Imatinib(STI571)

• Catalog No.: S2475
• CAS Number: 152459-95-5
• M. F.: C29H31N7O
• M. W.: 493.60274
• Storage: -20°C

SYNONYMS

• IUPAC name: N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)-4-[(4-methylpiperazin-1-yl)methyl]benzamide
• IUPAC Traditional name: imatinib mesylate
• Synonyms: Glivec; Gleevec; STI571

DATABASE IDS

• CAS Number: 152459-95-5

PROPERTIES

• Salt Data: Free Base
• Storage Condition: -20°C

DETAILS

Description (English)

Research Area

• Description: Immunology

Biological Activity

• Description: Imatinib is a multi-target inhibitor of v-Abl, c-Kit and PDGFR with IC50 of 0.6 μM, 0.1 μM and 0.1 μM, respectively.
• Targets: v-Abl; PDGFR; c-Kit
• IC50: 600 nM; 100 nM ^[1]; 100 nM ^[2]
• In Vitro: In vitro assays for inhibition of a panel of tyrosine and serine/threonine protein kinases show that Imatinib inhibits the v-Abl tyrosine kinase and PDGFR potently with an IC50 of 0.6 and 0.1 μM, respectively. ^[1] Imatinib inhibits the SLF-dependent activation of wild-type c-kit kinase activity with a IC50 for these effects of approximately 0.1 μM, which is similar to the concentration required for inhibition of PDGFR. ^[2] Imatinib exhibits growth-inhibitory activity on the human bronchial carcinoid cell line NCI-H727 and the human pancreatic carcinoid cell line BON-1 with an IC50 of 32.4 and 32.8 μM, respectively. ^[3] A recent study shows that Imatinib has the potential to exert its antileukemia effects in chronic myelogenous leukemia by down-regulating hERG1 K(+) channels, which are highly expressed in leukemia cells and appear of exceptional importance in favoring leukemogenesis. ^[4]
• In Vivo: Imatinib produces a different antitumor effect on three xenografted tumors derived from surgical samples of fresh human small cell lung cancers, with 80%, 40% and 78% growth inhibition of SCLC6, SCLC61 and SCLC108 tumors, respectively, and no significant inhibition of SCLC74 growth. ^[5] In high fat fed ApoE(-/-) mice, Imatinib significantly reduces the high fat-induced lipid staining area by 30%, 27% and 35% compared to high-fat diet untreated controls when dosed by gavage at 10, 20 and 40 mg/kg, respectively, and suppresses carotid artery lipid accumulation. ^[6]
• Clinical Trials: Imatinib is currently being investigated in Phase III clinical trials in patients with Sarcoma.

Protocol

• Protocol: Kinase Assay ^[1]
• PDGF receptor kinase activity: PDGF receptor is immunoprecipitated from BALB/c 3T3 cell extracts with rabbit antiserum to the murine PDGF receptor for 2 hours on ice. Protein A-Sepharose beads are used to collect the antigen-antibody complexes. The immunoprecipitates are washed twice with TNET (50 mM Tris, pH 7.5, 140 mM NaCl, 5 mM EDTA, 1% Triton X-100), once with TNE (50 mM Tris, pH 7.5, 140 mM EDTA), and once with kinase buffer (20 mM Tris, pH 7.5,10 mM MgCl₂). After stimulation with PDGF (50 ng/mL) for 10 minutes at 4 °C, different concentrations of drug are added to the reaction mixture. PDGF receptor kinase activity is determined by incubation with 10 μCi [7-^33P]-ATP and l μM ATP for 10 minutes at 4 °C. Immune complexes are separated by SDS-PAGE on 7.5% gels.
• Protocol: Cell Assay ^[3]
• Cell Lines: BON-1 cells and NCI-H727 cells
• Concentrations: ~100 μM
• Incubation Time: 48 hours
• Methods: BON-1 cells and NCI-H727 cells are seeded into flat-bottomed 96-well plates in triplicate and allowed to adhere overnight in 10% fetal bovine serum-supplemented DMEM or RPMI 1640 complete medium, respectively; the medium is then exchanged for serum-free medium (negative control) or serum-free medium containing serial dilutions of Imatinib. After 48 hours (control cultures do not reach confluence), the number of metabolically active cells is determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and absorbance is measured in a Packard Spectra microplate reader at 540 nm. Growth inhibition is calculated using the following formula: inhibition rate = (1 ? a / b) × 100%, where a and b are the absorbance values of the treated and control groups, respectively.
• Protocol: Animal Study ^[5]
• Animal Models: SCLC6, SCLC61, SCLC 74 and SCLC108 small cell lung cancers are injected into Swiss mice (nu/nu, female).
• Formulation: Imatinib is diluted in water.
• Doses: 70 or 100 mg/kg
• Administration: Administered via i.p.

References

• References: [1] Buchdunger E, et al. Proc Natl Acad Sci USA. 1995, 92(7), 2558–2562.
• References: [2] Heinrich MC, et al. Blood. 2000, 96(3), 925-932.
• References: [3] Yao JC, et al. Clin Cancer Res. 2007, 13(1), 234-240.
• References: [4] Zheng F, et al. Med Oncol, 2012, 29(3), 2127-2135.
• References: [5] Decaudin D, et al. Int J Cancer. 2005, 113(5), 849-856.
• References: [6] Ballinger ML, et al. J Cell Mol Med. 2010,14(6B), 1408-1418.

REFERENCES

• Buchdunger E, et al. Proc Natl Acad Sci USA. 1995, 92(7), 2558–2562.
• Heinrich MC, et al. Blood. 2000, 96(3), 925-932.
• Yao JC, et al. Clin Cancer Res. 2007, 13(1), 234-240.
• Zheng F, et al. Med Oncol, 2012, 29(3), 2127-2135.
• Decaudin D, et al. Int J Cancer. 2005, 113(5), 849-856.
• Ballinger ML, et al. J Cell Mol Med. 2010,14(6B), 1408-1418.