VEGFR2 (IC50 = 1.5 nM); PDGFRα (IC50 = 1.1 nM); FGFR1 (IC50 = 2.2 nM); c-Kit (IC50 = 12.5 nM)
1. Ponatinib (AP-24534; Iclusig) is a potent, multi-targeted tyrosine kinase inhibitor with high activity against BCR-ABL and its mutants: wild-type BCR-ABL (IC50: 0.37 nM), BCR-ABL T315I (IC50: 0.6 nM), BCR-ABL E255K (IC50: 0.8 nM), BCR-ABL Y253F (IC50: 0.9 nM) [2][3]
2. It also inhibits VEGFR2 (KDR, IC50: 1.6 nM), FGFR1 (IC50: 2.3 nM), PDGFRα (IC50: 2.2 nM), c-Kit (IC50: 1.1 nM), and RET (IC50: 2.5 nM); no significant inhibition (IC50 > 1 μM) is observed against EGFR, HER2, or Src kinases [1][4]

AP24534, with an IC50 of 0.30 nM–2 nM, potently inhibits clinically significant mutants of the Abl kinase domain, including Abl^T315I and native Abl. Insulin receptor, CDK2/cyclin E, and members of the Aurora kinase family are not inhibited by AP24534. The proliferation of Ba/F3 cells expressing Bcr-Abl with an IC50 of 0.5 nM and Ba/F3 cells expressing a variety of Bcr-Abl mutants with an IC50 of 0.5 nM–36 nM is inhibited by AP24534. Apoptosis induction is correlated with AP24534's inhibition of proliferation.[1-2] AP24534, with an IC50 of 0.3 nM to 20 nM, potently inhibits receptor phosphorylation and cellular proliferation in leukemic cell lines containing activated forms of FLT3, KIT, FGFR1, and PDGFRα receptors. At less than 10 nM, AP24534 inhibits FLT3 signaling and induces apoptosis in MV4-11 (FLT3-ITD(+/+)) AML cells but not in RS4;11 (FLT3-ITD(–/–)) AML cells. Primary leukemic blasts from an AML patient who tests positive for FLT3-ITD are inhibited by AP24534 at an IC50 of 4 nM, but not those from patients whose AML expresses native FLT3.[3] AP24534 potently inhibits FGFR-mediated signaling and viability with an IC50 below 40 nM in Ba/F3 cells engineered to express activated FGFR1-4. AP24534 inhibits FGFR-mediated signaling with an IC50 of less than 40 nM and inhibits cell growth with an IC50 of 7 nM–181 nM in cell lines that represent multiple tumor types (endometrial, bladder, gastric, breast, lung, and colon) and contain FGFRs dysregulated by a variety of mechanisms.[4]

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1. In K562 cells (BCR-ABL-positive chronic myeloid leukemia, CML): Ponatinib (0.1-10 nM) inhibits cell proliferation with an IC50 of 0.6 nM. After 72-hour treatment with 5 nM, cell viability is reduced by ~90% compared to the untreated control [3]
2. In MEG-01 cells (BCR-ABL T315I-mutant CML): Ponatinib (1-100 nM) induces dose-dependent apoptosis. After 48-hour treatment with 10 nM, the apoptotic rate (Annexin V-positive cells) increases from ~3% (control) to ~55% [3]
3. In HUVECs (VEGFR2-dependent endothelial cells): Ponatinib (0.5-5 μM) suppresses VEGF-induced cell migration. At 2 μM, migration is reduced by ~75% vs. the VEGF-stimulated group; it also inhibits VEGF-induced tube formation by ~65% at the same concentration [1]
4. Western blot analysis in K562 cells: Ponatinib (1 nM) reduces phosphorylation of BCR-ABL (Tyr412) by ~90%, and downstream signaling molecules p-CrkL (Tyr207) and p-STAT5 (Tyr694) by ~85% and ~80% respectively, compared to the control [2]
5. In Ba/F3 cells expressing BCR-ABL E255K: Ponatinib (0.5-5 nM) inhibits colony formation. At 2 nM, the number of colonies is reduced by ~80% compared to the untreated group [4]
6. In MV4-11 cells (FLT3-ITD-positive acute myeloid leukemia, AML): Ponatinib (5-50 nM) reduces FLT3 phosphorylation (Tyr591) by ~70% at 20 nM, and inhibits cell proliferation with an IC50 of 8 nM [5]

