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Gilteritinib

Catalog No.: GC19482

Gilteritinib (ASP2215, Xospata) for relapsed and /or refractory AML (R/R AML).

Gilteritinib Chemical Structure

Size Price Stock Qty
10mM (in 1mL DMSO)
$88.00
In stock
2mg
$58.00
In stock
5mg
$72.00
In stock
10mg
$115.00
In stock
50mg
$404.00
In stock
100mg
$512.00
In stock

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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

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Protocol

Kinase experiment [1]:

Preparation Method

Two concentrations of gilteritinib(1 nM and 5 nM) were tested to assess the inhibitory effect of each compound on TK activity and then a range of doses of gilteritinib was used for further studies to determine the IC 50 value of the kinase.

Reaction Conditions

1 nM and 5 nM Gilteritinib and protein

Applications

Gilteritinib inhibited the activity of eight of the 78 tested kinases by over 50% at concentrations of either 1 nM (FLT3, LTK, ALK, and AXL) or 5 nM (TRKA, ROS, RET, and MER). The IC50 values were 0.29 nM for FLT3 and 0.73 nM for AXL. Gilteritinib inhibited FLT3 at an IC50 value that was approximately 800-fold more potent than the concentration required to inhibit c-KIT (230 nM).

Cell experiment [2]:

Cell lines

MV4-11 cells

Preparation Method

MV4-11 cells were treated with DMSO or increasing concentrations of gilteritinib for 5 days, and cell viability was measured using CellTiter-Glo.

Reaction Conditions

10-11-10-7M gilteritinib for 5days

Applications

After 5 days of treatment,gilteritinib inhibited the growth of MV4-11 and MOLM-13 cells with mean IC 50 values of 0.92 nM(95%CI :0.23-3.6 nM) and 2.9 nM(95%CI :1.4-5.8 nM).

Animal experiment [3]:

Animal models

Female NOD-SCID mice

Preparation Method

In the intra-bone marrow transplantation (IBMT) model, MV4 11-luc cells (1 106 cells/mouse) were injected into the bone marrow of the left tibia of female NOD-SCID mice (day 0). After confirming tumor cell engraftment at day 14, mice were orally administered with once-daily vehicle control or gilteritinib at 30 mg/kg from day 15 to day 70. Tumor growth was monitored once a week during the dosing period and then every other week until day 100. Survival was also monitored daily until day 168.

Dosage form

30 mg/kg Gilteritinib from day 15 to day 70(orally)

Applications

Gilteritinib prolongs the survival of AML IBMT mice.

References:

[1].Mori M, Kaneko N, et,al. 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. doi: 10.1007/s10637-017-0470-z. Epub 2017 May 17. PMID: 28516360; PMCID: PMC5613053.

Background

Gilteritinib (ASP2215, Xospata) for relapsed and /or refractory AML (R/R AML). Gilteritinib is a small molecule dual inhibitor of FLT3/AXL with IC50s of 0.29 nM/0.73 nM[8].

When evaluated the antiproliferative activity of gilteritinib against MV4 11 and MOLM-13 cells, which endogenously express FLT3-ITD. After 5 days of treatment, gilteritinib inhibited the growth of MV4 11 and MOLM-13 cells with mean IC50 values of 0.92 nM (95% CI: 0.23 3.6 nM) and 2.9 nM[1]. gilteritinib has an inhibitory effect on ALK-TKI-resistant single mutants and I1171N compound mutants in vitro and in vivo. Gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer[3]. regardless of p53 status, treatment using gilteritinib induces PUMA in CRC cells via the NF-κB pathway after inhibition of AKT and activation of glycogen synthase kinase 3β (GSK-3β). PUMA was observed to be vital for apoptosis in CRC cells through treatment of gilteritinib[4]. Combination of Gilteritinib with ATO showed synergistic effects on inhibiting proliferation, increasing apoptosis and attenuating invasive ability in FLT3-ITD-mutated cells and reducing tumor growth in nude mice. Gilteritinib increased a 160KD form of FLT3 protein on the surface of cell membrane[5]. In the FLT3 signaling analyses, gilteritinib inhibited FLT3wt and FLT3-ITD to a similar degree in HEK293 and Ba/F3 cells, and similarly suppressed FLT3 downstream signaling molecules (including ERK1/2 and STAT5) in both the presence and absence of FL in MOLM-13 cells[6]. Combining gilteritinib with trametinib, a MEK1/2 inhibitor, is an effective means to target IgH-CRLF2-r ALL cells regardless of RAS mutational status[7].

Gilteritinib prolongs the survival of AML IBMT mice, MV4-11-luc tumor growth was significantly reduced during the first 2 weeks of treatment. Gilteritinib treatment significantly increased the survival of MV4-11 xenograft mice[1]. gilteritinib is already used to treat AML[2].

