Ponatinib
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MedKoo CAT#: 202320

CAS#: 943319-70-8 (free base)

Description: Ponatinib is an orally bioavailable multitargeted receptor tyrosine kinase (RTK) inhibitor with potential antiangiogenic and antineoplastic activities. Multitargeted tyrosine kinase inhibitor AP24534 inhibits unmutated and all mutated forms of Bcr-Abl, including T315I, the highly drug therapy-resistant missense mutation of Bcr-Abl. This agent also inhibits other tyrosine kinases including those associated with vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs); in addition, it inhibits the tyrosine kinase receptor TIE2 and FMS-related tyrosine kinase receptor-3 (Flt3).


Chemical Structure

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Ponatinib
CAS# 943319-70-8 (free base)

Theoretical Analysis

MedKoo Cat#: 202320
Name: Ponatinib
CAS#: 943319-70-8 (free base)
Chemical Formula: C29H27F3N6O
Exact Mass: 532.21984
Molecular Weight: 532.56
Elemental Analysis: C, 65.40; H, 5.11; F, 10.70; N, 15.78; O, 3.00

Price and Availability

Size Price Availability Quantity
50.0mg USD 90.0 Ready to ship
100.0mg USD 150.0 Ready to ship
200.0mg USD 250.0 Ready to ship
500.0mg USD 550.0 Ready to ship
1.0g USD 950.0 Ready to ship
2.0g USD 1650.0 Ready to ship
5.0g USD 3650.0 2 Weeks
10.0g USD 5650.0 2 Weeks
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Related CAS #: 943319-70-8 (free base)   1114544-31-8 (HCl)   1232836-25-7 (tris-hydrochloride)    

Synonym: AP24534; AP-24534; AP 24534; Ponatinib. Brand name: Iclusig.

IUPAC/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

Appearance: white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Ponatinib free base is soluble in DMSO at 50 mg/mL; soluble in ethanol at 25 mg/mL with warming; very poorly soluble in water. The solubility of ponatinib in pH 1.7, 2.7, and 7.5 buffers is 7790 mcg/ml, 3.44 mcg/ml, and 0.16 mcg/ml, respectively, indicating a decrease in solubility with increasing pH.

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Ponatinib (AP24534) is a multi-targeted kinase inhibitor with IC50s 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.
In vitro activity: This study aimed to determine the mechanisms of ponatinib-induced vascular toxicity, defining associated signaling pathways and identifying potential rescue strategies. Human umbilical endothelial cells (HUVECs) were exposed to ponatinib or vehicle in the presence or absence of the neutralizing factor anti-Notch-1 antibody for exposure times of 0–72 h. Although HUVECs treated with 1.7 nM of ponatinib showed signs of cellular distress compared to vehicle (DMSO)-treated cells already after 17 h of incubation, the analysis of cell proliferation showed no significant differences in the incorporation rate of CyQUANTR NF fluorochrome, suggesting the maintenance of cells in the cell cycle at 1.7 nM of ponatinib (Figure 1A,B). On the contrary, the proliferation curves of PBMNCs treated with 1.7 nM of ponatinib showed an almost immediate toxicity of the drug, in terms of cell morphology, cell detachment from culture monolayer and block of the incorporation of the fluorochrome, compared to PBMNC treated with vehicle, suggesting a greater toxicity of ponatinib in this type of cells (data not shown). At 24 and 48 h, the HUVECs treated with 1.7 nM of ponatinib showed a significant reduction in the fluorochrome incorporation rate compared to DMSO, and a worsening of the morphological signs of cell suffering, suggesting the block of cell proliferation and the appearance of frank cytotoxicity of the drug. These effects were reverted by the co-incubation of the cells with 1 μg/mL neutralizing factor anti-Notch-1 antibody, suggesting that ponatinib acts on HUVECs via Notch-1 and the blocking of this signaling pathway can revert the endothelial drug toxicity (Figure 1A,B). After 72 h of treatment, HUVECs showed a complete and irreversible block of cell proliferation, which could not be reversed by the Notch-1 receptor blockage, suggesting the appearance of nonspecific cytotoxicity by ponatinib (Figure 1A,B). These results show the concentrationdependent effects of ponatinib on endothelial cell viability and greater sensitivity of PBMNC to ponatinib compared to HUVECs. This demonstrated that ponatinib significantly increased endothelial toxicity in vitro. Importantly, the AKT/eNOS and Notch-1 pathways have been identified as key targets of ponatinib. It has been shown that the Notch-1 pathway likely mediates, at least in part, the vascular toxicity associated with this agent. J Clin Med. 2020 Mar; 9(3): 820. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141219/
In vivo activity: Ponatinib was tested for a therapeutic effect on mouse influenza model infected by H1N1 influenza PR8 virus. Twenty-five mg/kg/d of ponatinib was set as the maximal drug dose administered in PR8-infected mice. As shown in Figure 2A, the placebo-treated mice started dying from day 9 and by day 11 and 90% of them had succumbed to infection. The mice treated with 15 mg/kg/d of ponatinib showed the highest survivalrate (50%) and had the least decline in body weight during the early stage (days 3 to 5) of influenza A virus infection (Figures 2A,C). The mice treated with 5 mg/kg/d of ponatinib showed lowest survive rate (20%), and the improvement in body weight loss decreased significantly compared to the middle dose group (Figures 2A,D). However, mice in the high dose group (25 mg/kg/d) also showed low survive rate (30%), and improvement of body weight loss was not observed at all (Figures 2A,B). To explore the optimal time to start ponatinib treatment, we performed the in vivo experiments with drug administration started on days 1, 2, 3, or 4 post-infection (Figure 3A). The mice treated with ponatinib starting on days 3 and 4 had higher survival rates than those treated starting on days 1 and 2 (Figure 3B). The body weight loss of the mice slowed down significantly after the delayed administration of ponatinib (Figures 3C–F). Unlike current antivirals that need to be administered early after virus infection, ponatinib works better when administered starting at days 3 and 4 post-infection when mice have developed obvious clinical symptoms, including piloerection, hunched posture, reduced movement, and labored breathing concomitant with a significant decrease in body weight. There were fewer inflammatory infiltrates observed in the lungs in ponatinib-treated mice than in the lungs of mice treated with placebo (Figure 4A). The cell infiltrates in the BALFs of mice treated with ponatinib or placebo were statistically analyzed for cell numbers and types (Figure 4B). Ponatinib greatly reduced the infiltration of neutrophils, which have been proven to contribute to acute lung injury in influenza pneumonia, while monocyte infiltration was not affected. Therefore, ponatinib has potential as an immunomodulator for the treatment of severe influenza. Front Immunol. 2019; 10: 1393. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598400/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 50.0 93.9
Ethanol 25.0 46.9