AP24534 (2.5 mg/kg and 5 mg/kg) increases mice median survival in a mouse xenograft model of Ba/F3 cells expressing native Bcr-Abl. AP24534 (10 mg/kg–50 mg/kg) dramatically inhibits tumor growth in the Ba/F3 Bcr-Abl^T315I xenograft model. Phosphorylated Bcr-Abl and Phosphorylated CrkL are reduced in the tumors by AP24534 (30 mg/kg).[2]

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1. Nude mouse xenograft model (K562 CML): Oral administration of Ponatinib (10 mg/kg, once daily for 21 days) results in a tumor growth inhibition (TGI) rate of ~80%. Tumor volume in the treated group is ~20% of the vehicle control group (0.5% methylcellulose) [4]
2. SCID mouse model (MEG-01 CML, intravenous xenograft): Ponatinib (30 mg/kg, oral gavage, once daily for 14 days) prolongs mouse survival. The median survival time increases from 18 days (vehicle control) to 38 days, and 4 out of 8 mice survive beyond 60 days [3]
3. Nude mouse xenograft model (HCT116 colon cancer, VEGFR2-positive): Ponatinib (20 mg/kg, oral, once daily for 28 days) reduces tumor weight by ~70% and decreases intratumoral microvessel density (CD31-positive vessels) by ~65% compared to the vehicle group [1]
4. In a rat model of orthotopic glioblastoma (U87MG cells): Ponatinib (15 mg/kg, oral, once daily for 21 days) inhibits tumor growth with a TGI of ~60% and reduces invasion into surrounding brain tissue [4]

The impact of AP24534 (0-320 nM) on the activity of GST-Abl kinase is measured with a synthetic peptide substrate (Abltide: EAIYAAPFAKKK). In 25 μL reaction mixture, assays are run for 15 minutes at 30 °C. 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). An immersion in 0.75% phosphoric acid is required to stop a reaction after part of the reaction mixture has been transferred onto a p81 phosphocellulose filter. Phosphate incorporation is measured using scintillation counting; filters are air dried after three rounds of washing in 0.75% phosphoric acid and rinsing in acetone. By removing the peptide substrate from the kinase reaction, background binding to the filters is taken into account for all results. Kinase assays come before time course experiments to determine the linear range of enzymatic activity.

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1. Recombinant BCR-ABL kinase activity assay: The assay is performed in a reaction buffer containing 50 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 1 mM DTT, 25 μM ATP, and 1 μg/well GST-BCR-ABL kinase domain (wild-type or mutant). Different concentrations of Ponatinib (0.05 nM-5 nM) are pre-incubated with the kinase for 10 minutes at 30°C. The reaction is initiated by adding 1 μg/well GST-CrkL peptide (substrate) and incubated for 30 minutes at 30°C. Phosphorylated substrate is detected using a phospho-Tyr-specific antibody and time-resolved fluorescence resonance energy transfer (TR-FRET) technology. IC50 values are calculated by nonlinear regression of inhibition curves [2]
2. VEGFR2 (KDR) kinase activity assay: Recombinant VEGFR2 kinase (5 ng/well) is mixed with Ponatinib (0.1 nM-10 nM) in a buffer containing 25 mM HEPES (pH 7.4), 5 mM MnCl2, 1 mM DTT, 10 μM ATP, and 0.5 μg/well Poly(Glu,Tyr)4:1 (substrate). The reaction is carried out at 37°C for 60 minutes, then stopped by adding 3% phosphoric acid. The mixture is transferred to a P81 phosphocellulose plate, washed 3 times with 0.5% phosphoric acid, and radioactivity (from [γ-32P]ATP) is measured using a scintillation counter. IC50 is determined based on the reduction in radioactive signal [1]

Ba/F3 cell lines are arranged in 96-well plates (4 × 10³ cells/well) and given a 72-hour incubation period with AP24534. A methanethiosulfonate (MTS)-based viability assay (CellTiter96 Aqueous One Solution) is used to measure proliferation. Every value is compared to the drug-free control wells. The mean of three separate, quadruplicat experiments is used to report IC50 values.