References:
[1]: Mori M, Kaneko N, et,al. 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. doi: 10.1007/s10637-017-0470-z. Epub 2017 May 17. PMID: 28516360; PMCID: PMC5613053.
[2]: Perl AE, Martinelli G, et,al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-1740. doi: 10.1056/NEJMoa1902688. Erratum in: N Engl J Med. 2022 May 12;386(19):1868. PMID: 31665578.
[3]: Mizuta H, Okada K, et,al. Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer. Nat Commun. 2021 Feb 24;12(1):1261. doi: 10.1038/s41467-021-21396-w. PMID: 33627640; PMCID: PMC7904790.
[4]: Li L, Lin L, et,al. Gilteritinib induces PUMA-dependent apoptotic cell death via AKT/GSK-3β/NF-κB pathway in colorectal cancer cells. J Cell Mol Med. 2020 Feb;24(3):2308-2318. doi: 10.1111/jcmm.14913. Epub 2019 Dec 27. PMID: 31881122; PMCID: PMC7011145.
[5]: Hu X, Cai J, et,al.Arsenic trioxide potentiates Gilteritinib-induced apoptosis in FLT3-ITD positive leukemic cells via IRE1a-JNK-mediated endoplasmic reticulum stress. Cancer Cell Int. 2020 Jun 17;20:250. doi: 10.1186/s12935-020-01341-5. PMID: 32565734; PMCID: PMC7298957.
[6]: Kawase T, Nakazawa T, et,al. Effect of Fms-like tyrosine kinase 3 (FLT3) ligand (FL) on antitumor activity of gilteritinib, a FLT3 inhibitor, in mice xenografted with FL-overexpressing cells. Oncotarget. 2019 Oct 22;10(58):6111-6123. doi: 10.18632/oncotarget.27222. PMID: 31692922; PMCID: PMC6817455.
[7]: Sasaki K, Yamauchi T, et,al. Genome-wide CRISPR-Cas9 screen identifies rationally designed combination therapies for CRLF2-rearranged Ph-like ALL. Blood. 2022 Feb 3;139(5):748-760. doi: 10.1182/blood.2021012976. PMID: 34587248.
[8]:Zhao J, Song Y, Liu D. Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia. Biomark Res. 2019 Sep 11;7:19. doi: 10.1186/s40364-019-0170-2. Erratum in: Biomark Res. 2019 Oct 17;7:21. PMID: 31528345; PMCID: PMC6737601.

Chemical Properties

Cas No. 1254053-43-4 SDF
Synonyms ASP2215
Chemical Name N/A
Canonical SMILES NC(C1=NC(CC)=C(NC2CCOCC2)N=C1NC3=CC(OC)=C(N4CCC(N5CCN(C)CC5)CC4)C=C3)=O
Formula C₂₉H₄₄N₈O₃ M.Wt 552.71
Solubility Water : 2 mg/mL (3.27 mM);DMSO : 1.74 mg/mL (2.85 mM) Storage 4°C, stored under nitrogen
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

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Research Update

Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML

N Engl J Med2019 Oct 31;381(18):1728-1740.PMID: 31665578DOI: 10.1056/NEJMoa1902688

Background: Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. Methods: In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. Results: Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%). Conclusions: Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.).

Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia

Biomark Res2019 Sep 11;7:19.PMID: 31528345DOI: 10.1186/s40364-019-0170-2

FMS-like tyrosine kinase 3- internal tandem duplication (FLT3-ITD) remains as one of the most frequently mutated genes in acute myeloid leukemia (AML), especially in those with normal cytogenetics. The FLT3-ITD and FLT3-TKD (tyrosine kinase domain) mutations are biomarkers for high risk AML and are associated with drug resistance and high risk of relapse. Multiple FLT3 inhibitors are in clinical development, including lestaurtinib, tandutinib, quizartinib, midostaurin, gilteritinib, and crenolanib. Midostaurin and gilteritinib have been approved by FDA for Flt3 mutated AML. Gilteritinib (ASP2215, Xospata) is a small molecule dual inhibitor of FLT3/AXL. The ADMIRAL study showed that longer overall survival and higher response rate are associated with gilteritinib in comparison with salvage chemotherapy for relapse /refractory (R/R) AML. These data from the ADMIRAL study may lead to the therapy paradigm shift and establish gilteritinib as the new standard therapy for R/R FLT3-mutated AML. Currently, multiple clinical trials are ongoing to evaluate the combination of gilteritinib with other agents and regimens. This study summarized clinical trials of gilteritinib for AML.

Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

Nat Commun2021 Feb 24;12(1):1261.PMID: 33627640DOI: 10.1038/s41467-021-21396-w

ALK gene rearrangement was observed in 3%-5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI-resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

Gilteritinib

Review2020 Mar 24;4(6):1178-1191.PMID: 31643742DOI: 10.1182/bloodadvances.2019000174

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: potent targeting of FLT3 mutations in AML

Blood Adv2020 Mar 24;4(6):1178-1191.PMID: 32208491DOI: 10.1182/bloodadvances.2019000174

Since the discovery of FMS-like tyrosine kinase-3 (FLT3)-activating mutations as genetic drivers in acute myeloid leukemia (AML), investigators have tried to develop tyrosine kinase inhibitors that could effectively target FLT3 and alter the disease trajectory. Giltertinib (formerly known as ASP2215) is a novel compound that entered the field late, but moved through the developmental process with remarkable speed. In many ways, this drug's rapid development was facilitated by the large body of knowledge gained over the years from efforts to develop other FLT3 inhibitors. Single-agent gilteritinib, a potent and selective oral FLT3 inhibitor, improved the survival of patients with relapsed or refractory FLT3-mutated AML compared with standard chemotherapy. This continues to validate the approach of targeting FLT3 itself and establishes a new backbone for testing combination regimens. This review will frame the preclinical and clinical development of gilteritinib in the context of the lessons learned from its predecessors.

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