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Gilteritinib (formerly ASP-2215; ASP2215; Trade name: Xospata) is a potent small-molecule inhibitor of FLT3/AXL approved for treating acute myeloid leukemia (AML). It inhibits FLT3 and AXL with IC50 values of 0.29 nM and 0.73 nM, respectively. At an IC50 approximately 800-fold higher than that needed to inhibit c-KIT (230 nM), gelderitinib potently inhibits FLT3. For leukemias like AML with FLT3-ITD and FLT3-D835 mutations, gelderitinib may be used as a remedy. An IC50 value of 0.29 nM for FLT3 indicates that gelderitinib is approximately 800-fold more potent than c-KIT. Of the 78 tyrosine kinases examined in vitro, it inhibits FLT3, leukocyte tyrosine kinase (LTK), anaplastic lymphoma kinase (ALK), and AXL kinases by over 50% at 1 nM concentration. In order to treat patients with relapsed or refractory acute myeloid leukemia (AML), the US FDA approved gelderitinib in November of 2018.
Physicochemical Properties
| Molecular Formula | C29H44N8O3 |
| Molecular Weight | 552.71 |
| Exact Mass | 552.353 |
| Elemental Analysis | C, 63.02; H, 8.02; N, 20.27; O, 8.68 |
| CAS # | 1254053-43-4 |
| Related CAS # | Gilteritinib hemifumarate;1254053-84-3;Gilteritinib-d8;2377109-74-3 |
| PubChem CID | 49803313 |
| Appearance | Yellow solid powder |
| Density | 1.2±0.1 g/cm3 |
| Boiling Point | 696.9±55.0 °C at 760 mmHg |
| Flash Point | 375.3±31.5 °C |
| Vapour Pressure | 0.0±2.2 mmHg at 25°C |
| Index of Refraction | 1.627 |
| LogP | 4.35 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 10 |
| Rotatable Bond Count | 9 |
| Heavy Atom Count | 40 |
| Complexity | 785 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | O(C([H])([H])[H])C1C([H])=C(C([H])=C([H])C=1N1C([H])([H])C([H])([H])C([H])(C([H])([H])C1([H])[H])N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H])N([H])C1C(C(N([H])[H])=O)=NC(C([H])([H])C([H])([H])[H])=C(N=1)N([H])C1([H])C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] |
| InChi Key | GYQYAJJFPNQOOW-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C29H44N8O3/c1-4-23-28(31-20-9-17-40-18-10-20)34-29(26(33-23)27(30)38)32-21-5-6-24(25(19-21)39-3)37-11-7-22(8-12-37)36-15-13-35(2)14-16-36/h5-6,19-20,22H,4,7-18H2,1-3H3,(H2,30,38)(H2,31,32,34) |
| Chemical Name | 6-ethyl-3-[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide |
| Synonyms | ASP-2215; ASP2215; ASP 2215; Gilteritinib; Trade name: Xospata |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
FLT3 (IC50 = 0.29 nM); LTK (IC50 = 0.35 nM); AXL (IC50 = 0.73 nM); EML4-ALK (IC50 = 1.2 nM); c-KIT (IC50 = 230 nM)
The targets of Gilteritinib (ASP2215) are Fms-like tyrosine kinase 3 (FLT3) and AXL receptor tyrosine kinase; it is a type I tyrosine kinase inhibitor with high selectivity for FLT3 and AXL, and weak activity against c-KIT. [2] Gilteritinib (ASP2215) inhibits mutated forms of FLT3 including internal tandem duplication (FLT3-ITD), FLT3-D835Y point mutation, and FLT3-F691 mutation (inhibitory activity against FLT3-F691 is weaker); [2] |
| ln Vitro |
Gilteritinib (ASP2215), out of the 78 tyrosine kinases examined, inhibits the kinases FLT3, leukocyte tyrosine kinase (LTK), anaplastic lymphoma kinase (ALK), and AXL by more than 50% at 1 nM. For FLT3, the IC50 value is 0.29 nM, which makes it about 800-fold more potent than c-KIT[1]. Gilteritinib, at concentrations of either 1 nM (FLT3, LTK, ALK, and AXL) or 5 nM (TRKA, ROS, RET, and MER), inhibits the activity of eight of the 78 tested kinases by more than 50%. For FLT3, the IC50 is 0.29 nM, and for AXL, it is 0.73 nM. At an IC50 that is roughly 800-fold more potent than that needed to inhibit c-KIT (230 nM), gelderitinib inhibits FLT3. Gilteritinib's antiproliferative efficacy is assessed in relation to MV4-11 and MOLM-13 cells, which are endogenously FLT3-ITD-expressing. Gilteritinib inhibits the growth of MOLM-13 and MV4-11 cells after five days of treatment, with mean IC50s of 2.9 nM (95% CI: 1.4-5.8 nM) and 0.92 nM (95% CI: 0.23-3.6 nM), respectively. MV4-11 cell growth suppression is correlated with inhibition of FLT3 phosphorylation. Following two hours of treatment with 0.1 nM, 1 nM, and 10 nM Gilteritinib, respectively, the phosphorylated FLT3 levels are 57%, 8%, and 1% higher than those of the vehicle control cells. Furthermore, the suppression of phosphorylated ERK, STAT5, and AKT—all downstream targets of FLT3 activation—occurs at concentrations as low as 0.1 nM or 1 nM. Gilteritinib is administered to MV4-11 cells that expressed exogenous AXL in order to study its effects on AXL inhibition. Gilteritinib treatment reduces phosphorylated AXL levels by 38%, 29%, and 22% at concentrations of 1 nM, 10 nM, and 100 nM for 4 hours[2]. 