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Ravoxertinib (formerly known as GDC0994; RG7842) is a novel, potent, orally bioavailable inhibitor of extracellular signal-regulated kinase (ERK1/2) with potential antineoplastic activity. It blocks ERK1/2 with IC50 values of 1.1 nM and 0.3 nM, respectively. In the clinical trial NCT01875705, ravoxertinib is being examined in patients with locally advanced or metastatic solid tumors. It exhibits both in vivo and in vitro high anti-proliferative activity.
Physicochemical Properties
| Molecular Formula | C21H18CLFN6O2 |
| Molecular Weight | 439.85 |
| Exact Mass | 440.116 |
| Elemental Analysis | C, 57.21; H, 4.12; Cl, 8.04; F, 4.31; N, 19.06; O, 7.26 |
| CAS # | 1453848-26-4 |
| Related CAS # | Ravoxertinib hydrochloride;2070009-58-2 |
| PubChem CID | 71727581 |
| Appearance | White to yellow solid powder |
| Density | 1.5±0.1 g/cm3 |
| Boiling Point | 734.6±70.0 °C at 760 mmHg |
| Flash Point | 398.0±35.7 °C |
| Vapour Pressure | 0.0±2.5 mmHg at 25°C |
| Index of Refraction | 1.687 |
| LogP | 2.18 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 31 |
| Complexity | 709 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | ClC1C([H])=C([H])C(=C([H])C=1F)[C@@]([H])(C([H])([H])O[H])N1C([H])=C([H])C(C2C([H])=C([H])N=C(N([H])C3=C([H])C([H])=NN3C([H])([H])[H])N=2)=C([H])C1=O |
| InChi Key | RZUOCXOYPYGSKL-GOSISDBHSA-N |
| InChi Code | InChI=1S/C21H18ClFN6O2/c1-28-19(5-8-25-28)27-21-24-7-4-17(26-21)13-6-9-29(20(31)11-13)18(12-30)14-2-3-15(22)16(23)10-14/h2-11,18,30H,12H2,1H3,(H,24,26,27)/t18-/m1/s1 |
| Chemical Name | 1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyridin-2-one;hydrochloride |
| Synonyms | RG7842; GDC-0994; RG 7842; GDC 0994; GDC0994; RG-7842 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | ERK1 (IC50 = 6.1 nM); ERK2 (IC50 = 3.1 nM); p-RSK (IC50 = 12 nM) |
| ln Vitro |
Ravoxertinib (GDC-0994) also inhibits p90RSK with an IC50 of 12 nM[1]. Ravoxertinib (GDC-0994) has a biochemical potency of 1.1 nM and 0.3 nM, respectively, and is highly selective for ERK1 and ERK2[2]. Ravoxertinib (GDC0994; 50 nM, 0.5 µM, and 5 µM; 48 hours) reduces the viability of lung adenocarcinoma cell lines (A549, HCC827, and HCC4006)[3]. |
| ln Vivo | In CD-1 mice, a 10 mg/kg oral dose of Ravoxertinib (GDC-0994) adequate to provide the desired target coverage in CD-1 mice for at least 8 hours[1]. When given orally every day, Ravoxertinib exhibits significant single-agent activity in a number of in vivo cancer models, including KRAS- and BRAF-mutant human xenograft tumors in mice[2]. |
| Enzyme Assay | Ravoxertinib (GDC-0994) is an orally bioavailable ERK kinase inhibitor with an IC50 of 6.1 nM and 3.1 nM for ERK1 and ERK2, respectively. Additionally, p90RSK is inhibited by ravoxertinib (GDC-0994), with an IC50 of 12 nM. With a biochemical potency of 1.1 nM and 0.3 nM, respectively, ravoxertinib (GDC-0994) is highly selective for ERK1 and ERK2. |
| Cell Assay | GDC-0994 potently inhibits phospho-p90RSK in tumor cells. |
| Animal Protocol | Mice: PK/PD data for the mouse xenograft HCT116 model of ravoxertinib (GDC-0994). In nude mice, 400–600 mm3 of tumor volume is reached by HCT116 tumors. Tumor and plasma samples are collected 2, 8, 16, and 24 hours after the initial oral dose of 22 at 15, 30, or 100 mg/kg for mice versus the vehicle control alone (40% PEG400/60% (10% HPβCD)). Quantitative Western blotting is used to assess the relative levels of total p90RSK (tRSK) and phosphorylated p90RSK (pRSK) in tumors. At 2 hours after the dose, these levels are normalized to the vehicle control (set to 100%). LC-MS is used to determine the concentrations in plasma and tumors. |
| References |
[1]. Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Developme. [2]. Abstract DDT02-03: Discovery of GDC-0994, a potent and selective ERK1/2 inhibitor in early clinical development. Proceedings: AACR Annual Meeting 2014; April 5-9, 2014. [3]. Opportunity for Pharmaceutical Intervention in Lung Cancer: Selective Inhibition of JAK1/2 to Eliminate EMT-Derived Mesenchymal Cells. |
| Additional Infomation |
Ravoxertinib is under investigation in clinical trial NCT01875705 (A Dose-Escalation Study of GDC-0994 in Patients With Locally Advanced or Metastatic Solid Tumors). Ravoxertinib is an orally available inhibitor of extracellular signal-regulated kinase (ERK), with potential antineoplastic activity. Upon oral administration, ravoxertinib inhibits both ERK phosphorylation and activation of ERK-mediated signal transduction pathways. This prevents ERK-dependent tumor cell proliferation and survival. The mitogen-activated protein kinase (MAPK)/ERK pathway is upregulated in a variety of tumor cell types and plays a key role in tumor cell proliferation, differentiation and survival. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.67 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.67 mg/mL (3.79 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 16.7 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 3: ≥ 1.67 mg/mL (3.79 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 16.7 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. Solubility in Formulation 4: ≥ 1.67 mg/mL (3.79 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 5: 2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 30mg/mL Solubility in Formulation 6: 5 mg/mL (11.34 mM) in 30% PEG300 70% (10% HP-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2735 mL | 11.3675 mL | 22.7350 mL | |
| 5 mM | 0.4547 mL | 2.2735 mL | 4.5470 mL | |
| 10 mM | 0.2274 mL | 1.1368 mL | 2.2735 mL |