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    Ponatinib (AP-24534; Iclusig)
    Ponatinib (AP-24534; Iclusig)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0491
    CAS #: 943319-70-8 Purity ≥98%

    Description: Ponatinib (formerly known as AP24534; trade name Iclusig) is a novel, orally bioavailable multi-targeted kinase inhibitor with potent antitumor activity. It inhibits Abl, PDGFRα, VEGFR2, FGFR1 and Src with IC50 of 0.37 nM, 1.1 nM, 1.5 nM, 2.2 nM and 5.4 nM in cell-free assays, respectively. It has the potential for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib inhibits unmutated and all mutated forms of Bcr-Abl, including T315I, the highly drug therapy-resistant missense mutation of Bcr-Abl. Ponatinib was approved by the US FDA on December 14, 2012, for patients with resistant or intolerant CML and Ph+ ALL.

    References: Cancer Cell. 2009 Nov 6;16(5):401-12; J Med Chem. 2010 Jun 24;53(12):4701-19.

    Related CAS: 1114544-31-8 (HCl); 1232836-25-7 (tris-hydrochloride); 943319-70-8 (free base) 

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    Molecular Weight (MW)532.56
    FormulaC29H27F3N6O
    CAS No.943319-70-8(free base); 
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 30 mg/mL (56.3 mM)
    Water: <1 mg/mL
    Ethanol:<1 mg/mL
    Solubility (In vivo)30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL
    SynonymsAP-24534; AP24534; Ponatinib; AP 24534; Trade name: Iclusig. 

    Chemical Name: 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide.

    InChi Key: PHXJVRSECIGDHY-UHFFFAOYSA-N

    InChi Code: InChI=1S/C29H27F3N6O/c1-20-5-6-22(16-21(20)8-10-25-18-33-27-4-3-11-34-38(25)27)28(39)35-24-9-7-23(26(17-24)29(30,31)32)19-37-14-12-36(2)13-15-37/h3-7,9,11,16-18H,12-15,19H2,1-2H3,(H,35,39)

    SMILES Code: O=C(NC1=CC=C(CN2CCN(C)CC2)C(C(F)(F)F)=C1)C3=CC=C(C)C(C#CC4=CN=C5C=CC=NN54)=C3


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    In Vitro

    In vitro activity: 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. In leukemic cell lines containing activated forms of FLT3, KIT, FGFR1, and PDGFRα 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 native FLT3. 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.


    Kinase Assay: 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 μL reaction mixture: 8 mM MOPS (pH 7), 0.2 mM EDTA, 50 μM Abltide, 30 mM MgCl2, 10 mM β-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 µM ATP/γ-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. 


    Cell Assay: Ba/F3 cell lines are distributed in 96-well plates (4 × 103 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 quadruplicat.

    In VivoIn 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.
    Animal modelMouse xenograft models of Ba/F3 cells expressing Bcr-Abl or Bcr-AblT315I
    Formulation & DosageDissolved in 25 mM citrate buffer, pH 2.75;  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;  Oral gavage
    References

    Cancer Cell. 2009 Nov 6;16(5):401-12; J Med Chem. 2010 Jun 24;53(12):4701-19.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    Ponatinib (AP24534)

    Ponatinib (AP24534)
    Ponatinib (AP24534)


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