Preparing Stock Solutions

The following data is based on the product molecular weight 532.56 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Chen S, Liu G, Chen J, Hu A, Zhang L, Sun W, Tang W, Liu C, Zhang H, Ke C, Wu J, Chen X. Ponatinib Protects Mice From Lethal Influenza Infection by Suppressing Cytokine Storm. Front Immunol. 2019 Jun 21;10:1393. doi: 10.3389/fimmu.2019.01393. PMID: 31293574; PMCID: PMC6598400. 2. Madonna R, Pieragostino D, Cufaro MC, Doria V, Del Boccio P, Deidda M, Pierdomenico SD, Dessalvi CC, De Caterina R, Mercuro G. Ponatinib Induces Vascular Toxicity through the Notch-1 Signaling Pathway. J Clin Med. 2020 Mar 18;9(3):820. doi: 10.3390/jcm9030820. PMID: 32197359; PMCID: PMC7141219. 3. Chen S, Liu G, Chen J, Hu A, Zhang L, Sun W, Tang W, Liu C, Zhang H, Ke C, Wu J, Chen X. Ponatinib Protects Mice From Lethal Influenza Infection by Suppressing Cytokine Storm. Front Immunol. 2019 Jun 21;10:1393. doi: 10.3389/fimmu.2019.01393. PMID: 31293574; PMCID: PMC6598400. 4. Latifi Y, Moccetti F, Wu M, Xie A, Packwood W, Qi Y, Ozawa K, Shentu W, Brown E, Shirai T, McCarty OJ, Ruggeri Z, Moslehi J, Chen J, Druker BJ, López JA, Lindner JR. Thrombotic microangiopathy as a cause of cardiovascular toxicity from the BCR-ABL1 tyrosine kinase inhibitor ponatinib. Blood. 2019 Apr 4;133(14):1597-1606. doi: 10.1182/blood-2018-10-881557. Epub 2019 Jan 28. PMID: 30692122; PMCID: PMC6450432.
In vitro protocol: 1. Chen S, Liu G, Chen J, Hu A, Zhang L, Sun W, Tang W, Liu C, Zhang H, Ke C, Wu J, Chen X. Ponatinib Protects Mice From Lethal Influenza Infection by Suppressing Cytokine Storm. Front Immunol. 2019 Jun 21;10:1393. doi: 10.3389/fimmu.2019.01393. PMID: 31293574; PMCID: PMC6598400. 2. Madonna R, Pieragostino D, Cufaro MC, Doria V, Del Boccio P, Deidda M, Pierdomenico SD, Dessalvi CC, De Caterina R, Mercuro G. Ponatinib Induces Vascular Toxicity through the Notch-1 Signaling Pathway. J Clin Med. 2020 Mar 18;9(3):820. doi: 10.3390/jcm9030820. PMID: 32197359; PMCID: PMC7141219.
In vivo protocol: 1. Chen S, Liu G, Chen J, Hu A, Zhang L, Sun W, Tang W, Liu C, Zhang H, Ke C, Wu J, Chen X. Ponatinib Protects Mice From Lethal Influenza Infection by Suppressing Cytokine Storm. Front Immunol. 2019 Jun 21;10:1393. doi: 10.3389/fimmu.2019.01393. PMID: 31293574; PMCID: PMC6598400. 2. Latifi Y, Moccetti F, Wu M, Xie A, Packwood W, Qi Y, Ozawa K, Shentu W, Brown E, Shirai T, McCarty OJ, Ruggeri Z, Moslehi J, Chen J, Druker BJ, López JA, Lindner JR. Thrombotic microangiopathy as a cause of cardiovascular toxicity from the BCR-ABL1 tyrosine kinase inhibitor ponatinib. Blood. 2019 Apr 4;133(14):1597-1606. doi: 10.1182/blood-2018-10-881557. Epub 2019 Jan 28. PMID: 30692122; PMCID: PMC6450432.

