Ponatinib | CAS:943319-70-8

Chemscene社は、高品質な低分子化合物を提供しているメーカーです。
Chemscene社のPonatinib(CAS:943319-70-8)をご紹介します。

※本製品は研究用です。研究用以外には使用できません。

Name:Ponatinib; AP24534
Cat. No. :CS-0204
CAS No. :943319-70-8
Formula:C29H27F3N6O
M. Wt. : 532.56
Solubility:DMSO: ≥ 50 mg/mL

Ponatinib is a potent, orally available multi-targeted kinase inhibitor with IC50 of 0.37 nM, 1.1 nM, 1.5 nM, 2.2 nM, and 5.4 nM for Abl, PDGFRα, VEGFR2, FGFR1, and Src, respectively.IC50 & Target: IC50: 0.37 nM (Abl), 0.24 nM (Lyn), 1.1 nM (PDGFRα), 1.5 nM (VEGFR2), 2.2 nM (FGFR1), 5.4 nM (Src)[1]In Vitro: Ponatinib (AP24534) potently inhibits native ABL (IC50: 0.37 nM), ABLT315I (IC50: 2.0 nM), and other clinically important ABL kinase domain mutants (IC50: 0.30-0.44 nM). Ponatinib also inhibits SRC (IC50: 5.4 nM) and members of the VEGFR, FGFR, and PDGFR families of receptor tyrosine kinases. Ponatinib potently inhibits proliferation of Ba/F3 cells expressing native BCR-ABL (IC50: 0.5 nM). All BCR-ABL mutants tested 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 PDGFRα with IC50 values of 13, 13, 2, and 1 nM, respectively. Ponatinib inhibits phosphorylation of all 4 RTKs in a dose-dependent manner, with IC50 values between 0.3 to 20 nM. Consistent with these activated receptors being important in driving leukemogenesis Ponatinib also potently inhibits the viability of all 4 cell lines with IC50 values of 0.5 to 17 nM. In contrast, the IC50 for inhibition of RS4;11 cells which express native (unmutated) FLT3, is more than 100 nM[2].In Vivo: In a survival model in which mice are instead injected with Ba/F3 BCR-ABLT315I cells, administration of Dasatinib at doses as high as 300 mg/kg has no effect on survival time. By contrast, treatment with Ponatinib (AP24534) prolongs survival in a dose-dependent manner. Ponatinib dosed orally for 19 days at 5, 15, and 25 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 subcutaneously into mice. Tumor growth is inhibited by Ponatinib in a dose-dependent manner compare to vehicle-treated mice, with significant suppression of tumor growth upon daily oral dosing at 10 and 30 mg/kg (%T/C = 68% and 20%, respectively; p[1]. Ponatinib (1-25 mg/kg) is administered orally, once daily for 28 days, to mice bearing MV4-11 xenografts. Ponatinib potently inhibits tumor growth in a dose-dependent manner. Administration of 1 mg/kg, the lowest dose tested, leads to significant inhibition of tumor growth (TGI=46%, P[2].

Uchida T, et al. Hes1 upregulation contributes to the development of FIP1L1-PDGRA-positive leukemia in blast crisis. Exp Hematol. 2014 May;42(5):369-379.e3. Gozgit JM, et al. Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. Mol Cancer Ther, 2011, 10(6), 1028-1035. O'Hare T, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell, 2009, 16(5), 401-412.