1. Anti-proliferative activity in AML cell lines: Gilteritinib (ASP2215) was tested on MV4-11 and MOLM-13 AML cell lines (harboring FLT3 mutations) as well as Ba/F3 cells expressing mutated FLT3 (FLT3-ITD, FLT3-D835Y, FLT3-ITD-D835Y). MV4-11 cells were treated with DMSO or increasing concentrations of gilteritinib for 5 days, and cell viability was measured using CellTiter-Glo; the results showed dose-dependent inhibition of cell growth (mean ± SEM, quadruplicate experiments, representative result from three independent experiments). MOLM-13 cells were treated in the same manner as MV4-11, with consistent dose-dependent growth inhibition observed [2] 2. Inhibition of FLT3 phosphorylation and downstream signaling: MV4-11 cells were treated with DMSO or increasing concentrations of Gilteritinib (ASP2215) for 2 hours. Immunoprecipitation and immunoblot analysis showed that gilteritinib dose-dependently decreased the phosphorylation level of FLT3 (densitometry values provided below blots, triplicate experiments). Additionally, immunoblot analysis revealed that gilteritinib reduced the phosphorylation levels of FLT3 downstream targets including AKT, ERK, and STAT5 in MV4-11 cells (triplicate experiments) [2] 3. Inhibition of different FLT3 mutations: Gilteritinib (ASP2215) demonstrated potent inhibitory activity against FLT3-ITD and FLT3-D835Y mutations in cellular assays, and inhibited FLT3-F691 mutations to a lesser degree [2] |
| ln Vivo |
After administering oral Gilteritinib at a dose of 10 mg/kg for four days, the concentration of the drug in tumors in MV4-11 xenografted mice was found to be over 20 times higher than that in plasma. MV4-11 tumor growth is dose-dependently inhibited during a 28-day treatment with gelderitinib, and at doses greater than 6 mg/kg, total tumor regression is induced. Furthermore, gerteritinib prolongs the survival of mice receiving intravenous MV4-11 cell transplants and reduces the tumor burden in the bone marrow[1]. 1. Plasma and tumor distribution in MV4-11 xenograft model: Nude mice subcutaneously xenografted with MV4-11 cells were treated with a single oral dose of Gilteritinib (ASP2215) (1 mg/kg, 6 mg/kg, 10 mg/kg). Plasma and tumor concentrations of gilteritinib were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The results showed high intratumor distribution of gilteritinib, with data presented as mean ± SD (2 or 3 animals for plasma, 3 animals for tumor) [2] 2. Inhibition of FLT3/STAT5 phosphorylation in xenograft tumors: Male mice xenografted with MV4-11 cells were orally treated with vehicle control or increasing concentrations of Gilteritinib (ASP2215). Protein lysates were collected over a 24-hour time course: (1) The ratio of phospho-FLT3 to total FLT3 was determined by ELISA, with results presented as the ratio of phosphorylated protein levels normalized to total protein levels relative to vehicle control; (2) The ratio of phospho-STAT5 to total STAT5 was measured by immunoblot, with the same normalization method applied [2] 3. Antitumor activity in MV4-11 xenograft model: Male mice xenografted with MV4-11 cells were orally treated with vehicle control or increasing concentrations of Gilteritinib (ASP2215) (1 mg/kg, 3 mg/kg, 6 mg/kg, 10 mg/kg) for 28 days. Gilteritinib dose-dependently reduced tumor volume (mean ± SEM, n=6 mice/group; P < 0.05, P < 0.01, P < 0.001 vs control on Day 28, Dunnett’s test), while no significant changes in body weight were observed, indicating no overt toxicity [2] 4. Tumor regression in FLT3 mutant-expressing xenograft models: Male nude mice xenografted with Ba/F3 cells expressing FLT3-ITD, FLT3-D835Y, or FLT3-ITD-D835Y were treated with 10 mg/kg or 30 mg/kg once-daily oral Gilteritinib (ASP2215) for up to 7 days after confirmed tumor growth. Gilteritinib induced significant tumor regression in all three models (mean ± SEM, n=5 mice/group; P < 0.01, P < 0.001 vs control on Day 7, Dunnett’s test) [2] 5. Reduction of leukemic burden and improved survival in intra-bone marrow transplantation model: Female NOD-SCID mice engrafted with MV4-11-luc cells were treated once daily with vehicle or 30 mg/kg Gilteritinib (ASP2215) for 56 days starting on day 15. Whole-body imaging showed that gilteritinib significantly decreased MV4-11-luc cell bone marrow infiltration (mean ± SEM, n=10 mice/group; P < 0.001 vs control on day 42, Student’s t-test). Kaplan–Meier analysis demonstrated that gilteritinib significantly improved mouse survival (P < 0.001 vs control, Log-rank test) [2] |
