Imatinib (STI571)

 

Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw

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]
Features

Protocol(Only for Reference)

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.

Cell Assay: ^[3]

Cell lines	BON-1 cells and NCI-H727 cells
Concentrations	~100 μM
Incubation Time	48 hours
Method	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.

Animal Study: ^[5]

Animal Models	SCLC6, SCLC61, SCLC 74 and SCLC108 small cell lung cancers are injected into Swiss mice (nu/nu, female).
Dosages	70 or 100 mg/kg
Administration	Administered via i.p.
Solubility	30% propylene glycol, 5% Tween 80, 65% D5W, 30 mg/mL

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT01650467	Not yet recruiting	Leukemia, Myeloid, Chronic-Phase	Centre Hospitalier Universitaire de Nmes	2013-10
NCT01781975	Not yet recruiting	Diabetes Mellitus, Type I|Diabetes Mellitus, Insulin-Dependent, 1|Type 1 Diabetes Mellitus|Insulin-Dependent Diabetes Mellitus 1|IDDM	University of California, San Francisco	2013-11	Phase 2
NCT01991379	Recruiting	Gastrointestinal Stromal Tumor (GIST)	Memorial Sloan-Kettering Cancer Center|Novartis	2013-11	Phase 1|Phase 2
NCT02013089	Recruiting	Gastrointestinal Cancers	Sun Yat-sen University	2013-12
NCT02001818	Not yet recruiting	Chronic Myeloid Leukaemia	Australasian Leukaemia and Lymphoma Group|Merck Sharp & Dohme (Australia) Pty Limited|Novartis Pharmaceuticals	2014-06	Phase 2

Chemical Information

Download Imatinib (STI571) SDF

Chemical Name

Customer Reviews (4)

Click to enlarge	Rating
	Source	Leukemia Research 36 (2012) 1311– 1314. Imatinib (STI571) purchased from Selleck
	Method	Thymidine uptake Uptake assay
	Cell Lines	K562, MEG-01 cells
	Concentrations	0.1-10 uM
	Incubation Time	20 min
	Results	The effect of imatinib on nucleoside transport was first examined with thymidine. At a 10-M concentration, imatinib was able to inhibit the entry of radiolabeled thymidine in K562 cells by 76%. Imatinib was still efficient and blocked by 43% the entry of thymidine at 1 uM, but its effect on thymidine transport at 0.1 uM was not significant (Fig. 1a).

Product Citations (10)

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  Decoupling of tumor-initiating activity from stable immunophenotype in HoxA9-Meis1-driven AML. [Gibbs KD Jr, et al. Cell Stem Cell 2012;10(2):210-7]

  
  PubMed: 22305570


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  Pharmacokinetic impact of SLCO1A2 polymorphisms on imatinib disposition in patients with chronic myeloid leukemia. [Yamakawa Y, et al. Clin Pharmacol Ther 2011;90(1):157-63]

  
  PubMed: 21633340


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  Cannabidiol causes activated hepatic stellate cell death through a mechanism of endoplasmic reticulum stress-induced apoptosis. [Lim MP, et al. Cell Death Dis 2011;2:e170]

  
  PubMed: 21654828