Ponatinib-AP24534-DataSheet-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEPonatinibCat. No.: HY-12047CAS No.: 943319-70-8Synonyms: AP24534分式: CHFNO分量: 532.56作靶点: Bcr-Abl; PDGFR; VEGFR; FGFR; Src; Autophagy作通路: Protein Tyrosine Kinase/RTK; Autophagy储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 mo

2、nths-20C 1 month溶解性数据体外实验 DMSO : 50 mg/mL (93.89 mM)* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制备储备液1 mM 1.8777 mL 9.3886 mL 18.7772 mL5 mM 0.3755 mL 1.8777 mL 3.7554 mL10 mM 0.1878 mL 0.9389 mL 1.8777 mL请根据产品在不同溶剂中的溶解度，选择合适的溶剂配制储备液，并请注意储备液的保存式和期限。体内实验 请根据您的实验动物

3、和给药式选择适当的溶解案，配制前请先配制澄清的储备液，再依次添加助溶剂(为保证实验结果的可靠性，体内实验的作液，建议您现现配，当天使；澄清的储备液可以根据储存条件，适当保存；以下溶剂前的百分 指该溶剂在您配制终溶液中的体积占)：1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 10 mg/mL (18.78 mM); Clear solution2. 请依序添加每种溶剂： 10% DMSO 90% corn oilSolubility: 10 mg/mL (18.78 mM); Clear solution1

4、/3 Master of Small Molecules 您边的抑制剂师www.MedChemEBIOLOGICAL ACTIVITY物活性 Ponatinib种有效的，可服的多靶点激酶抑制剂，抑制Abl，PDGFR，VEGFR2，FGFR1 和 Src 的 IC50分别为0.37 nM， 1.1 nM，1.5 nM，2.2 nM和5.4 nM。IC50 & Target VEGFR2 PDGFR FGFR1 c-Kit1.5 nM (IC50) 1.1 nM (IC50) 2.2 nM (IC50) 12.5 nM (IC50)体外研究 Ponatinib (AP24534) potentl

5、y inhibits native ABL (IC50: 0.37 nM), ABLT315I (IC50: 2.0 nM), and otherclinically important ABL kinase domain mutants (IC50: 0.30-0.44 nM). Ponatinib also inhibits SRC (IC50: 5.4nM) and members of the VEGFR, FGFR, and PDGFR families of receptor tyrosine kinases. Ponatinibpotently inhibits prolifer

6、ation of Ba/F3 cells expressing native BCR-ABL (IC50: 0.5 nM). All BCR-ABL mutantstested remained sensitive to Ponatinib (IC50: 0.5-36 nM) including BCR-ABLT315I (IC50: 11 nM) 1.Ponatinib (AP24534) inhibits the in vitro kinase activity of FLT3, KIT, FGFR1, and PDGFR with IC50 valuesof 13, 13, 2, and

7、 1 nM, respectively. Ponatinib inhibits phosphorylation of all 4 RTKs in a dose-dependentmanner, with IC50 values between 0.3 to 20 nM. Consistent with these activated receptors being important indriving leukemogenesis Ponatinib also potently inhibits the viability of all 4 cell lines with IC50 valu

8、es of 0.5 to17 nM. In contrast, the IC50 for inhibition of RS4;11 cells which express native (unmutated) FLT3, is morethan 100 nM 2.体内研究 In a survival model in which mice are instead injected with Ba/F3 BCR-ABLT315I cells, administration ofDasatinib at doses as high as 300 mg/kg has no effect on sur

9、vival time. By contrast, treatment with Ponatinib(AP24534) prolongs survival in a dose-dependent manner. Ponatinib dosed orally for 19 days at 5, 15, and25 mg/kg prolongs median survival to 19.5, 26, and 30 days, respectively compare to 16 days for vehicle-treated mice (pT315I cells are injected sub

10、cutaneously into mice. Tumor growth is inhibited by Ponatinib in adose-dependent manner compare to vehicle-treated mice, with significant suppression of tumor growth upondaily oral dosing at 10 and 30 mg/kg (%T/C = 68% and 20%, respectively; p 1. Ponatinib (1-25 mg/kg) isadministered orally, once da

11、ily for 28 days, to mice bearing MV4-11 xenografts. Ponatinib potently inhibitstumor growth in a dose-dependent manner. Administration of 1 mg/kg, the lowest dose tested, leads tosignificant inhibition of tumor growth (TGI=46%, P 2.PROTOCOLCell Assay 1 Ba/F3 cell lines are distributed in 96-well pla

12、tes (4103 cells/well) and incubated with escalatingconcentrations of Ponatinib for 72 hr. The inhibitor ranges used are: 0-625 nM for cells expressing BCR-ABLand 0-10,000 nM for BCR-ABL negative cells. Proliferation is measured using a methanethiosulfonate (MTS)-based viability assay. IC50 values ar

13、e reported as the mean of three independent experiments performed inquadruplicate. For cell proliferation experiments with CML or normal primary cells, mononuclear cells areplated in 96-well plates (5104 cells/well) over graded concentrations of Ponatinib (0-1000 nM) in RPMIsupplemented with 10% FBS

14、, L-glutamine, penicillin/streptomycin, and 100 M -mercaptoethanol. Followinga 72 hr incubation, cell viability is assessed by subjecting cells to an MTS assay 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.2/3 Master of Small Molecules 您边的抑制剂师www.Me

15、dChemEAnimal Mice 1Administration 1 For Ba/F3 survival model, Ba/F3 cells expressing native BCR-ABL or BCR-ABLT315I are injected into the tailvein of female SCID mice (100 L of a 1107 cells/mL suspension in serum-free medium). Beginning 72 hrlater mice are treated once daily by oral gavage with vehi

16、cle (25 mM citrate buffer, pH 2.75), Ponatinib, orDasatinib for up to 19 consecutive days. Moribund animals are sacrificed as per IACUC guidelines. Onnecropsy, mice have marked splenomegaly due to tumor cell infiltration. Survival data are analyzed usingKaplan-Meier method, and statistical significa

17、nce is evaluated with a Log-rank test comparing the survivaltime of each treatment group with the vehicle group. For Ba/F3 Tumor Model, Ba/F3 BCR-ABLT315I cells areimplanted subcutaneously into the right flank of female nude mice (100 L of a 1107 cells/mL cellsuspension in serum-free medium). Mice a

18、re randomized to treatment groups when the average tumorvolume reaches approximately 500 mm3. Mice are treated once daily by oral gavage with vehicle (25 mMcitrate buffer, pH 2.75) or Ponatinib for up to 19 consecutive days. Tumor volume (mm3) is calculated. Todetermine tumor growth inhibition when

19、the treatment period is finished, mean tumor volume for treatmentgroup/mean tumor volume for control group (%T/C) is calculated at the final measurement.MCE has not independently confirmed the accuracy of these methods. They are for reference only.户使本产品发表的科研献 Sci Transl Med. 2018 Jul 18;10(450). pii

20、: eaaq1093. J Med Chem. 2019 May 23;62(10):5006-5024. Clin Chim Acta. 2018 May;480:180-185. Exp Hematol. 2014 May;42(5):369-379.e3. Leuk Res. 2016 Jun;45:24-32.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. OHare T, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leuke