CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML)
CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML)
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DOI：
10.1016/s1535-6108(02)00070-3
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发表时间：
2002-06-01
期刊：
影响因子：
50.3
通讯作者：
Giese, NA
中科院分区：
文献类型：
--
作者：
Kelly, LM;Yu, JC;Giese, NA
高达30%的急性骨髓性白血病（AML）患者在FLT 3受体的近膜结构域内存在激活的内部串联重复（ITD），这表明它可能是激酶抑制剂治疗的靶点。为此，我们开发了CT 53518，这是一种有效的拮抗剂，可抑制FLT 3、血小板衍生生长因子受体（PDGFR）和c-Kit（IC 50类似于200 nM），而其他酪氨酸或丝氨酸/苏氨酸激酶则未受到显著抑制。在表达不同FLT 3-ITD突变体的Ba/F3细胞中，CT 53518抑制IL-3非依赖性细胞生长和FLT 3-ITD自磷酸化，IC 50为10-100 nM。在人FLT 3-ITD阳性AML细胞系中，CT 53518诱导细胞凋亡并抑制FLT 3-ITD磷酸化、细胞增殖以及通过MAP激酶和PI 3激酶途径的信号传导。在FLT 3-ITD诱导疾病的裸鼠模型和鼠骨髓移植模型中均证实了CT 53518的治疗功效。
Up to 30% of acute myelogenous leukemia (AML) patients harbor an activating internal tandem duplication (ITD) within the juxtamembrane domain of the FLT3 receptor, suggesting that it may be a target for kinase inhibitor therapy. For this purpose we have developed CT53518, a potent antagonist that inhibits FLT3, platelet-derived growth factor receptor (PDGFR), and c-Kit (IC50 similar to200 nM), while other tyrosine or serine/threonine kinases were not significantly inhibited. In Ba/F3 cells expressing different FLT3-ITD mutants, CT53518 inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC50 of 10-100 nM. In human FLT3-ITD-positive AML cell lines, CT53518 induced apoptosis and inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the MAP kinase and PI3 kinase pathways. Therapeutic efficacy of CT53518 was demonstrated both in a nude mouse model and in a murine bone marrow transplant model of FLT3-ITD-induced disease.