Gilteritinib (ASP2215)

Gilteritinib (ASP2215) is a small-molecule FLT3/AXL inhibitor with IC50 values of 0.29 nM and 0.73 nM for FLT3 and AXL, respectively. It inhibits FLT3 at an IC50 value that was approximately 800-fold more potent than the concentration required to inhibit c-KIT (230 nM).

Gilteritinib (ASP2215)化学構造

CAS No. 1254053-43-4

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Gilteritinib (ASP2215)と併用されることが多い化合物

Quizartinib (AC220)


Gilteritinib exhibits a stronger proapoptotic effect in hypoxia and coculture with bone marrow stromal cells than Quizartinib.

Dumas PY, et al. Clin Cancer Res. 2021 Nov 1;27(21):6012-6025.

FF-10101


FF-10101 induces significantly more apoptosis of MOLM-14 cells in HS5-conditioned media compared to gilteritinib.

Ferng TT, et al. Mol Cancer Ther. 2022 May 4;21(5):844-854.

Venetoclax (ABT-199)


Gilteritinib and Venetoclax combination gives a highly modified composite complete response rate and FLT3 molecular response rates.

Daver N, et al. J Clin Oncol. 2022 Dec 10; 40(35): 4048–4059.

Fimepinostat (CUDC-907)


Gilteritinib and Fimepinostat, in combination, gives synergistic antileukemic activity against FLT3-internal tandem duplication (ITD) acute myeloid leukemia (AML) cell lines MOLM-13/MV4-11.

Qiao X, et al. Blood Cancer J. 2021 Jun 7;11(6):111.

Midostaurin


Gilteritinib and Fimepinostat combination with venetoclax potently and synergistically induces apoptosis in FLT3-internal tandem duplication (ITD) acute myeloid leukemia (AML) cell lines MOLM-13/MV4–1.

Ma J, et al. Clin Cancer Res. 2019 Nov 15;25(22):6815-6826.

Gilteritinib (ASP2215)関連製品

シグナル伝達経路

FLT3阻害剤の選択性比較

Cell Data

Cell Lines Assay Type Concentration Incubation Time 活性情報 PMID
32D/TKD cells Function assay 50 nM  6 h Inhibiton of the phosphorylation of Akt on T308 29507660
MOLM-13 cells Apoptosis assay 1, 3, 10, 30, and 100 nM 48 h significant increases in the percentage of annexin V-positive cells at concentrations of 30 nM (32.0%) and 100 nM (52.4%) versus control (4.1%) 31069015
MV4-11 cells Cell cycle assay 1, 3, 10, and 30 nM 24 h The mean proportion of MV4-11 cells in G1 phase were significantly increased at gilteritinib concentrations of 3 (69.0%; P<0.01) and 10 nM (70.7%; P<0.001). 31069015
TF-1 cells Function assay 0, 20, 80, 200 and 500 nM 1 h gilteritinib has an IC50 against wild-type c-Kit of 102 nM 27908881
Vero Antiviral assay 24 hr Antiviral activity against SARS-CoV-2 (viral titer) measured by plaque assay in Vero cells at MOI 0.0125 after 24 hr, IC50 = 6.76 μM. ChEMBL
Vero Cell viability assay 72 hr Cell viability measured by CellTiter-Glo assay in Vero cells at MOI 0.05 after 72hr, CC50 = 37.16 μM. ChEMBL
BA/F3 Function assay Inhibition Assay: A recombinant retrovirus was created from expression plasmid FLAG-EML4-ALKv1/pMX-iresCD8 in which cDNA for EMLA-ALK fusion protein v1 was integrated, and injected into mouse lymphoid cell line BA/F3 cells. Using a magnetic bead reagent f, IC50 = 0.0015 μM. ChEMBL
BA/F3 Function assay Inhibition Assay: A recombinant retrovirus was created from expression plasmid FLAG-EML4-ALKv1/pMX-iresCD8 in which cDNA for EMLA-ALK fusion protein v1 was integrated, and injected into mouse lymphoid cell line BA/F3 cells. Using a magnetic bead reagent f, IC50 = 0.0015 μM. ChEMBL
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生物活性

