Ponatinib (AP24534)

製品コードS1490 バッチS149012

印刷

化学情報

Chemical Structure Synonyms AP24534 Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C29H27F3N6O
分子量 532.56 CAS No. 943319-70-8
Solubility (25°C)* 体外 DMSO 25 mg/mL (46.94 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 Ponatinib is a novel, potent multi-target inhibitor of 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. Ponatinib (AP24534) inhibits autophagy.
in vitro AP24534 potently inhibits native Abl, AblT315I, and other clinically important Abl kinase domain mutants with IC50 of 0.30 nM–2 nM. This compound doesn't inhibit Aurora kinase family members, nor does it inhibit insulin receptor or CDK2/cyclin E. It 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 this chemical is correlated with induction of apoptosis. [1-2] In leukemic cell lines containing activated forms of FLT3, KIT, FGFR1, and PDGFRα receptors, it 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, this inhibitor inhibits FLT3 signaling and induced apoptosis at less than 10 nM. It 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. [3] In Ba/F3 cells engineered to express activated FGFR1-4, this agent 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, it 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, this compound (2.5 mg/kg and 5 mg/kg) prolongs mice median survival. In the xenograft model of Ba/F3 Bcr-AblT315I, this compound (10 mg/kg–50 mg/kg) significantly suppresses tumor growth. It (30 mg/kg) decreases the phosphorylated Bcr-Abl and phosphorylated CrkL levels in the tumors. [2]

プロトコル(参考用のみ)

キナーゼアッセイ 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 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.
細胞アッセイ 細胞株 Ba/F3 cells expressing Bcr-Abl or a range of single mutations in the kinase domain of Bcr-Abl
濃度 0-625 nM
反応時間 72 hours
実験の流れ Ba/F3 cell lines are distributed in 96-well plates (4 × 103 cells/well) and incubated with this compound 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.
動物実験 動物モデル Mouse xenograft models of Ba/F3 cells expressing Bcr-Abl or Bcr-AblT315I
投薬量 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
投与方法 Oral gavage once daily

参考

  • https://pubmed.ncbi.nlm.nih.gov/19878872/
  • https://pubmed.ncbi.nlm.nih.gov/20513156/
  • https://pubmed.ncbi.nlm.nih.gov/21482694/
  • https://pubmed.ncbi.nlm.nih.gov/22238366/
  • https://pubmed.ncbi.nlm.nih.gov/15256422/

カスタマーフィードバック

Data from [Cancer Cell, 2012, 22(5), 656-667 ]

, , Mol Cancer Ther, 2017, 16(8):1623-1633

Data from [Data independently produced by , , Nature, 2016, 534(7609):647-51]

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Ponatinib and other clinically approved inhibitors of Src and Rho-A kinases abrogate dengue virus serotype 2- induced endothelial permeability [ Virulence, 2025, 16(1):2489751] PubMed: 40189910
Brain FGF2 and NCAM1 contribute to FGFR1-dependent progression of ER+ breast cancer brain metastases in young and aged hosts [ bioRxiv, 2025, 2025.06.07.658373] PubMed: 40666846
Molecular Interaction of Soluble Klotho with FGF23 in the Pathobiology of Aortic Valve Lesions Induced by Chronic Kidney Disease [ Int J Biol Sci, 2024, 20(9):3412-3425] PubMed: 38993571
Leishmania braziliensis enhances monocyte responses to promote anti-tumor activity [ Cell Rep, 2024, 43(3):113932] PubMed: 38457336
The molecular basis of Abelson kinase regulation by its αI-helix [ Elife, 2024, 12RP92324] PubMed: 38588001
Buparlisib and ponatinib inhibit aggressiveness of cholangiocarcinoma cells via suppression of IRS1-related pathway by targeting oxidative stress resistance [ Biomed Pharmacother, 2024, 180:117569] PubMed: 39418964
Sensitizing cholangiocarcinoma to chemotherapy by inhibition of the drug-export pump MRP3 [ Biomed Pharmacother, 2024, 180:117533] PubMed: 39405909

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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