FLT3 x TOPK

更新于：2024-11-01

基本信息

关联

项与 FLT3 x TOPK 相关的药物

HSD1169

靶点

FLT3 x TOPK

作用机制

FLT3抑制剂 [+1]

在研机构

Purdue University

原研机构

Purdue University

在研适应症

髓系白血病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 FLT3 x TOPK 相关的临床结果

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100 项与 FLT3 x TOPK 相关的转化医学

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0 项与 FLT3 x TOPK 相关的专利（医药）

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项与 FLT3 x TOPK 相关的文献（医药）

2018-04-01·Future Medicinal Chemistry4区 · 医学

Dual FLT3/TOPK Inhibitor with Activity against FLT3-ITD Secondary Mutations Potently Inhibits Acute Myeloid Leukemia Cell Lines

4区 · 医学

Article

作者: Sintim, Herman O ; Lapidus, Rena G ; Hernandez, Delmis E ; Dayal, Neetu ; Sooreshjani, Moloud Aflaki ; Opoku-Temeng, Clement ; Carter-Cooper, Brandon A

Aim: Approximately 30% of acute myeloid leukemia (AML) patients carry FLT3 tyrosine kinase domain (TKD) mutations or internal tandem duplication (FLT3-ITD). Currently there is a paucity of compounds that are active against drug-resistant FLT3-ITD, which contains secondary mutations in the TKD, mainly at residues D835/F691. Results: HSD1169, a novel compound, is active against FLT3-ITD (D835 or F691). HSD1169 is also active against T-LAK cell-originated protein kinase (TOPK), a collaborating kinase that is highly expressed in AML cell lines. HSD1169 was active against MV4–11 and Molm-14 (FLT3-ITD cell lines) but not NOMO-1 or HL60 (FLT3-WT cell lines). HSD1169 was also active against sorafenib-resistant Molm13-res cell line (containing FLT3-ITD/D835Y). Conclusion: HSD1169 or an analog could become a therapeutic agent for AML containing drug-resistant FLT3-ITD.

2015-10-20·Oncotarget

T-LAK cell-originated protein kinase presents a novel therapeutic target inFLT3-ITD mutated acute myeloid leukemia

Article

作者: Malnassy, Gregory ; Matsuo, Yo ; Alachkar, Houda ; Park, Jae-Hyun ; Mutonga, Martin ; Woods, Alex ; Nakamura, Yusuke ; Stock, Wendy ; Takamatsu, Naofumi ; Meng, Liping ; Odenike, Olatoyosi ; Raca, Gordana ; Kline, Justin ; Fulton, Noreen ; Miyamoto, Takashi

Gain-of-function mutations of FLT3 (FLT3-ITD), comprises up to 30% of normal karyotype acute myeloid leukemia (AML) and is associated with an adverse prognosis. Current FLT3 kinase inhibitors have been tested extensively, but have not yet resulted in a survival benefit and novel therapies are awaited. Here we show that T-LAK cell-originated protein kinase (TOPK), a mitotic kinase highly expressed in and correlated with more aggressive phenotype in several types of cancer, is expressed in AML but not in normal CD34+ cells and that TOPK knockdown decreased cell viability and induced apoptosis. Treatment of AML cells with TOPK inhibitor (OTS514) resulted in a dose-dependent decrease in cell viability with lower IC50 in FLT3-mutated cells, including blasts obtained from patients relapsed after FLT3-inhibitor treatment. Using a MV4-11-engrafted mouse model, we found that mice treated with 7.5 mg/kg IV daily for 3 weeks survived significantly longer than vehicle treated mice (median survival 46 vs 29 days, P < 0.001). Importantly, we identified TOPK as a FLT3-ITD and CEBPA regulated kinase, and that modulating TOPK expression or activity resulted in significant decrease of FLT3 expression and CEBPA phosphorylation. Thus, targeting TOPK in FLT3-ITD AML represents a novel therapeutic approach for this adverse risk subset of AML.