| Enzyme Assay |
TK-ELISA or off-chip mobility shift assays are used to test the kinase inhibitory activity of Gilteritinib against a panel of 78 tested kinases, with ATP concentrations roughly equivalent to each kinase's Km value. Initially, the inhibitory effect of each compound on TK activity is evaluated at two concentrations of Gilteritinib (1 nM and 5 nM). Next, additional research employing a range of Gilteritinib doses is carried out to ascertain IC50 values for c-KIT and kinases whose activity is inhibited by more than half at 1 nM Gilteritinib. FLT3, LTK, AXL, and c-KIT IC50 studies are carried out using TK-ELISA and MSA assays; the HTRF KinEASE-TK assay is used to determine the IC50 value of echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK)[2]. Initial kinase activity assays were conducted to evaluate the selectivity of Gilteritinib (ASP2215). The assay system included purified FLT3, AXL, c-KIT, and other tyrosine kinases (specific kinases not specified). Gilteritinib was incubated with the kinases in the presence of ATP and specific substrates (substrate details not provided) under optimized reaction conditions (temperature, incubation time not specified). The kinase activity was measured using a detection method (not specified) to determine the inhibitory effect of gilteritinib on each kinase. The results confirmed high selectivity of gilteritinib for FLT3 and AXL, with weak activity against c-KIT; [2] |
| Cell Assay |
The CellTiter-Glo Luminescent Cell Viability Assay is used to evaluate the impact of gelderitinib on MV4-11 and MOLM-13 cells. Further research is done to investigate the impact of quizartinib and gilteritinib on Ba/F3 cells that express FLT3-ITD, FLT3-D835Y, FLT3-ITD-D835Y, FLT3-ITD-F691 L, or FLT3-ITD-F691I. For five days, DMSO or increasing concentrations of Gilteritinib (0.01, 0.1, 1, 10, and 100 nM) are applied to MV4-11 and MOLM-13 cells. CellTiter-Glo is used to measure the viability of the cells[2]. 1. AML cell viability assay: - Step 1: MV4-11 and MOLM-13 AML cells were seeded in suitable culture plates at a specific density (not specified) and cultured under standard conditions (temperature, CO2 concentration not mentioned) to ensure cell adherence and logarithmic growth. - Step 2: The cells were treated with DMSO (control) or serial concentrations of Gilteritinib (ASP2215) and incubated for 5 days. - Step 3: Cell viability was quantified using the CellTiter-Glo assay (detection principle not specified), with data collected in quadruplicate and presented as mean ± SEM. The experiment was repeated three times, and a representative result was reported [2] 2. Immunoprecipitation and immunoblot for FLT3 phosphorylation: - Step 1: MV4-11 cells were cultured in complete medium until reaching the desired confluency (not specified), then treated with DMSO or increasing concentrations of Gilteritinib (ASP2215) for 2 hours. - Step 2: Cells were harvested and lysed with a lysis buffer (components not specified), and protein concentration was determined (method not specified). - Step 3: FLT3 protein was immunoprecipitated from cell lysates using a specific antibody against FLT3 (antibody details not provided), and the immunoprecipitates were separated by SDS-PAGE (gel concentration not specified). - Step 4: The separated proteins were transferred to a membrane (type not specified), probed with primary antibodies against phosphorylated FLT3 and total FLT3, followed by secondary antibody incubation. - Step 5: Protein bands were detected (detection method not specified), and densitometry analysis was performed to quantify band intensities (values listed below blots). The experiment was conducted in triplicate [2] 3. Immunoblot for FLT3 downstream signaling proteins: - Step 1: MV4-11 cells were treated with DMSO or increasing concentrations of Gilteritinib (ASP2215) for 2 hours as described above. - Step 2: Cell lysates were prepared, and equal amounts of protein were separated by SDS-PAGE, transferred to a membrane, and probed with primary antibodies against phosphorylated AKT, ERK, STAT5, and total forms of these proteins (loading control not specified). - Step 3: Protein bands were detected and analyzed (triplicate experiments) [2] |
