Ponatinib

Hersteller	Selleckchem
Kategorie	Oncology Neuroscience Metabolism Diabetes Cholesterol & Lipid Metabolism Regulation of Appetite Molecular Targets for Neuroscience Cardiovascular Research Thrombosis & Hemostasis Inhibitors & Compound Libraries Small Molecules By Organ Lung Cancer Bladder Cancer Colorectal Cancer Breast Cancer Heart & Blood Cancer Testicular & Prostate Cancer
Typ	Inhibitors
Specific against	other
Menge	10 mM/1 ml
ArtNr	S1490-10mM
Targets	SRC, BCR
CAS-Nr.	943319-70-8
eClass 6.1	30220300
eClass 9.0	32160605
Lieferbar
Administration	Oral gavage once daily
Animal Models	Mouse xenograft models of Ba/F3 cells expressing Bcr-Abl or Bcr-AblT315I
Cell lines	Ba/F3 cells expressing Bcr-Abl or a range of single mutations in the kinase domain of Bcr-Abl
Chemical Name	3-(2-(imidazo[1, 2-b]pyridazin-3-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
Clinical Trials	AP24534 is currently under Phase II clinical trials in treatment with leukemia.
Concentrations	0-625 nM
Description	AP24534 is a novel, potent multi-target inhibitor of Abl, PDGFRalpha, VEGFR2, FGFR1 and Src with IC50 of 0.37 nM, 1.1 nM, 1.5 nM, 2.2 nM and 5.4 nM, respectively.
Dosages	2.5 mg/kg and 5 mg/kg for Ba/F3 Bcr-Abl, 2.5 mg/kg–50 mg/kg for Ba/F3 Bcr-AblT315I
Formulation	Dissolved in 25 mM citrate buffer, pH 2.75
IC50	0.37 nM, 0.37 nM, 0.37 nM, 0.37 nM, 0.37 nM, 0.37 nM
In vitro	AP24534 potently inhibits native Abl, AblT315I, and other clinically important Abl kinase domain mutants with IC50 of 0.30 nM–2 nM. AP24534 doesn't inhibit Aurora kinase family members, nor does it inhibit insulin receptor or CDK2/cyclin E. AP24534 inhibits proliferation of Ba/F3 cells expressing Bcr-Abl with IC50 of 0.5 nM, as well as Ba/F3 cells expressing a range of Bcr-Abl mutants with IC50 of 0.5 nM–36 nM. The inhibition of proliferation by AP24534 is correlated with induction of apoptosis. [1-2] In leukemic cell lines containing activated forms of FLT3, KIT, FGFR1, and PDGFRalpha receptors, AP24534 potently inhibits receptor phosphorylation and cellular proliferation with IC50 of 0.3 nM to 20 nM. In MV4-11 (FLT3-ITD(+/+)) but not RS4, 11 (FLT3-ITD(–/–)) AML cells, AP24534 inhibits FLT3 signaling and induced apoptosis at less than 10 nM. AP24534 inhibits viability of primary leukemic blasts from a FLT3-ITD positive AML patient with IC50 of 4 nM but not those from patients with AML expressing nati [3] In Ba/F3 cells engineered to express activated FGFR1-4, AP24534 potently inhibits FGFR-mediated signaling and viability with IC50 lower than 40 nM. In cell lines representing multiple tumor types (endometrial, bladder, gastric, breast, lung, and colon), and containing FGFRs dysregulated by a variety of mechanisms, AP24534 inhibits FGFR-mediated signaling with IC50 less than 40 nM and inhibits cell growth with IC50 of 7 nM–181 nM. [4]
In vivo	In a mouse xenograft model of Ba/F3 cells expressing native Bcr-Abl, AP24534 (2.5 mg/kg and 5 mg/kg) prolongs mice median survival. In the xenograft model of Ba/F3 Bcr-AblT315I, AP24534 (10 mg/kg–50 mg/kg) significantly suppresses tumor growth. AP24534 (30 mg/kg) decreases the phosphorylated Bcr-Abl and phosphorylated CrkL levels in the tumors. [2]
Incubation Time	72 hours
Kinase Assay	Peptide substrate phosphorylation assays with GST-Abl kinase domains, The effect of AP24534 (0-320 nM) on GST-Abl kinase activity is assessed by using a synthetic peptide substrate (Abltide: EAIYAAPFAKKK). Assays are carried out at 30 C for 15 min in 25 uL reaction mixture: 8 mM MOPS (pH 7), 0.2 mM EDTA, 50 uM Abltide, 30 mM MgCl2, 10 mM beta-glycerol phosphate, 1 mM EGTA, 0.002% Brij-35, 0.4 mM DTT, 0.2 mg/mL BSA, 0.4 mM sodium orthovanadate, 10 nM WT or mutant GST-Abl kinase, and 100 uM ATP/gamma-32[P]ATP (5000 cpm/pmol). Reactions are terminated by transferring a portion of the reaction mixture onto a p81 phosphocellulose filter and immersing in 0.75% phosphoric acid. Filters are washed 3 times in 0.75% phosphoric acid, rinsed in acetone, and air dried, phosphate incorporation is determined by scintillation counting. All results are corrected for background binding to the filters, as determined by omitting peptide substrate from the kinase reaction. Time course experiments to establish the linear range of enzymatic activity precedes kinase assays.
Method	Ba/F3 cell lines are distributed in 96-well plates (4x103 cells/well) and incubated with AP24534 for 72 hours. Proliferation is measured using a methanethiosulfonate (MTS)-based viability assay (CellTiter96 Aqueous One Solution). All values are normalized to the control wells with no drug. IC50 values are reported as the mean of three independent experiments performed in quadruplicate.
Molecular Weight (MW)	532, 56
Picture ChemicalStructure Description	Ponatinib (AP24534) Chemical Structure
Solubility (25C)	DMSO 30 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL
Storage	2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO

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Menge: 10 mM/1 ml

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