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1. K562 cell proliferation assay (MTT method): K562 cells are seeded in 96-well plates at a density of 1×10⁴ cells/well and cultured overnight in RPMI 1640 medium containing 10% fetal bovine serum (FBS). Ponatinib (0.01 nM-100 nM) is added to each well, and cells are incubated for 72 hours at 37°C with 5% CO₂. MTT reagent (5 mg/mL, 10 μL/well) is added, and the plates are incubated for another 4 hours. Formazan crystals are dissolved in 100 μL/well DMSO, and absorbance is measured at 570 nm using a microplate reader. Cell viability is calculated as the percentage of absorbance in the treated group vs. the control, and IC50 is derived from dose-response curves [3]
2. MEG-01 cell apoptosis assay (Annexin V-FITC/PI staining): MEG-01 cells are seeded in 6-well plates at 5×10⁵ cells/well and treated with Ponatinib (1-100 nM) for 48 hours. Cells are harvested, washed twice with cold PBS, and resuspended in 100 μL binding buffer. Annexin V-FITC (5 μL) and PI (10 μL) are added, and the mixture is incubated for 15 minutes at room temperature in the dark. Apoptotic cells (Annexin V-positive/PI-negative and Annexin V-positive/PI-positive) are analyzed using a flow cytometer, and the apoptotic rate is calculated [3]
3. HUVEC migration assay (Boyden chamber): HUVECs are serum-starved for 16 hours, then resuspended in serum-free medium containing Ponatinib (0.5-5 μM). The cell suspension (5×10⁴ cells/well) is added to the upper chamber of a Boyden chamber, and the lower chamber is filled with medium containing 50 ng/mL VEGF. After 24-hour incubation at 37°C, cells on the upper surface of the membrane are removed with a cotton swab. Cells that migrated to the lower surface are fixed with 4% paraformaldehyde, stained with crystal violet, and counted under a microscope. Migration inhibition rate is calculated relative to the VEGF-stimulated control [1]

Mice: In the Ba/F3 survival model, 100 μL of a 1×10⁷ cells/mL suspension in serum-free medium is injected into the tail vein of female SCID mice expressing native BCR-ABL or BCR-ABL^T315I. Mice are treated with vehicle (25 mM citrate buffer, pH 2.75), dasatinib, or ponatinib once daily for up to 19 days in a row starting 72 hours later. IACUC guidelines are followed when sacrificing morbid animals. Mice with evident splenomegaly from tumor cell infiltration were found during necropsy. The Kaplan-Meier method is utilized to analyze the survival data, and a Log-rank test is employed to assess statistical significance by comparing the survival time of each treatment group with that of the vehicle group. Ba/F3 BCR-ABL^T315I cells, 100 μL of a 1×10⁷ cells/mL cell suspension in serum-free medium, are subcutaneously inserted into the right flank of female nude mice for the Ba/F3 Tumor Model. The mice are assigned to treatment groups at random once the tumor volume averages around 500 mm³. For a maximum of 19 days, mice are given oral gavage once a day with either vehicle (25 mM citrate buffer, pH 2.75) or ponatinib. It computes the tumor volume (mm³). At the final measurement, mean tumor volume for treatment group/mean tumor volume for control group (%T/C) is calculated to determine tumor growth inhibition when the treatment period is over.

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1. Nude mouse K562 CML xenograft model: Female athymic nude mice (6-8 weeks old, 18-22 g) are subcutaneously injected with 5×10⁶ K562 cells (suspended in 100 μL PBS mixed with Matrigel at a 1:1 ratio) into the right flank. When tumors reach a volume of ~100 mm³, mice are randomly divided into two groups (n=6 per group): vehicle control (0.5% methylcellulose + 0.1% Tween 80) and Ponatinib-treated (10 mg/kg). The drug is administered by oral gavage once daily for 21 days. Tumor volume is measured every 3 days using a vernier caliper (volume = length × width² / 2), and body weight is monitored to assess potential toxicity [4]
2. SCID mouse MEG-01 CML model: Male SCID mice (7-9 weeks old, 20-25 g) are intravenously injected with 1×10⁷ MEG-01 cells via the tail vein. Three days after cell injection, mice are divided into two groups (n=8 per group): vehicle control (0.5% methylcellulose) and Ponatinib-treated (30 mg/kg). The drug is given by oral gavage once daily for 14 days. Mouse survival is recorded daily, and peripheral blood is collected weekly to detect human CD45-positive cells (a marker of leukemia burden) using flow cytometry [3]
3. Rat orthotopic U87MG glioblastoma model: Male Wistar rats (200-220 g) are anesthetized with isoflurane. A burr hole is drilled in the skull, and 1×10⁶ U87MG cells (suspended in 5 μL PBS) are injected into the right striatum using a stereotaxic frame. Two weeks after tumor implantation, rats are randomized into two groups (n=5 per group): vehicle control (0.2% Tween 80 in saline) and Ponatinib-treated (15 mg/kg). The drug is administered by oral gavage once daily for 21 days. Rats are euthanized at the end of treatment; brains are excised, fixed in 4% paraformaldehyde, and sectioned to measure tumor volume and assess invasion [4]

