);2070009-54-8
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| PubChem CID |
53262550
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| Appearance |
Light yellow to yellow solid powder
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
52
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| Complexity |
1120
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC(C)OC1=C(C=C2CC(=O)N([C@H](C2=C1)C3=CC=C(C=C3)Cl)C4=CC=C(C=C4)N(C)CC5CCC(CC5)N6CCN(C(=O)C6)C)OC.OS(=O)(=O)O
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| InChi Key |
YFLKIFVIZIALIA-GHVGLMRRSA-N
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| InChi Code |
InChI=1S/C38H47ClN4O4.H2O4S/c1-25(2)47-35-22-33-28(20-34(35)46-5)21-36(44)43(38(33)27-8-10-29(39)11-9-27)32-16-14-30(15-17-32)41(4)23-26-6-12-31(13-7-26)42-19-18-40(3)37(45)24-42;1-5(2,3)4/h8-11,14-17,20,22,25-26,31,38H,6-7,12-13,18-19,21,23-24H2,1-5H3;(H2,1,2,3,4)/t26?,31?,38-;/m0./s1
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| Chemical Name |
(1S)-1-(4-chlorophenyl)-6-methoxy-2-[4-[methyl-[[4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl]methyl]amino]phenyl]-7-propan-2-yloxy-1,4-dihydroisoquinolin-3-one;sulfuric acid
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| Synonyms |
NVP-CGM097 sulfate; NVP-CGM-097 (sulfate); NVP-CGM097 sulfate; CGM-097 Sulfate; CGM 097 Sulfate; NVP CGM097 sulfate
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~100 mg/mL (132.0 mM)
H2O: ~100 mg/mL (132.0 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.30 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (3.30 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (3.30 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 50 mg/mL (66.02 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.3204 mL | 6.6021 mL | 13.2041 mL | |
| 5 mM | 0.2641 mL | 1.3204 mL | 2.6408 mL | |
| 10 mM | 0.1320 mL | 0.6602 mL | 1.3204 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01760525 | Completed | Drug: CGM097 | Solid Tumor With p53 Wild Type Status |
Novartis Pharmaceuticals | March 20, 2013 | Phase 1 |
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