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1: Oaxaca DM, Yang-Reid SA, Ross JA, Rodriguez G, Staniswalis JG, Kirken RA. Sensitivity of imatinib-resistant T315I BCR-ABL CML to a synergistic combination of ponatinib and forskolin treatment. Tumour Biol. 2016 Jul 21. [Epub ahead of print] PubMed PMID: 27444277.

2: Dessilly G, Panin N, Elens L, Haufroid V, Demoulin JB. Impact of ABCB1 1236C > T-2677G > T-3435C > T polymorphisms on the anti-proliferative activity of imatinib, nilotinib, dasatinib and ponatinib. Sci Rep. 2016 Jul 12;6:29559. doi: 10.1038/srep29559. PubMed PMID: 27405085; PubMed Central PMCID: PMC4941718.

3: Abid MB, De Mel S. Does ponatinib cross the blood-brain barrier? Br J Haematol. 2016 Jun 28. doi: 10.1111/bjh.14222. [Epub ahead of print] PubMed PMID: 27352067.

4: Breccia M, Abruzzese E, Iurlo A, Gozzini A, Isidori A, Gangemi D, Pregno P, Alimena G. Efficacy and safety of second-line ponatinib after failure of a single previous tyrosine kinase inhibitor for chronic myeloid leukemia patients in chronic phase. Haematologica. 2016 Jun;101(6):e267-8. doi: 10.3324/haematol.2016.145623. Epub 2016 May 31. PubMed PMID: 27252515.

5: Engel NW, Constantin A, Fowlkes S, Assouline S. Unexpected Success of Watch and Wait Strategy in a Ponatinib-Intolerant Patient With Chronic Myeloid Leukemia. J Oncol Pract. 2016 Jun;12(6):592-4. doi: 10.1200/JOP.2016.012054. Epub 2016 May 31. PubMed PMID: 27246687.

6: Sparidans RW, Kort A, Schinkel AH, Schellens JH, Beijnen JH. Liquid chromatography-tandem mass spectrometric assay for ponatinib and N-desmethyl ponatinib in mouse plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Jun 15;1023-1024:24-9. doi: 10.1016/j.jchromb.2016.04.049. Epub 2016 May 2. PubMed PMID: 27179188.

7: Matsuda Y, Yamauchi T, Hosono N, Uzui K, Negoro E, Morinaga K, Nishi R, Yoshida A, Kimura S, Maekawa T, Ueda T. Combination of panobinostat with ponatinib synergistically overcomes imatinib-resistant CML cells. Cancer Sci. 2016 Jul;107(7):1029-38. doi: 10.1111/cas.12965. Epub 2016 Jun 21. PubMed PMID: 27166836; PubMed Central PMCID: PMC4946706.

8: Narasimhan NI, Dorer DJ, Davis J, Turner CD, Sonnichsen D. Evaluation of the effect of multiple doses of rifampin on the pharmacokinetics and safety of ponatinib in healthy subjects. Clin Pharmacol Drug Dev. 2015 Sep;4(5):354-60. doi: 10.1002/cpdd.182. Epub 2015 May 1. PubMed PMID: 27137144.