| Animal Protocol |
Mice: In nude mice transplanted with MV4-11 AML cells, antitumor activity is assessed. Additionally, the pharmacokinetics in xenografted mice are examined. Gilteritinib (10 mg/kg) is given orally to MV4-11 xenografted mice for a period of four days as part of their treatment. Gilteritinib treatment for 28 days causes total tumor regression at doses greater than 6 mg/kg and dose-dependent inhibition of MV4-11 tumor growth[1]. 1. MV4-11 subcutaneous xenograft model (pharmacokinetic analysis): - Step 1: MV4-11 AML cells were subcutaneously injected into nude mice (gender/age not specified) at a specific cell number (not specified) to establish xenograft models. - Step 2: When tumors reached a certain volume (not specified), mice were administered a single oral dose of Gilteritinib (ASP2215) at 1 mg/kg, 6 mg/kg, or 10 mg/kg (drug dissolution formula/vehicle not specified). - Step 3: Blood and tumor samples were collected at predetermined time points (not specified) after administration. - Step 4: Plasma and tumor concentrations of gilteritinib were measured by HPLC-MS/MS, with data presented as mean ± SD (2 or 3 animals for plasma, 3 animals for tumor) [2] 2. MV4-11 subcutaneous xenograft model (pharmacodynamic and efficacy analysis): - Step 1: MV4-11 cells were subcutaneously implanted into male nude mice (n=6 per group) to establish xenograft models. - Step 2: After tumor establishment (specific volume not specified), mice were orally administered vehicle control or Gilteritinib (ASP2215) at 1 mg/kg, 3 mg/kg, 6 mg/kg, or 10 mg/kg once daily for 28 days (drug formulation not specified). - Step 3: For pharmacodynamic analysis: Tumor tissues were collected over a 24-hour time course, protein lysates were prepared, and the ratio of phospho-FLT3/total FLT3 (ELISA) and phospho-STAT5/total STAT5 (immunoblot) was determined. - Step 4: For efficacy analysis: Tumor volume and body weight were measured regularly (interval not specified) over the 28-day treatment period, with statistical analysis (Dunnett’s test) performed on Day 28 [2] 3. Ba/F3-FLT3 mutant subcutaneous xenograft model: - Step 1: Ba/F3 cells expressing FLT3-ITD, FLT3-D835Y, or FLT3-ITD-D835Y were subcutaneously injected into male nude mice (n=5 per group) to establish xenograft models. - Step 2: After confirmed tumor growth (specific volume not specified), mice were orally administered vehicle control, 10 mg/kg, or 30 mg/kg Gilteritinib (ASP2215) once daily for up to 7 days (drug formulation not specified). - Step 3: Tumor volume was measured at specified time points (not specified), and statistical analysis (Dunnett’s test) was performed on Day 7 [2] 4. Intra-bone marrow transplantation model of AML: - Step 1: MV4-11-luc cells (luciferase-expressing MV4-11 cells) were engrafted into female NOD-SCID mice via intra-bone marrow injection (injection site/cell number not specified). - Step 2: Starting on day 15 after engraftment, mice (n=10 per group) were orally administered vehicle control or 30 mg/kg Gilteritinib (ASP2215) once daily for 56 days (drug formulation not specified). - Step 3: Whole-body bioluminescence imaging was performed at specified time points (e.g., day 21, day 42) to monitor MV4-11-luc cell bone marrow infiltration (imaging parameters not specified). - Step 4: Mouse survival was recorded, and Kaplan–Meier analysis (Log-rank test) was conducted to evaluate the effect of gilteritinib on survival [2] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion In preclinical trials, the maximal plasma concentration of gilteritinib was observed 2 hours after oral administration and followed by a maximal intratumor concentration after 4-8 hours. The maximum concentration, as well as the AUC, were modified correspondingly with the dose and were reported to be 374 ng/ml and 6943 ng.h/ml, respectively. The steady-state plasma level is reached within 15 days of dosing with an approximate 10-fold bioaccumulation. In a fasted state in humans, the tmax is reported to