Ponatinib (AP24534)

Ponatinib (AP24534) 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, respectively.

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Ponatinib (AP24534) Chemical Structure

Ponatinib (AP24534) Chemical Structure
Molecular Weight: 532.56

Validation & Quality Control

Customer Reviews(1)

Quality Control & MSDS

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Product Information

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  • Research Area
  • Ponatinib (AP24534) Mechanism

Product Description

Biological Activity

Description Ponatinib (AP24534) 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, respectively.
Targets Abl [1] PDGFRβ [1] VEGFR2 [1] FGFR1 [1] c-Src [1]

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IC50 0.37 nM 1.1 nM 1.5 nM 2.2 nM 5.4 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 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. [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]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

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.

Cell Assay: [2]

Cell lines Ba/F3 cells expressing Bcr-Abl or a range of single mutations in the kinase domain of Bcr-Abl
Concentrations 0-625 nM
Incubation Time 72 hours
Method 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

Animal Study: [1]

Animal Models Mouse xenograft models of Ba/F3 cells expressing Bcr-Abl or Bcr-AblT315I
Formulation Dissolved in 25 mM citrate buffer, pH 2.75
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
Administration Oral gavage once daily
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, , 10 mg/mL
* 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.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km
Example

For example, to convert the dose of resveratrol used in a mouse (22.4 mg/kg) to a dose based on surface area for rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] O'Hare T, et al. Cancer Cell, 2009, 16(5), 401-412.

[2] Huang WS, et al. J Med Chem, 2010, 53(12), 4701-4719.

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Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01888562 Not yet recruiting Endometrial Neoplasms Washington University School of Medicine October 2014 --
NCT01935336 Recruiting Adenocarcinoma of the Lung|Extensive Stage Small Cell Lung Cancer|Limited Stage Small Cell Lung Cancer|Recurrent Non-small Cell Lung Cancer|Recurrent Small Cell Lung Cancer|Stage IIIA Non-small Cell Lung Cancer|Stage IIIB Non-small Cell Lung Cancer|Stage IV Non-small Cell Lung Cancer University of Colorado, Denver|Ariad Pharmaceuticals September 2013 Phase 2
NCT01813734 Suspended Non Small Cell Lung Cancer Massachusetts General Hospital September 2013 Phase 2
NCT01874665 Recruiting GIST Ariad Pharmaceuticals May 2013 Phase 2
NCT01641107 Suspended Philadelphia Positive|BCR-ABL Positive|Acute Lymphoblastic Leukemia Gruppo Italiano Malattie EMatologiche dellAdulto April 2013 Phase 2

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Chemical Information

Download Ponatinib (AP24534) SDF
Molecular Weight (MW) 532.56
Formula

C29H27F3N6O

CAS No. 943319-70-8
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 30 mg/mL (56 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol, 10 mg/mL
* <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.
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

Research Area

Customer Reviews (1)


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Rating
Source Cancer Cell, 2012, 22(5), 656-667 . Ponatinib (AP24534) purchased from Selleck
Method Western blot
Cell Lines RCH-ACV cells
Concentrations 50 nM
Incubation Time 1-24 h
Results Treatment of these cells with a CSK inhibitor (BMS-599626) or a BTK inhibitor (PCI-32765) did not recapitulate the dasatinib/ponatinib phenotype.

Product Citations (9)

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