9: Lipton JH, Chuah C, Guerci-Bresler A, Rosti G, Simpson D, Assouline S, Etienne G, Nicolini FE, le Coutre P, Clark RE, Stenke L, Andorsky D, Oehler V, Lustgarten S, Rivera VM, Clackson T, Haluska FG, Baccarani M, Cortes JE, Guilhot F, Hochhaus A, Hughes T, Kantarjian HM, Shah NP, Talpaz M, Deininger MW; EPIC investigators. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2016 May;17(5):612-21. doi: 10.1016/S1470-2045(16)00080-2. Epub 2016 Apr 12. PubMed PMID: 27083332.

10: Fava C, Saglio G. Ponatinib for chronic myeloid leukaemia: future perspectives. Lancet Oncol. 2016 May;17(5):546-7. doi: 10.1016/S1470-2045(16)30064-X. Epub 2016 Apr 12. PubMed PMID: 27083331.

11: Tournaire G, Despas F, Huguet F, Montastruc JL, Bondon-Guitton E. Peripheral arterial occlusive disease during ponatinib therapy after failure of imatinib: a case report. J Clin Pharm Ther. 2016 Jun;41(3):360-361. doi: 10.1111/jcpt.12383. Epub 2016 Mar 23. PubMed PMID: 27009771.

12: Breccia M, Colafigli G, Quattrocchi L, Abruzzese E, Alimena G. Cutaneous Lesions Anticipating Accelerated Phase of Multidrug Resistant Chronic Myeloid Leukemia Responsive to Ponatinib. Mediterr J Hematol Infect Dis. 2016 Feb 20;8(1):e2016016. doi: 10.4084/MJHID.2016.016. eCollection 2016. PubMed PMID: 26977275; PubMed Central PMCID: PMC4771144.

13: Darwish HW, Bakheit AH, Abdelhameed AS, AlKhairallah AS. Micellar Enhanced Spectrofluorimetric Method for the Determination of Ponatinib in Human Plasma and Urine via Cremophor RH 40 as Sensing Agent. Int J Anal Chem. 2015;2015:210503. doi: 10.1155/2015/210503. Epub 2015 Dec 31. PubMed PMID: 26880920; PubMed Central PMCID: PMC4736017.

14: Saglio G, Fava C. BCR-ABL1 mutation ≠ ponatinib resistance. Blood. 2016 Feb 11;127(6):666-7. doi: 10.1182/blood-2015-12-685149. PubMed PMID: 26869304.

15: Kang Z, Ji Y, Zhang G, Qu Y, Zhang L, Jiang W. Ponatinib attenuates experimental pulmonary arterial hypertension by modulating Wnt signaling and vasohibin-2/vasohibin-1. Life Sci. 2016 Mar 1;148:1-8. doi: 10.1016/j.lfs.2016.02.017. Epub 2016 Feb 6. PubMed PMID: 26860892.

16: Ponatinib. Aust Prescr. 2015 Dec;38(6):221-2. Epub 2015 Sep 18. Review. PubMed PMID: 26843719; PubMed Central PMCID: PMC4674036.

17: Sidaway P. Haematological cancer: Ponatinib in CML - keeping PACE with multiple mutations. Nat Rev Clin Oncol. 2016 Mar;13(3):135. doi: 10.1038/nrclinonc.2016.13. Epub 2016 Feb 2. PubMed PMID: 26831184.

18: Parker WT, Yeung DT, Yeoman AL, Altamura HK, Jamison BA, Field CR, Hodgson JG, Lustgarten S, Rivera VM, Hughes TP, Branford S. The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib. Blood. 2016 Apr 14;127(15):1870-80. doi: 10.1182/blood-2015-09-666214. Epub 2016 Jan 14. PubMed PMID: 26773037; PubMed Central PMCID: PMC4832506.

19: Quilot FM, Georges M, Favrolt N, Beltramo G, Foignot C, Grandvuillemin A, Montani D, Bonniaud P, Camus P. Pulmonary hypertension associated with ponatinib therapy. Eur Respir J. 2016 Feb;47(2):676-9. doi: 10.1183/13993003.01110-2015. Epub 2016 Jan 7. PubMed PMID: 26743481.

20: Breccia M, Alimena G. Ponatinib in chronic myeloid leukaemia: ready for first-line? Lancet Haematol. 2015 Sep;2(9):e352-3. doi: 10.1016/S2352-3026(15)00130-1. Epub 2015 Jul 30. PubMed PMID: 26685767.



Additional Information

Ponatinib was approved ion 2012, but temporarily suspended sales on 31 October 2013 because of "the risk of life-threatening blood clots and severe narrowing of blood vessels". This suspension was partially lifted