product name SCH772984
Description: SCH772984 is a novel, potent and ATP-competitive iinhibitor of ERK1/2 with IC50 of 4 nM and 1 nM in cell-free assay, respectively. SCH772984 was identified by an affinity-based mass spectroscopy high-throughput platform. Although it displays behaviors of both type I and type II kinase inhibitors, SCH772984 is highly selective against only seven kinases, including CLK2, FLT4, GSG2, MAP4K4, MAPK1, MINK1, PRKD1 and TTK, out of a wide range of 300 tested with more than 50% inhibition at a concentration of 1 μmol/L.
References: Cancer Discov. 2013 Jul;3(7):742-50.
587.67
Formula
C33H33N9O2
CAS No.
942183-80-4
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 0.1 mg/mL (0.17 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
5% DMSO+30% PEG 300+ddH2O: 0.6 mg/mL
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19415341
| In Vitro |
In vitro activity: SCH772984 is a novel, selective and ATP competitive inhibitor of ERK1/2. SCH772984 inhibits phosphorylation of the ERK substrate p90 ribosomal S6 kinase (T359/S363 phospho-RSK) in a dose-dependent manner. SCH772984 also inhibits phosphorylation of residues in the activation loop of ERK itself. SCH772984 demonstrates EC50 values <500 nM in approximately 88% and 49% of BRAF-mutant or RAS-mutant tumor lines, respectively. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. Kinase Assay: SCH772984 is tested in 8 point dilution curves in duplicate against purified ERK2 or ERK1. The enzyme is added to the reaction plate. and incubated with the compound before adding a solution of substrate peptide and ATP. 14μl of diluted enzyme (0.3ng active ERK2 per reaction) is added to each well of a 384-well plate. The plates are gently shaken to mix the reagents and incubated for 45 minutes at room temperature. The reaction is stopped with 60μl of IMAP Binding Solution (1:2200 dilutions of IMAP beads in 1X Binding Buffer). The plates are incubated at room temperature for an additional 0.5 hours to allow complete binding of phosphopeptides to the IMAP beads. Plates are read on the LJL Analyst. Cell Assay: Cell proliferation experiments are performed in a 96-well format (six replicates), and cells (BRAF-mutant or RAS-mutant tumor lines) are plated at 4,000/well density. At 24 h after cell seeding, cells are treated with DMSO or 9 point IC50 dilution (0.001-10 μM) at 1% DMSO final for all concentrations. Viability is assayed on 5 days after dosing using ViaLight luminescence kit following the manufacturer’s recommendations. For cell line panel viability assay, cells are treated with SCH772984 for 4 days and assayed by CellTiterGlo luminescent cell viability assay. |
|---|---|
| In Vivo | The therapeutic effects of combining the CDK inhibitor Dinaciclib with inhibitors of ERK inhibitor SCH772984 were evaluated using two orthotopic patient-derived human pancreatic cancer xenograft models (Panc253 and Panc265). These models closely resemble the physiological and pathological conditions of pancreatic cancer in humans. A 2-3 mm3 tumor explant was implanted into the pancreas of nude mice and ultrasound imaging was used to measure the tumor size (3D) before randomization and treatment, which began when tumors grew to 50-100 mm3. The combination of Dinaciclib (20 mg/kg, i.p., t.i.w.) and SCH772984 (25 mg/kg, i.p., b.i.d.) dramatically inhibited the growth of primary orthotopic Panc265 (82.5%, p < 0.001) and Panc253 (95.7%, p <0.001) versus control, and also the number of metastatic lesions of both Panc265 (94.9%, p <0.001) and Panc253 (92.4%, p <0.02). |
| Animal model | Nude mice |
| Formulation & Dosage | 25 mg/kg; i.p. injection |
| References | Cancer Discov. 2013 Jul;3(7):742-50. |