be of 4-6 hours. The Cmax and AUC were decreased by 26% and 10% respectively by the co-ingestion of a high-fat meal with a tmax delay of 2 hours. From the administered dose, gilteritinib is mainly excreted in feces which represents 64.5% of the administered dose while 16.4% is recovered in urine either as the unchanged drug or as its metabolites. The estimated apparent central and peripheral volume of distribution is 1092 L and 1100 L respectively. This value indicated an extensive tissue distribution. The estimated clearance of gilteritinib is 14.85 L/h. Metabolism / Metabolites Gilteritinib is primarily metabolized in the liver by the activity of CYP3A4. Its metabolism is driven by reactions of N-dealkylation and oxidation which forms the metabolite M17, M16 and M10. From the plasma concentration, the major form is the unchanged drug. Biological Half-Life The reported median half-life of gilteritinib was of approximate 45-159 hours. 1. Absorption and distribution: Gilteritinib (ASP2215) was orally administered to nude mice bearing MV4-11 xenografts, and it showed rapid absorption (no Tmax data provided) and high distribution in xenografted tumors. Plasma and tumor concentrations were measured by HPLC-MS/MS after a single oral dose (1 mg/kg, 6 mg/kg, 10 mg/kg), with high intratumor concentrations observed; [2] |
| Toxicity/Toxicokinetics |
Hepatotoxicity Elevations in serum aminotransferase levels are common during gilteritinib therapy occurring in 78% of patients and rising above 5 times the upper limit of the normal range in 12%. Gilteritinib has had limited clinical use but has not been linked to instances of acute liver injury with symptoms or jaundice. Because of the limited clinical experience with the use of FLT3 inhibitors, their potential for causing liver injury is not well defined. Likelihood score: E* (unproved but suspected cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on gilteritinib during breastfeeding. It is 94% bound to plasma proteins, so amounts in milk are likely to be low; however, it has a long half-life of about 113 hours. The manufacturer recommends that breastfeeding be discontinued during gilteritinib therapy and for 2 months after the last dose. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Gilteritinib is reported to be highly bound to plasma proteins, representing 94% of the dose. From this ratio, the main protein-bound is serum albumin. 1. In vivo toxicity in mouse models: No overt toxicity was observed in mouse models treated with Gilteritinib (ASP2215). In the MV4-11 xenograft model, 28-day treatment with gilteritinib (1–10 mg/kg once daily) did not cause significant changes in mouse body weight, indicating good tolerability [2] |
| References |
[1]. ASP2215, a novel FLT3/AXL inhibitor: Preclinical evaluation in acute myeloid leukemia (AML). 2014 ASCO Annual Meeting. [2]. Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest New Drugs. 2017 Oct;35(5):556-565. |
| Additional Infomation |
Gilteritinib is a member of the class of pyrazines that is pyrazine-2-carboxamide which is substituted by {3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}nitrilo, (oxan-4-yl)nitrilo and ethyl groups at positions 3,5 and 6, respectively. It is a potent inhibitor of FLT3 and AXL tyrosine kinase receptors (IC50 = 0.29 nM and 0.73 nM, respectively). Approved by the FDA for the treatment of acute myeloid leukemia in patients who have a FLT3 gene mutation. It has a role as an apoptosis inducer, an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor and an antineoplastic agent. It is a N-methylpiperazine, a member of piperidines, a secondary amino compound, a monomethoxybenzene, a member of pyrazines, a primary carboxamide, an aromatic amine and a member of oxanes. Gilteritinib, also known as ASP2215, is a small molecule part of the FLT3 tyrosine kinase inhibitors that presented a greater selectivity and potency when compared with other agents from this group. It is a pyrazinecarboxamide derivative that showed high selectivity to FLT3 preventing the c-Kit -driven myelosuppression observed in other therapies. Gilteritinib was developed by Astellas Pharma and FDA approved on November 28, 2018. This drug was approved after being designed as an orphan drug with a fast track and priority review status. Gilteritinib is an orally available small molecule inhibitor