Kelly Louise M, Yu Jin-Chen, Boulton Christina L, Apatira Mutiah, Li Jason, Sullivan Carol M, Williams Ifor, Amaral Sonia M, Curley David P, Duclos Nicole, Neuberg Donna, Scarborough Robert M, Pandey Anjali, Hollenbach Stanley, Abe Keith, Lokker Nathalie A, Gilliland D Gary, Giese Neill A
Division of Hematology/Oncology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Cancer Cell. 2002 Jun;1(5):421-32. doi: 10.1016/s1535-6108(02)00070-3.
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 (IC(50) approximately 200 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 IC(50) 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.
高达30%的急性髓性白血病（AML）患者在FLT3受体的近膜结构域内存在激活型内部串联重复（ITD），这表明它可能是激酶抑制剂治疗的一个靶点。为此，我们开发了CT53518，一种强效拮抗剂，可抑制FLT3、血小板衍生生长因子受体（PDGFR）和c-Kit（IC50约为200 nM），而其他酪氨酸或丝氨酸/苏氨酸激酶未受到明显抑制。在表达不同FLT3-ITD突变体的Ba/F3细胞中，CT53518抑制IL-3非依赖性细胞生长和FLT3-ITD自身磷酸化，IC50为10-100 nM。在人FLT3-ITD阳性AML细胞系中，CT53518诱导细胞凋亡，并抑制FLT3-ITD磷酸化、细胞增殖以及通过MAP激酶和PI3激酶途径的信号传导。CT53518的治疗效果在裸鼠模型和FLT3-ITD诱导疾病的小鼠骨髓移植模型中均得到了证实。