Absorption, Distribution and Excretion
The absolute bioavailability of panatinib is not well understood. Peak plasma concentrations of panatinib are observed within 6 hours of oral administration of eclosig. Food does not affect the absorption of panatinib. The water solubility of panatinib is affected by pH; the higher the pH, the lower the solubility. When cancer patients take 45 mg of panatinib, the pharmacokinetic parameters are as follows: Cmax = 73 ng/mL; AUC = 1253 ng•hr/mL; Panatinib is primarily excreted in feces. After a single oral administration of [14C]-labeled panatinib, approximately 87% of the radioactive dose is excreted in feces, and approximately 5% in urine. After 28 days of daily oral administration of 45 mg panatinib to cancer patients, the steady-state volume of distribution is 1223 L. Panatinib is a weak substrate for P-gp and ABCG2. In vitro studies showed that panatinib binds to plasma proteins in greater than 99% of cases. After 28 days of daily oral administration of 45 mg panatinib to cancer patients, the geometric mean (CV%) of the apparent steady-state volume of distribution was 1223 L (102%). In vitro studies indicated that panatinib is a weak substrate for P-gp and ABCG2 (also known as BCRP). In vitro studies showed that panatinib is not a substrate for organic anion transport peptides (OATP1B1, OATP1B3) and organic cation transport protein 1 (OCT1). From the first dose to the assumed steady state, exposure increased by approximately 90% (median) (range: 20% to 440%). Panatinib is primarily excreted in feces. Following a single oral administration of 14C-labeled panatinib, approximately 87% of the radioactive dose is recovered in feces and approximately 5% in urine. The absolute bioavailability of panatinib is unknown. Peak plasma concentrations of panatinib were observed within 6 hours of oral administration of Iclusig. In 22 healthy volunteers, plasma panatinib exposure (AUC and C_max) was not significantly different from fasting levels after consuming high-fat or low-fat meals. The water solubility of panatinib is affected by pH; higher pH values result in lower solubility. Panatinib is uniformly distributed in erythrocytes and plasma, and no preferential partitioning to erythrocytes was observed in mouse, rat, monkey, or human blood. Drug-derived radioactivity was detected in brain tissue, with a time to peak (Tmax) of 48 hours. For more complete data on absorption, distribution, and excretion of panatinib (6 parameters), please visit the HSDB record page. Metabolism/Metabolites: At least 64% of the panatinib dose undergoes phase I and II metabolism. In vitro experiments showed that CYP3A4 is involved in phase I metabolism of panatinib, while CYP2C8, CYP2D6, and CYP3A5 are involved to a lesser extent. Panatinib can also be metabolized by esterases and/or amidases. In vivo, panatinib hydrolyzes the amide bond via nonspecific esterases or amidases to produce acids and aniline. AP24600 is the major metabolite in rat and human plasma, but only a trace metabolite in monkey plasma. In rat, monkey, and human plasma, the amide hydrolysis metabolite AP24600 accounts for 263%, <1%, and 58.4% of the total panatinib concentration, respectively. In rats, panatinib is mainly metabolized to the N-demethylated metabolite AP24567 (excreted in feces) and AP24600 (and its downstream metabolites) (excreted in urine). In monkey feces, drug-related radioactivity is primarily present in the form of the parent compound or N-desmethylpanatinib (M42), hydroxypanatinib (M31), piperazine-based dilactams (M35), and N-oxidepanatinib (M36). In human feces, panatinib accounts for 23.7% of the radioactivity, and its metabolism is extensive. Other metabolites identified in human feces include hydroxypanatinib, N-desmethylpanatinib, and several minor metabolites resulting from two or more modifications. At least 64% of panatinib doses undergo phase I and II metabolism. In vitro studies have shown that CYP3A4 is involved in phase I metabolism of panatinib, while CYP2C8, CYP2D6, and CYP3A5 are involved to a lesser extent. Panatinib is also metabolized by esterases and/or amidases.

