SCH772984

SKU: orb1301104

Description

SCH772984 is a potent, selective, and ATP-competitive ERK1/2 inhibitor (IC50=4/1 nM). It demonstrates antitumor efficacy in both in vitro and in vivo models of cancers harboring BRAF or RAS mutations, making it a valuable tool for MAPK pathway research.

Research Area

Signal Transduction

Key Properties

• CAS Number: 942183-80-4
• MW: 587.67
• Purity: 98.75% (May vary between batches)
• Formula: C₃₃H₃₃N₉O₂
• SMILES: O=C(CN1CC[C@H](C1)C(=O)Nc1ccc2[nH]nc(-c3ccncc3)c2c1)N1CCN(CC1)c1ccc(cc1)-c1ncccn1
• Target: MEK,ERK
• Solubility: Ethanol:< 1 mg/mL (insoluble or slightly soluble);H2O:< 1 mg/mL (insoluble or slightly soluble);10% DMSO+90% Saline:0.54 mg/mL (0.92 mM);DMSO:16.7 mg/mL (28.42 mM)

Bioactivity

• Target IC50:
  ERK2:1 nM (cell free)|H727 cells:115 nM|ERK1:4 nM (cell free)|SH-SY5Y cells:50 nM|HCT116 cells:50 nM|U-937 cells:1.7 µM
• In Vivo:
  METHODS: To detect anti-tumor activity in vivo, SCH772984 (25-50 mg/kg) was administered intraperitoneally to Nude mice bearing MiaPaCa xenografts twice daily for 14 days. RESULTS: Tumor regression was observed at both doses, 9% at the 25 mg/kg dose and 36% at the 50 mg/kg dose.
• In Vitro:
  METHODS: Twenty-one melanoma cell lines containing mutations in the BRAF gene were treated with SCH772984 (0-10 µM) for 72-120 h. Cell viability was measured by CellTiter-Glo Luminescent Cell Viability Assay. RESULTS: Among 21 cell lines, sensitivity to SCH-772984 was categorized into 3 groups: highly sensitive (IC50< 1 µM), moderately sensitive (IC50= 1-2 µM) and resistant (IC50> 2 µM). METHODS: BRAF mutant A375 cells were treated with SCH772984 (0.1-2 µmol/L) for 4 h, and the expression levels of target proteins were detected by Western Blot. RESULTS: Epirubicin significantly increased sub-G cells in G2/M block.
• Cell Research:
  For resistant cell line creation, cells were grown in Dulbecco's modified Eagle medium with 10% heat-inactivated FBS media and increasing concentrations of inhibitor (PLX4032, 0.1–10 μmol/L; GSK1120212, 0.01–1 μmol/L) over approximately 4 to 8 months until resistant cells acquired growth properties similar to na ve parental cells (at their top drug concentrations). For combination resistance, cells were incubated as above but with alternative dose escalation until a top concentration was acquired (PLX4032 10 μmol/L and GSK1120212 1 μmol/L). Stocks and dilutions of PLX4032, GSK1120212, and SCH772984 were made in DMSO solvent. Cell proliferation experiments were carried out in a 96-well format (six replicates), and cells were plated at a density of 4,000 cells per well. At 24 hours after cell seeding, cells were treated with DMSO or a 9-point IC50 dilution (0.001–10 μmol/L) at a final concentration of 1% DMSO for all concentrations. Viability was assayed 5 days after dosing using the ViaLight luminescence kit following the manufacturer's recommendations (n = 6, mean ± SE). For the cell line panel viability assay, cells were treated with SCH772984 for 4 days and assayed by the CellTiterGlo luminescent cell viability assay. For IncuCyte analysis, cells were plated as above in 96-well plates, and image-based cell confluence data were collected every 2 hours during live growth. For engineered resistant lines, cells were infected with lentivirus produced from lentiORF constructs expressing either RFP, KRASG13D, BRAFV600E, truncated BRAFV600E lacking exons 2–8 (Δ2-8), MEK1P124L, MEK1F129L, or constitutively active MEK1DD (S218D+S222D). Cells were selected in blasticidin (20 μg/mL) and used for ViaLight assays as described above .
• Animal Research:
  Nude mice were injected subcutaneously with specific cell lines, grown to approximately 100 mm^3, randomized to treatment groups (10 mice/group), and treated intraperitoneally with either SCH772984 or vehicle according to the dosing schedule indicated in the figure legends. Tumor length (L), width (W), and height (H) were measured during and after the treatment periods by a caliper twice weekly on each mouse and then used to calculate tumor volume using the formula (L × W × H)/2. Animal body weights were measured on the same days twice weekly. Data were expressed as mean ± SEM. Upon completion of the experiment, vehicle- and SCH772984-treated tumor biopsies were processed for Western blot analysis .

Storage & Handling

• Storage: store at low temperature | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice/Shipping at ambient temperature.
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

inhibit, Extracellular signal regulated kinases, ERK2, ERK, ERK1, Inhibitor, SCH772984, SCH-772984, SCH 772984

Compound Identifiers

PubChem CID

24866313