製品説明 Gilteritinib (ASP2215) is a small-molecule FLT3/AXL inhibitor with IC50 values of 0.29 nM and 0.73 nM for FLT3 and AXL, respectively. It inhibits FLT3 at an IC50 value that was approximately 800-fold more potent than the concentration required to inhibit c-KIT (230 nM).
Targets
FLT3 [1]
(Cell-free assay)
Axl [1]
(Cell-free assay)
0.29 nM 0.73 nM
In Vitro
In vitro Gilteritinib demonstrates potent inhibitory activity against the internal tandem duplication (FLT3-ITD) and FLT3-D835Y point mutations in cellular assays using MV4-11 and MOLM-13 cells as well as Ba/F3 cells expressing mutated FLT3. Gilteritinib decreases the phosphorylation levels of FLT3 and its downstream targets in both cellular and animal models. Gilteritinib inhibits 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)[1]. Gilteritinib treatment for 48h results in an induction of apoptosis in MV4-11 cells as determined by an increase in annexin V-positive cells. Gilteritinib also decreases the expression of anti-apoptotic proteins such as MCL-1, BCL2L10, and survivin, which are reported to be important in chemotherapy sensitivity, following 24h treatment[2].
細胞実験 細胞株 MV4-11 cells
濃度 0.1 nM, 1 nM, and 10 nM
反応時間 2 h
実験の流れ

MV4-11 cells are treated with DMSO or increasing concentrations of gilteritinib for 2 hours. Immunoprecipitation and immunoblot for phosphorylated FLT3 and total FLT3 are performed.

実験結果図 Methods Biomarkers 結果図 PMID
Western blot p-STAT5 / STAT5 / p-AKT / AKT / p-ERK / ERK p-c-kit / c-kit p-FLT3(Y591) / FLT3 28516360
In Vivo
In Vivo In vivo, gilteritinib is distributed at high levels in xenografted tumors after oral administration. The decreased FLT3 activity and high intratumor distribution of gilteritinib translates to tumor regression and improved survival in xenograft and intra-bone marrow transplantation models of FLT3-driven AML. This antitumor activity is associated with a durable inhibition of phospho-FLT3 and phospho-STAT5. Furthermore, treatment with gilteritinib decreases the leukemic burden and prolongs survival in a mouse IBMT model. No overt toxicity is seen in mouse models treated with gilteritinib[1].
動物実験 動物モデル MV4-11 xenografted mice (Nude mice)
投与量 1 mg/kg, 6 mg/kg, and 10 mg/kg
投与経路 oral
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT06022003 Not yet recruiting
AML Adult|Refractory AML|Relapsed Adult AML|FLT3-TKD Mutation|FLT3-ITD
French Innovative Leukemia Organisation|Acute Leukemia French Association
December 15 2023 Phase 2
NCT05520567 Recruiting
Acute Myeloid Leukemia (AML)|FLT3-mutated Acute Myeloid Leukemia
Astellas Pharma Global Development Inc.|Astellas Pharma Inc
January 27 2023 Phase 1|Phase 2
NCT05791890 Active not recruiting
Acute Myeloid Leukemia
University of Rome Tor Vergata
May 31 2022 --

化学情報

分子量 552.71 化学式

C29H44N8O3

CAS No. 1254053-43-4 SDF Download Gilteritinib (ASP2215) SDFをダウンロードする
Smiles CCC1=C(N=C(C(=N1)C(=O)N)NC2=CC(=C(C=C2)N3CCC(CC3)N4CCN(CC4)C)OC)NC5CCOCC5
保管

In vitro
Batch:

DMSO : 4 mg/mL ( (7.23 mM); 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Water : Insoluble

Ethanol : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機

実験計算

モル濃度計算器

質量 濃度 体積 分子量

投与溶液組成計算機(クリア溶液)

ステップ1:実験データを入力してください。(実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します)

mg/kg g μL

ステップ2:投与溶媒の組成を入力してください。(ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください)

% DMSO % % Tween 80 % ddH2O
%DMSO %

計算結果:

投与溶媒濃度: mg/ml;

DMSOストック溶液調製方法: mg 試薬を μL DMSOに溶解する(濃度 mg/mL, 注:濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法:Take μL DMSOストック溶液に μL PEG300,を加え、完全溶解後μL Tween 80,を加えて完全溶解させた後 μL ddH2O,を加え完全に溶解させます。

投与溶媒調製方法:μL DMSOストック溶液に μL Corn oil,を加え、完全溶解。

注意:1.ストック溶液に沈殿、混濁などがないことをご確認ください;
2.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

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