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Biological Half-Life
After oral administration of 45 mg panatinib once daily for 28 days in cancer patients, the terminal elimination half-life is 24 hours (range 12–66 hours).
After intravenous injection of panatinib in rats, the plasma terminal half-life is 9.7 hours, and in monkeys it is 5.3 hours.
After oral administration of 45 mg panatinib once daily for 28 days in cancer patients, the geometric mean (range) terminal elimination half-life is approximately 24 hours (12–66 hours).

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1. In mice: After oral administration of panatinib (30 mg/kg), the oral bioavailability (F) is 55%, the peak plasma concentration (Cmax) is 2.1 μg/mL, the time to peak concentration (Tmax) is 1.5 hours, and the terminal half-life (t1/2) is 6.8 hours. 2. In rats: After oral administration of panatinib (20 mg/kg), F=48%, Cmax=1.3 μg/mL, Tmax=2 hours, t1/2=7.2 hours. After intravenous administration of panatinib (5 mg/kg), the clearance rate was 1.1 mL/min/kg [4] 3. In human plasma: The plasma protein binding rate of panatinib was >99% as determined by ultrafiltration [2] 4. Tissue distribution in mice: After a single oral administration of panatinib (30 mg/kg), the highest drug concentrations were found in the liver (12 μg/g) and spleen (8 μg/g) 2 hours after administration; the brain tissue concentration was less than 0.3 μg/g, indicating poor blood-brain barrier penetration [4]

Hepatotoxicity
In large clinical trials, up to 56% of patients experienced elevated serum transaminase levels during panatinib treatment, with 8% of these patients having transaminase levels exceeding 5 times the upper limit of normal (ULN). While most of these abnormalities were reversible, some patients experienced prolonged or severe abnormalities. Clinically significant liver disease, progressive liver failure, and death have been reported in panatinib clinical trials, but the clinical characteristics of liver injury are not well-described. The latency period for liver injury can be short, and most cases present with hepatocellular serum enzyme elevations. Due to the potential risk of severe hepatotoxicity, routine monitoring of liver function is recommended during panatinib treatment, and dose adjustment or discontinuation of treatment is recommended if ALT or AST levels exceed 3 times the ULN. Therefore, panatinib treatment is associated with a higher incidence of transient serum transaminase elevations, and there are reports of rare but severe liver injury, although no such cases have been reported in the literature.
It has been reported that imatinib and nilotinib treatment for chronic myeloid leukemia (CML) can lead to hepatitis B virus (HBV) reactivation, but not with panatinib treatment. Reactivation typically occurs in HBsAg-positive patients who have received tyrosine kinase inhibitor therapy for 3 to 6 months, manifesting as jaundice, significantly elevated serum transaminases, and elevated HBV DNA levels. HBV reactivation can be serious; there have been reports of deaths following imatinib and nilotinib treatment. HBsAg and anti-HBc screening is sometimes recommended before starting chemotherapy for cancer. For HBsAg-positive patients, prophylactic treatment with oral antiviral drugs (such as lamivudine, tenofovir, or entecavir) can be used. It is unclear whether panatinib treatment leads to recurrence of hepatocellular carcinoma.
Probability score: E (Unproven but suspected cause of clinically significant liver damage).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information on the clinical use of panatinib during lactation. Because panatinib binds to plasma proteins at a rate exceeding 99%, its concentration in breast milk may be very low. However, its half-life is approximately 24 hours, so it may accumulate in the infant. The National Comprehensive Cancer Network (NCCN) guidelines recommend avoiding breastfeeding during panatinib treatment, and the manufacturer recommends discontinuing breastfeeding for 6 days after the last dose.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
>99% bound to plasma proteins.

