Gilteritinib (Synonyms: ASP2215) |
| Catalog No.GC19482 |
Gilteritinib (ASP2215, Xospata) for relapsed and /or refractory AML (R/R AML).
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Cas No.: 1254053-43-4
Sample solution is provided at 25 µL, 10mM.
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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.
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