Ponatinib free base | CAS#943319-70-8 | Bcr-Abl inhibitor

MedKoo Cat#: 202320 | Name: Ponatinib

Description:

WARNING: This product is for research use only, not for human or veterinary use.

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

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: 532.2198

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
100mg	USD 150.00	Ready to ship
200mg	USD 225.00	Ready to ship
500mg	USD 385.00	Ready to ship
1g	USD 685.00	Ready to ship
2g	USD 1,150.00	Ready to ship
5g	USD 2,350.00	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

More Info

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

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#TZC50707

QC Data

View QC data: current batch, Lot#TZC50707

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

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/

	Solvent	mg/mL	mM
Solubility
	DMSO	50.0	93.90
	Ethanol	25.0	46.90

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

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.

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:

In vivo protocol:

1: Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2025 update on diagnosis, therapy, and monitoring. Am J Hematol. 2024 Aug 2. doi: 10.1002/ajh.27443. Epub ahead of print. PMID: 39093014. 2: Kaiser F, Lunghi M, Cardinali D, Bellomarino V, Beldinanzi M, Starza ID, Malfona F, Basilico CM, Defina M, Mastaglio S, Giglio F, Lazzarotto D, Salutari P, Piccini M, Cardinali V, Pierini A, Fracchiolla NS, Di Biase F, Annunziata M, Di Trani M, Foa R, Chiaretti S. Ponatinib alone or with chemo-immunotherapy in heavily pre-treated Philadelphia-like acute lymphoblastic leukemia: a CAMPUS ALL real-life study. Haematologica. 2024 Aug 1. doi: 10.3324/haematol.2024.285258. Epub ahead of print. PMID: 39086308. 3: Khan AAS, Yousaf MA, Azhar J, Maqbool MF, Bibi R. Repurposing FDA approved drugs against monkeypox virus DNA dependent RNA polymerase: virtual screening, normal mode analysis and molecular dynamics simulation studies. Virusdisease. 2024 Jun;35(2):260-270. doi: 10.1007/s13337-024-00869-8. Epub 2024 Jun 11. PMID: 39071866; PMCID: PMC11269544. 4: S A, Shah A, Ashish A, Kumar Singh N, Kaur M, Kumar Yadav A, Singh R. BCR-ABL kinase domain mutations in CML patients, experience from a tertiary care center in North India. Leuk Res Rep. 2023 Dec 24;21:100403. doi: 10.1016/j.lrr.2023.100403. PMID: 39035746; PMCID: PMC11258388. 5: Kantarjian H, Short NJ, Haddad FG, Jain N, Huang X, Montalban-Bravo G, Kanagal-Shamanna R, Kadia TM, Daver N, Chien K, Alvarado Y, Garcia-Manero G, Issa GC, Garris R, Nasnas C, Nasr L, Ravandi F, Jabbour E. Results of the Simultaneous Combination of Ponatinib and Blinatumomab in Philadelphia Chromosome-Positive ALL. J Clin Oncol. 2024 Jul 19:JCO2400272. doi: 10.1200/JCO.24.00272. Epub ahead of print. PMID: 39028925. 6: Liu X, Fan W, Lin S, Chen J, Zhang S, Li X, Jin M, He Q. Anti-thrombotic effect of protoparaxotriol saponins from Panax notoginseng using zebrafish model. J Cardiovasc Pharmacol. 2024 Jun 19. doi: 10.1097/FJC.0000000000001604. Epub ahead of print. PMID: 39027983. 7: García Molina A. Asciminib for third-line treatment of chronic myeloid leukemia: Cost-effectiveness analysis based on treatment-free remission approach. Farm Hosp. 2024 Jul 15:S1130-6343(24)00100-4. English, Spanish. doi: 10.1016/j.farma.2024.06.004. Epub ahead of print. PMID: 39013681. 8: Zibrova D, Ernst T, Hochhaus A, Heller R. The BCR::ABL1 tyrosine kinase inhibitors ponatinib and nilotinib differentially affect endothelial angiogenesis and signalling. Mol Cell Biochem. 2024 Jul 15. doi: 10.1007/s11010-024-05070-5. Epub ahead of print. PMID: 39009935. 