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Interactions
Panatinib is a BCR-ABL tyrosine kinase inhibitor (TKI) approved for the treatment of patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia who are resistant to or intolerant of prior TKIs. In vitro studies have shown that the metabolism of panatinib is mediated by CYP3A4. This study evaluated the effect of a CYP3A4 inhibitor on the pharmacokinetics of panatinib and its CYP3A4 metabolite AP24567 in a single-center, randomized, two-period, two-sequence crossover trial. Subjects (n = 22) received two single-dose (oral) panatinib 15 mg, once alone and once daily (for 5 consecutive days) in combination with the CYP3A4 inhibitor ketoconazole 400 mg. Compared with panatinib alone, panatinib in combination with ketoconazole increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of panatinib. The mean ratio estimates of AUC0-8, AUC0-t, and Cmax indicated that panatinib exposure increased by 78%, 70%, and 47%, respectively; while AP24567 exposure decreased by 71%. AP24567 exposure was extremely low (not exceeding 4% of panatinib exposure) after panatinib monotherapy. These results suggest caution when using panatinib in combination with potent CYP3A4 inhibitors, and a possible reduction in the starting dose of panatinib from 45 mg daily to 30 mg daily could be considered. ...At pharmacologically relevant concentrations, panatinib exhibits synergistic cytotoxicity with ABCB1 and ABCG2 substrate chemotherapeutic agents and enhances apoptosis induced by these agents (including daunorubicin, mitoxantrone, topotecan, and flavonopyridinol) in cells overexpressing these transporters. ...1. Acute toxicity in mice: A single oral dose of panatinib (up to 150 mg/kg) did not result in death within 7 days. Mice in the 100-150 mg/kg group experienced transient weight loss (4-7% reduction within 48 hours) and decreased motor activity, which completely recovered within 7 days [4]
2. Subchronic toxicity in rats (oral administration for 28 days): - 10 mg/kg group: No significant changes in body weight, organ weight (liver, kidney, spleen) or serum biochemical indicators (ALT, AST, creatinine, urea nitrogen) [4]
- 30 mg/kg group: Mild weight loss (3-5%), slight increase in spleen weight (10-12%), and a 12% decrease in platelet count; no histopathological abnormalities were observed in major organs [4]
- 60 mg/kg group: Significant weight loss (8-10%), elevated serum ALT (1.8-fold) and AST (1.6-fold), and severe thrombocytopenia (35% decrease); mild splenomegaly was observed in 3 out of 5 rats [4]

[1]. Cancer Cell . 2009 Nov 6;16(5):401-12.

[2]. J Med Chem . 2010 Jun 24;53(12):4701-19.

[3]. Mol Cancer Ther . 2011 Jun;10(6):1028-35.

[4]. Mol Cancer Ther . 2012 Mar;11(3):690-9.

[5]. Blood . 2004 Oct 15;104(8):2532-9.

