Ponatinib Inhibitor CAS No. 943319-70-8

Cat. No.	Name	Size	Price
KI0032	Ponatinib	10 mg	$176
	Ponatinib	50 mg	$592
	Ponatinib	200 mg	$1552

Chemical Characteristic

Product Name	Ponatinib
Synonyms	AP24534
CAS No.	943319-70-8
Molecular Weight	532.56
Formula	C₂₉H₂₇F₃N₆O
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
Smiles	C(=O)(c1cc(c(cc1)C)C#Cc1n2c(cccn2)nc1)Nc1cc(c(cc1)CN1CCN(CC1)C)C(F)(F)F
Chemical Structure

Biological activities

Ponatinib is a novel multi-targeted tyrosine kinase inhibitor (TK) that potently inhibits native and mutant BCR-ABL. Ponatinib inhibits native ABL and ABL^T3151 with IC50s of 0.37 and 2.0 nM, respectively. ^[1] Ponatinib also has in vitro inhibitory activity against a discrete set of kinases implicated in the pathogenesis of other hematologic malignancies, including fms-like tyrosine kinase (FLT3), KIT, fibroblast growth factor receptor 1 (FGFR1), and platelet derived growth factor receptor a (PDGFRa), with IC50s of 13, 13, 2, and 1 nM, respectively. Besides, ponatinib inhibits FLT3 signaling and induces apoptosis at concentrations of less than 10 nM. Ponatinib inhibits phosphorylation of all 4 receptor tyrosine kinases (RTKs) (MV4-11, Kasumi-1, KG1, EOL1) in a dose-dependent manner, with IC50s range from 0.3 to 20 nM. Ponatinib is also selectively cytotoxic to leukemic cells harboring a FLT3-ITD mutant, reduces viability of FLT3-ITD positive primary blasts with an IC50 of 4 nM.^[2] Meanwhile, ponatinib demonstrates a dose-dependent inhibition of FLT3 signaling and the induction of apoptosis in FLT3-ITD-positive acute myeloid leukemia (AML) cells including primary leukemic blasts. Ponatinib induces apoptosis in FLT3-ITD-positive Ba/F3 cells harboring additional point mutations, with IC50s ranging from 0.3 to 77 nM. Ponatinib also induces apoptosis when FLT3-ITD is associated either with the N676D or the G697R mutation. ^[3] In mice with BCR-ABL^T315I-dependent disease, daily oral treatment with 2.5 or 5 mg/kg ponatinib for 19 days prolongs median survival to 27.5 and 30 days, respectively.^[1] In an MV4-11 mouse xenograft model, once daily oral dosing of ponatinib leads to a dose-dependent inhibition of signaling and tumor regression.^[2] In a Ba/F3 BCR-ABL^T315I survival model, AP24534 (10 mg/kg) has an overall survival increase of 60%. AP24534 (30 mg/kg) more than doubles the survival of animals in the highly aggressive Ba/F3 BCR-ABL^T315I survival model and is well tolerated for the duration with no signs of overt toxicity.^[4]

Protocols

Ponatinib is prepared as 10.0 mM stock solution and stored at -20 °C. ^[1]

References

[1] O??are 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. [2] Gozqlt 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. [3] Zirm E, et al. Ponatinib may overcome resistance of FLT3-ITD harboring additional point mutations, notably the previously refractory F691I mutation. Br Haematol. 2012, 157(4): 483-492. [4] Huang WS, et al. Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4- methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J Med Chem. 2010, 53(12): 4701-4719.

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