9: Wang S, Gan L, Han L, Deng P, Li Y, He D, Chi H, Zhu L, Li Y, Long R, Gan Z. Design, synthesis, and biological evaluation of naphthalene imidazo[1,2-b]pyridazine hybrid derivatives as VEGFR selective inhibitors. Arch Pharm (Weinheim). 2024 Jul 15:e2400411. doi: 10.1002/ardp.202400411. Epub ahead of print. PMID: 39008876. 10: Mosa FES, Alqahtani MA, El-Ghiaty MA, El-Mahrouk SR, Barakat K, El-Kadi AOS. Modulation of aryl hydrocarbon receptor activity by tyrosine kinase inhibitors (ponatinib and tofacitinib). Arch Biochem Biophys. 2024 Jul 9;759:110088. doi: 10.1016/j.abb.2024.110088. Epub ahead of print. PMID: 38992456. 11: Biondi F, Ghelardoni S, Moscato S, Mattii L, Barachini S, Novo G, Zucchi R, De Caterina R, Madonna R. Empagliflozin restores autophagy and attenuates ponatinib-induced cardiomyocyte senescence and death. Vascul Pharmacol. 2024 Jun;155:107300. doi: 10.1016/j.vph.2024.107300. PMID: 38985602. 12: Ali MA, Aiman W, Kantarjian H, Jabbour E, Ravandi F, Jain N, Short NJ, Sasaki K. Efficacy of Chemotherapy-Free Regimens in the Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis. Clin Lymphoma Myeloma Leuk. 2024 Jun 12:S2152-2650(24)00230-1. doi: 10.1016/j.clml.2024.06.002. Epub ahead of print. PMID: 38972767. 13: Aldaz P, Olias-Arjona A, Lasheras-Otero I, Ausin K, Redondo-Muñoz M, Wellbrock C, Santamaria E, Fernandez-Irigoyen J, Arozarena I. Drug-Induced Reorganisation of Lipid Metabolism Limits the Therapeutic Efficacy of Ponatinib in Glioma Stem Cells. Pharmaceutics. 2024 May 29;16(6):728. doi: 10.3390/pharmaceutics16060728. PMID: 38931850; PMCID: PMC11206984. 14: Walczak P, Fodil S, Vignal N, Cabannes-Hamy A, Boissel N, Raffoux E, Cayuela JM, Goldwirt L, Lengliné E. Cerebrospinal fluid distribution and pharmacokinetics of ponatinib in Ph1-positive acute lymphoblastic leukemia. Blood. 2024 Jun 25:blood.2024024838. doi: 10.1182/blood.2024024838. Epub ahead of print. PMID: 38917352. 15: Mahapatra S, Kar P. Computational biophysical characterization of the effect of gatekeeper mutations on the binding of ponatinib to the FGFR kinase. Arch Biochem Biophys. 2024 Aug;758:110070. doi: 10.1016/j.abb.2024.110070. Epub 2024 Jun 21. PMID: 38909834. 16: Byrne N, Forde K, Mcdonald S, Malladi R, Chan S. Ponatinib-induced lamellar ichthyosis-like drug eruption. Eur J Dermatol. 2024 Apr 1;34(2):236-238. doi: 10.1684/ejd.2024.4670. PMID: 38907571. 17: Abou Dalle I, Moukalled N, El Cheikh J, Mohty M, Bazarbachi A. Philadelphia- chromosome positive acute lymphoblastic leukemia: ten frequently asked questions. Leukemia. 2024 Jun 20. doi: 10.1038/s41375-024-02319-2. Epub ahead of print. PMID: 38902471. 18: Batool M, Qazi RE, Mudassir MA, Sajid Z, Zaman R, Rauf MA, Kousar S, Ahmad I, Rehman FU, Mian AA. Titania-Graphene Oxide Nanocomposite-Based Philadelphia- Positive Leukemia Therapy. ACS Appl Bio Mater. 2024 Jul 15;7(7):4352-4365. doi: 10.1021/acsabm.4c00207. Epub 2024 Jun 20. PMID: 38900491. 19: Candoni A, Chiusolo P, Lazzarotto D, Sartor C, Dargenio M, Chiaretti S, Skert C, Giglio F, Trappolini S, Fracchiolla NS, Medici S, Bresciani P, Cuoghi A, Papayannidis C. Ponatinib as a Prophylactic or Pre-Emptive Strategy to Prevent Cytological Relapse after Allogeneic Stem Cell Transplantation in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Transplanted in Complete Cytological Remission. Cancers (Basel). 2024 May 31;16(11):2108. doi: 10.3390/cancers16112108. PMID: 38893226; PMCID: PMC11171293. 20: Chee L, Lee N, Grigg A, Chen M, Schwarer A, Szer J, Ratnasingam S, Raj S, Lukito P, Yeung D, Hughes T, Shanmuganathan N. Clinical outcomes of chronic myeloid leukaemia patients taking asciminib through a Managed Access Programme (MAP) in Australia. Intern Med J. 2024 Jul;54(7):1214-1218. doi: 10.1111/imj.16446. Epub 2024 Jun 17. PMID: 38884158.