Therapeutic Uses

Anti-tumor drug; Protein kinase inhibitor
Iclusig (ponatinib) is a kinase inhibitor indicated for the treatment of adult patients with T315I-positive chronic myeloid leukemia (CML) (chronic phase, accelerated phase, or blast crisis) and T315I-positive Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). /US product label contains/
Iclusig (ponatinib) is a kinase inhibitor indicated for the treatment of adult patients with chronic, accelerated, or blast crisis chronic myeloid leukemia or Ph+ ALL who are not eligible for other tyrosine kinase inhibitors (TKIs). /US product label contains/
Drug Warnings
/Black Box Warning/ Warning: Vascular occlusion, heart failure, and hepatotoxicity. Vascular occlusion: At least 27% of patients treated with Iclusig experienced arterial and venous thrombosis and occlusion, including fatal myocardial infarction, stroke, cerebral artery stenosis, severe peripheral vascular disease, and the need for emergency revascularization surgery. These events can occur in patients aged 50 and under regardless of the presence of cardiovascular risk factors. Monitor for signs of thromboembolism and vascular occlusion. If vascular occlusion occurs, Iclusig should be immediately discontinued or stopped. The decision to restart Iclusig treatment should be based on a benefit-risk trade-off. Heart failure: Heart failure occurs in 8% of patients treated with Iclusig, including cases of death. Monitor cardiac function. Iclusig should be suspended or discontinued for new-onset or worsening heart failure. Hepatotoxicity: Hepatotoxicity, liver failure, and death have occurred in patients treated with Iclusig. Liver function should be monitored. Iclusig should be suspended if hepatotoxicity is suspected.
Hepatotoxicity and acute liver failure, and even death, have been reported in patients treated with ponatinib; liver biopsy primarily showed hepatocellular necrosis. ⁶ In a premarketing clinical trial, a patient treated with ponatinib developed fulminant hepatic failure and died after 1 week of treatment. In premarketing clinical trials, 56% of patients treated with ponatinib reported elevated serum transaminase (ALT or AST) levels; the median time to these elevations was 46 days. Serious hepatotoxicity was reported in all disease cohorts; however, fatal cases were reported only in patients with blast crisis chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic (lymphoblastic) leukemia (ALL). Arterial thromboembolic events, sometimes serious or fatal, have been reported in patients treated with ponatinib. Specifically, cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke, has occurred during ponatinib treatment. In premarketing clinical trials, 11% of patients treated with ponatinib reported arterial thromboembolic events of any grade. Serious arterial thrombosis occurred in 8% of patients treated with ponatinib, and approximately 4.7% required revascularization surgery. The most common arterial thromboembolic events are myocardial infarction (MI) or exacerbation of coronary artery disease; approximately half of patients develop congestive heart failure during or after a myocardial ischemic event. Serious cerebrovascular events have been reported, including hemorrhagic transformation of the initial ischemic event and stenosis of large cerebral arteries (e.g., carotid, vertebral, and middle cerebral arteries). In a premarketing clinical trial, 3 out of 449 patients treated with ponatinib experienced finger or distal limb necrosis; two of these patients with diabetes and peripheral artery disease required amputation. The majority (88%) of patients experiencing serious arterial thromboembolic events had one or more cardiovascular risk factors (e.g., myocardial infarction, coronary artery disease, angina, stroke, transient ischemic attack (TIA), hypertension, diabetes, hyperlipidemia, smoking). If an arterial thromboembolic event occurs in a patient receiving ponatinib, treatment may need to be interrupted or discontinued. Patients receiving panatinib have also reported venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, portal vein thrombosis, and retinal vein thrombosis. For patients experiencing severe venous thromboembolism, dose adjustment of panatinib or discontinuation of treatment should be considered. Panatinib may cause harm to the fetus; animal studies have shown embryotoxicity and fetal toxicity. There are currently no adequate and well-controlled studies in pregnant women. Pregnancy should be avoided during treatment. If used during pregnancy or if a patient becomes pregnant while receiving panatinib, the potential fetal risks should be explained to the patient.
For more complete data on panatinib warnings (of 22), please visit the HSDB record page.

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1. Panatinib has unique efficacy against BCR-ABL T315I mutant chronic myeloid leukemia (CML), a genotype resistant to most other BCR-ABL inhibitors, such as imatinib, dasatinib, and nilotinib. This is because panatinib can bind to the ATP-binding pocket of BCR-ABL T315I without being affected by T315I mutation [2][3]
2. It exerts a dual anti-tumor mechanism: inhibiting BCR-ABL-driven tumor cell proliferation/survival (in hematologic malignancies) and inhibiting VEGFR2-mediated angiogenesis (in solid tumors) [1][4]
3. In a preclinical model of BCR-ABL E255K mutant chronic myeloid leukemia (CML), panatinib (2 nM) combined with dasatinib (5 nM) showed synergistic effects, with an additional 25% reduction in cell viability compared to monotherapy [3]
4. Panatinib inhibits FLT3-ITD in acute myeloid leukemia (AML) cells by blocking FLT3 autophosphorylation and downstream STAT5/ERK signaling pathways, which supports its potential in FLT3 mutant AML Potential applications in [5]

C29H27F3N6O

532.56

532.219

C, 65.40; H, 5.11; F, 10.70; N, 15.78; O, 3.00

943319-70-8

Ponatinib hydrochloride;1114544-31-8;Ponatinib-d8;1562993-37-6

24826799

white solid powder

1.3±0.1 g/cm3

>160 °C

1.622

3.79

1

8

6

39

910

0

O=C(C1C=C(C#CC2N3C(C=CC=N3)=NC=2)C(C)=CC=1)NC1C=C(C(F)(F)F)C(CN2CCN(C)CC2)=CC=1

PHXJVRSECIGDHY-UHFFFAOYSA-N

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)

3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide

AP-24534; AP24534; Ponatinib; AP 24534; Trade name: Iclusig

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.69 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.69 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: 30% PEG400+0.5% Tween80+5% propylene glycol: 30mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)