of FMS-like tyrosine kinase 3 (FLT3) which is used as an antineoplastic agent in the treatment of acute myeloid leukemia with FLT3 mutations. Gilteritinib is associated with a moderate rate of serum aminotransferase elevations during therapy and is suspected to cause rare instances of clinically apparent acute liver injury. Gilteritinib is an orally bioavailable inhibitor of the receptor tyrosine kinases (RTKs) FMS-like tyrosine kinase 3 (FLT3; STK1; FLK2), AXL (UFO; JTK11), anaplastic lymphoma kinase (ALK; CD246), and leukocyte receptor tyrosine kinase (LTK), with potential antineoplastic activity. Upon administration, gilteritinib binds to and inhibits both the wild-type and mutated forms of FLT3, AXL, ALK and LTK. This may result in an inhibition of FLT3-, AXL-, ALK-, and LTK-mediated signal transduction pathways and reduced proliferation in cancer cells that overexpress these RTKs. FLT3, AXL, ALK, and LTK, which are overexpressed or mutated in a variety of cancer cell types, play key roles in tumor cell growth and survival. See also: Gilteritinib Fumarate (has salt form). Drug Indication Gilteritinib is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia with an FLT3 mutation detected by an FDA-approved test. This indication was expanded for a companion diagnostic to include use with gilteritinib such as the LeukoStrat CDx FLT3 Mutation Assay. Acute myeloid leukemia is cancer that impacts the blood and bone marrow with a rapid progression. This condition produces low numbers of normal blood cells and the requirement of continuous need for transfusions. Xospata is indicated as monotherapy for the treatment of adult patients who have relapsed or refractory acute myeloid leukaemia (AML) with a FLT3 mutation. , Mechanism of Action Gilteritinib is a potent selective inhibitor of both of the mutations, internal tandem duplication (ITD) and tyrosine kinase domain (TKD), of the FLT3 receptor. In the same note, gilteritinib also inhibits AXL and ALK tyrosine kinases. FLT3 and AXL are molecules involved in the growth of cancer cells. The activity of gilteritinib permits an inhibition of the phosphorylation of FLT3 and its downstream targets such as STAT5, ERK and AKT. The interest in FLT3 transmembrane tyrosine kinases was raised when studies reported that approximately 30% of the patients with acute myeloid leukemia presented a mutationally activated isoform. As well, the mutation ITD is associated with poor patient outcomes while the mutation TKD produces a resistance mechanism to FLT3 tyrosine kinase inhibitors and the AXL tyrosine kinase tends to produce a resistance mechanism to chemotherapies. 1. Background and classification: Gilteritinib (ASP2215) is a novel, type I tyrosine kinase inhibitor with high selectivity for FLT3 and AXL. FLT3 is one of the most frequently mutated genes in acute myeloid leukemia (AML), and FLT3 mutations are associated with poor overall survival; AXL plays a role in FLT3 activation and AML pathogenesis [2] 2. Mechanism of action: Gilteritinib (ASP2215) exerts antileukemic activity by inhibiting the phosphorylation of mutated FLT3 and its downstream signaling pathways (AKT, ERK, STAT5), thereby suppressing AML cell proliferation and inducing tumor regression in vivo [2] 3. Clinical potential: Preclinical studies demonstrated that Gilteritinib (ASP2215) has potent antileukemic activity in FLT3-mutated AML cell lines and mouse models (xenograft and intra-bone marrow transplantation models), with no overt toxicity. These results indicate that gilteritinib may be an important next-generation FLT3 inhibitor for the treatment of FLT3 mutation-positive AML [2] 4. Computational modeling: Computational modeling of Gilteritinib (ASP2215) binding to wild-type FLT3 was performed. Gilteritinib was modeled as a ball-and-stick model, with atoms colored by element type; the protein surface was colored by electrostatic potential. The gatekeeper residue F691 was highlighted, and the binding mode of gilteritinib to FLT3 was visualized [2] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 10 mg/mL (18.09 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 5%DMSO+40%PEG300+5%Tween80+50%ddH2O: 0.2mg/ml (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8093 mL | 9.0463 mL | 18.0927 mL | |
| 5 mM | 0.3619 mL | 1.8093 mL | 3.6185 mL | |
| 10 mM | 0.1809 mL | 0.9046 mL | 1.8093 mL |