Ravoxertinib (GDC-0994; RG-7842)

Alias: RG7842; GDC-0994; RG 7842; GDC 0994; GDC0994; RG-7842
Cat No.:V0466 Purity: ≥98%
Ravoxertinib (formerly known as GDC0994; RG7842) is a novel, potent, orally bioavailable inhibitor of extracellular signal-regulated kinase (ERK1/2) with potential antineoplastic activity.
Ravoxertinib (GDC-0994; RG-7842) Chemical Structure CAS No.: 1453848-26-4
Product category: ERK
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of Ravoxertinib (GDC-0994; RG-7842):

  • Ravoxertinib hydrochloride (GDC-0994; RG7842)
Official Supplier of:
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

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.

Biological Activity I Assay Protocols (From Reference)
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.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C21H18CLFN6O2
Molecular Weight
439.85
Exact Mass
440.12
Elemental Analysis
C, 57.21; H, 4.12; Cl, 8.04; F, 4.31; N, 19.06; O, 7.26
CAS #
1453848-26-4
Appearance
Solid powder
SMILES
CN1C(=CC=N1)NC2=NC=CC(=N2)C3=CC(=O)N(C=C3)[C@H](CO)C4=CC(=C(C=C4)Cl)F
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)
Solubility Data
Solubility (In Vitro)
DMSO: ~87 mg/mL (~197.8 mM)
Water: <1 mg/mL
Ethanol: ~87 mg/mL (~197.8 mM)
Solubility (In Vivo)
2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 30mg/mL
 (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

*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.

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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In vivo Formulation Calculator (Clear solution)
Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)
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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.

Biological Data
  • GDC-0994 (Ravoxertinib)

    UV traces from incubation of6with hepatocytes att= 3 h (M3 = compound7): h = human, m = mouse, r = rat, d = dog, c = cynomolgus monkey.

    GDC-0994 (Ravoxertinib)

    Compound exposure vs time in a multidose mouse PK study with compound22, formulated in 40% PEG400/60% (10% HPβCD) water.2016 Jun 23;59(12):5650-60.

  • GDC-0994 (Ravoxertinib)

    Crystal structures of22bound to ERK2 (brown) and CDK2 (purple): (A) compound22bound to ERK2; (B) superposition of ERK2 and CDK2 cocrystal structures with compound22. Red dotted lines indicate hydrogen bonds. Red spheres indicate water molecules.


    GDC-0994 (Ravoxertinib)

    HCT116 study PK/PD analysis with compound22: PK/PD data for22in the HCT116 mouse xenograft model.2016 Jun 23;59(12):5650-60.

  • GDC-0994 (Ravoxertinib)

    Activity of22against 279 kinases at 1 μM. Illustration reproduced courtesy of Cell Signaling Technology.


    GDC-0994 (Ravoxertinib)

    HCT116 mouse xenograft data with compound22.2016 Jun 23;59(12):5650-60.

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