Abstract:
:Advances in the understanding of the molecular basis for acute myeloid leukemia (AML) have generated new potential targets for treatment. Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in AML and mutations in this gene are associated with poor overall survival. AXL plays a role in the activation of FLT3 and has been implicated in the pathogenesis of AML. The studies reported here evaluated the ability of a novel FLT3/AXL inhibitor, gilteritinib, to block mutated FLT3 in cellular and animal models of AML. Initial kinase studies showed that gilteritinib, a type I tyrosine kinase inhibitor, was highly selective for both FLT3 and AXL while having weak activity against c-KIT. Gilteritinib demonstrated 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 also inhibited FLT3-F691 mutations, although to a lesser degree, in these assays. Furthermore, gilteritinib decreased the phosphorylation levels of FLT3 and its downstream targets in both cellular and animal models. In vivo, gilteritinib was distributed at high levels in xenografted tumors after oral administration. The decreased FLT3 activity and high intratumor distribution of gilteritinib translated to tumor regression and improved survival in xenograft and intra-bone marrow transplantation models of FLT3-driven AML. No overt toxicity was seen in mouse models treated with gilteritinib. These results indicate that gilteritinib may be an important next-generation FLT3 inhibitor for use in the treatment of FLT3 mutation-positive AML.
journal_name
Invest New Drugsjournal_title
Investigational new drugsauthors
Mori M,Kaneko N,Ueno Y,Yamada M,Tanaka R,Saito R,Shimada I,Mori K,Kuromitsu Sdoi
10.1007/s10637-017-0470-zsubject
Has Abstractpub_date
2017-10-01 00:00:00pages
556-565issue
5eissn
0167-6997issn
1573-0646pii
10.1007/s10637-017-0470-zjournal_volume
35pub_type
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journal_title:Investigational new drugs
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doi:10.1007/s10637-012-9888-5
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journal_title:Investigational new drugs
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journal_title:Investigational new drugs
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journal_title:Investigational new drugs
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更新日期:1987-01-01 00:00:00
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pub_type: 杂志文章,随机对照试验
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journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
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更新日期:2010-08-01 00:00:00
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journal_title:Investigational new drugs
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journal_title:Investigational new drugs
pub_type: 杂志文章
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journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章,多中心研究
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更新日期:2001-01-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章,评审
doi:10.1007/BF00173788
更新日期:1984-01-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章,评审
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journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
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更新日期:2019-02-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1023/a:1014469828729
更新日期:2002-02-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9577-1
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doi:10.1007/s10637-019-00876-3
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journal_title:Investigational new drugs
pub_type: 杂志文章
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journal_title:Investigational new drugs
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journal_title:Investigational new drugs
pub_type: 杂志文章
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-011-9768-4
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-008-9130-7
更新日期:2008-10-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
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更新日期:2020-08-11 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-018-0584-y
更新日期:2018-12-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究,随机对照试验
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更新日期:2012-04-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
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更新日期:2016-12-01 00:00:00
abstract::Trimetrexate (TMTX) is an analog of methotrexate and a potent inhibitor of the enzyme dihydrofolate reductase. In this phase I study, TMTX was given intravenously to 32 patients as a constant infusion over 24 hours every 28 days. The maximum-tolerated dose of TMTX was 200 mg/m2, with myelosuppression as the dose-limit...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00177251
更新日期:1990-05-01 00:00:00
abstract::4-demethoxydaunorubicin (4-dm DNR), a new analog of daunorubicin, was tested at an every 3-week dose schedule in 63 evaluable patients with various forms of disseminated malignancy. Utilizing the intravenous (i.v.) route of administration, the maximum tolerated dose (MTD) was 15-18 mg/m2; with the oral route the MTD w...
journal_title:Investigational new drugs
pub_type: 杂志文章
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更新日期:1983-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1007/BF00216925
更新日期:1990-02-01 00:00:00