Ki11502, a novel multitargeted receptor tyrosine kinase inhibitor, induces growth arrest and apoptosis of human leukemia cells in vitro and in vivo
Ki11502, a novel multitargeted receptor tyrosine kinase inhibitor, induces growth arrest and apoptosis of human leukemia cells in vitro and in vivo
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DOI：
10.1182/blood-2007-06-098079
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发表时间：
2008-05-15
期刊：
影响因子：
20.3
通讯作者：
Yokoyama, Akihito
中科院分区：
文献类型：
--
作者：
Nishioka, Chie;Ikezoe, Takayuki;Yokoyama, Akihito
Ki11502 是一种新型多靶点受体酪氨酸激酶 (RTK) 抑制剂，对血小板衍生生长因子受体 α/β (PDGFR α/β) 具有选择性。 Ki11502（0.1-1 nM，2 天）在具有激活的 FIP1 样 1/PDGFR α 融合基因的嗜酸性粒细胞白血病 EOL-1 细胞中显着引起生长停滞、G(0)/G(1)、细胞周期停滞和与 Bcl-2 家族蛋白下调相关的细胞凋亡。 Ki11502 降低 EOL-1 细胞中 p-PDGFR α 及其下游信号（包括 p-Akt、p-ERK 和 p-STAT5）的水平。值得注意的是，Ki11502 对伊马替尼耐药的 PDGFR α T6741 突变体也有活性。此外，Ki11502 还可抑制双表型白血病 MV4-11 和急性髓性白血病 MOLM13 以及新分离的具有 FMS 样酪氨酸激酶 3 (FLT3) 激活突变的白血病细胞的增殖。这与药物抑制 FLT3 及其下游信号通路同时发生，通过使用磷酸特异性抗体的荧光激活细胞分选来测量。此外，Ki11502 完全抑制 SCID 小鼠中作为肿瘤异种移植物生长的 EOL-1 细胞的增殖，没有任何明显的副作用。总而言之，Ki11502 对特定的白血病亚型（包括具有伊马替尼耐药突变的白血病亚型）具有深远的抗增殖作用。
Ki11502 is a novel multitargeted receptor tyrosine kinase (RTK) inhibitor with selectivity against platelet-derived growth factor receptor alpha/beta (PDGFR alpha/beta). Ki11502 (0.1-1 nM, 2 days) profoundly caused growth arrest, G(0)/G(1), cell-cycle arrest, and apoptosis associated with down-regulation of Bcl-2 family proteins in the eosinophilic leukemia EOL-1 cells having the activated FIP1-like 1/PDGFR alpha fusion gene. Ki11502 decreased levels of p-PDGFR alpha and its downstream signals, including p-Akt, p-ERK, and p-STAT5, in EOL-1 cells. Of note, Ki11502 was also active against imatinib-resistant PDGFR alpha T6741 mutant. In addition, Ki11502 inhibited proliferation of biphenotipic leukemia MV4-11 and acute myelogenous leukemia MOLM13 and freshly isolated leukemia cells having activating mutations in FMS-like tyrosine kinase 3 (FLT3). This occurred in parallel with the drug inhibiting FLT3 and its downstream signal pathways, as measured by fluorescence-activated cell sorting using the phospho-specific antibodies. In addition, Ki11502 totally inhibited proliferation of EOL-1 cells growing as tumor xenografts in SCID mice without any noticeable adverse effects. Taken together, Ki11502 has profound anti proliferative effects on select subsets of leukemia including those possessing imatinib-resistant mutation.