期刊
CANCER CELL
卷 1, 期 5, 页码 433-443出版社
CELL PRESS
DOI: 10.1016/S1535-6108(02)00069-7
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资金
- NCI NIH HHS [P01 CA66996] Funding Source: Medline
- NIDDK NIH HHS [P01 DK50654] Funding Source: Medline
Constitutively activating FLT3 receptor mutations have been found in 35% of patients with acute myeloblastic leukemia (AML). Here we report the identification of a small molecule Fill tyrosine kinase inhibitor PKC412, which selectively induced G1 arrest and apoptosis of Ba/F3 cell lines expressing mutant FLT3 (IC50 < 10 nM) by directly inhibiting the tyrosine kinase. Ba/F3-FLT3 cell lines made resistant to PKC412 demonstrated overexpression of mutant FLT3, confirming that FLT3 is the target of this drug. Finally, progressive leukemia was prevented in PKC412-treated Balb/c mice transplanted with marrow transduced with a FLT3-ITD-expressing retrovirus. PKC412 is a potent inhibitor of mutant Ill and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors.
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