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].
参考文献:
[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]。
| 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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参考文献: [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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