Gilteritinib
(Synonyms: 吉列替尼,ASP2215) 目录号 : GC19482
A FLT3 inhibitor
Cas No.:1254053-43-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Kinase experiment [1]: | |
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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. |
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Reaction Conditions |
1 nM and 5 nM Gilteritinib and protein |
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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]: | |
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Cell lines |
MV4-11 cells |
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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. |
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Reaction Conditions |
10-11-10-7M gilteritinib for 5days |
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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]: | |
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Animal models |
Female NOD-SCID mice |
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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. |
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Dosage form |
30 mg/kg Gilteritinib from day 15 to day 70 orally. |
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Applications |
Gilteritinib prolongs the survival of AML IBMT mice. |
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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. |
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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.
Gilteritinib（ASP2215，Xospata）用于复发和/或难治性 AML (R/R AML)。 Gilteritinib 是一种小分子 FLT3/AXL 双重抑制剂，IC50 为 0.29 nM/0.73 nM[8]。
当评估 gilteritinib 对 MV4 11 和 MOLM- 的抗增殖活性时13 个内源性表达 FLT3-ITD 的细胞。处理 5 天后，gilteritinib 抑制 MV4 11 和 MOLM-13 细胞的生长，平均 IC50 值为 0.92 nM（95% CI:0.23 3.6 nM）和 2.9 nM[1]。 gilteritinib 在体外和体内对 ALK-TKI 耐药的单一突变体和 I1171N 复合突变体具有抑制作用。 Gilteritinib 对 NTRK 重排癌症有效，包括耐 entrectinib 的 NTRK1 G667C 突变和 ROS1 融合阳性癌症[3]。无论 p53 状态如何，使用 gilteritinib 治疗通过 NF-κ 在 CRC 细胞中诱导 PUMA；抑制 AKT 和激活糖原合酶激酶后的 B 通路 3β； (GSK-3β)。通过 gilteritinib[4] 的治疗，观察到 PUMA 对 CRC 细胞的凋亡至关重要。 Gilteritinib 与 ATO 的组合在 FLT3-ITD 突变细胞中显示出抑制增殖、增加细胞凋亡和减弱侵袭能力以及减少裸鼠肿瘤生长的协同作用。 Gilteritinib 增加细胞膜表面 160KD 形式的 FLT3 蛋白[5]。在 FLT3 信号分析中，gilteritinib 在 HEK293 和 Ba/F3 细胞中以相似的程度抑制 FLT3wt 和 FLT3-ITD，并且在 MOLM 中存在和不存在 FL 的情况下同样抑制 FLT3 下游信号分子（包括 ERK1/2 和 STAT5） -13 个细胞[6]。将 gilteritinib 与 trametinib（一种 MEK1/2 抑制剂）联合使用是靶向 IgH-CRLF2-r ALL 细胞的有效手段，无论 RAS 突变状态如何[7]。
Gilteritinib 可延长对于 AML IBMT 小鼠的存活率，MV4-11-luc 肿瘤生长在治疗的前 2 周内显着减少。 Gilteritinib 治疗显着提高了 MV4-11 异种移植小鼠的存活率[1]。 gilteritinib 已用于治疗 AML[2]。
| Cas No. | 1254053-43-4 | SDF | |
| 别名 | 吉列替尼,ASP2215 | ||
| Canonical SMILES | NC(C1=NC(CC)=C(NC2CCOCC2)N=C1NC3=CC(OC)=C(N4CCC(N5CCN(C)CC5)CC4)C=C3)=O | ||
| 分子式 | C₂₉H₄₄N₈O₃ | 分子量 | 552.71 |
| 溶解度 | Water : 2 mg/mL (3.27 mM);DMSO : 1.74 mg/mL (2.85 mM) | 储存条件 | 4°C, stored under nitrogen |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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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 |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML
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.).
Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial
The phase 3 ADMIRAL (NCT02421939; Study ID: 2215-CL-0301) trial showed superior overall survival in patients with relapsed/refractory FLT3-mutation-positive acute myeloid leukemia (AML) randomized 2:1 to receive the oral FMS-like tyrosine kinase 3 inhibitor gilteritinib vs those randomized to receive salvage chemotherapy (SC). Here we provide a follow-up of the ADMIRAL trial 2 years after the primary analysis to clarify the long-term treatment effects and safety of gilteritinib in these patients with AML. At the time of this analysis, the median survival follow-up was 37.1 months, with deaths in 203 of 247 and 97 of 124 patients in the gilteritinib and SC arms, respectively; 16 gilteritinib-treated patients remained on treatment. The median overall survival for the gilteritinib and SC arms was 9.3 and 5.6 months, respectively (hazard ratio, 0.665; 95% confidence interval [CI], 0.518, 0.853; two-sided P = .0013); 2-year estimated survival rates were 20.6% (95% CI, 15.8, 26.0) and 14.2% (95% CI, 8.3, 21.6). The gilteritinib-arm 2-year cumulative incidence of relapse after composite complete remission was 75.7%, with few relapses occurring after 18 months. Overall, 49 of 247 patients in the gilteritinib arm and 14 of 124 patients in the SC arm were alive for ≿ years. Twenty-six gilteritinib-treated patients remained alive for ≿ years without relapse; 18 of these patients underwent transplantation (hematopoietic stem cell transplantation [HSCT]) and 16 restarted gilteritinib as post-HSCT maintenance therapy. The most common adverse events of interest during years 1 and 2 of gilteritinib therapy were increased liver transaminase levels; adverse event incidence decreased in year 2. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival vs SC. This trial was registered at www.clinicaltrials.gov as #NCT02421939.
Gilteritinib
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.
Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia
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
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.