[PDF][PDF] Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412
E Weisberg, C Boulton, LM Kelly, P Manley, D Fabbro… - Cancer cell, 2002 - cell.com
E Weisberg, C Boulton, LM Kelly, P Manley, D Fabbro, T Meyer, DG Gilliland, JD Griffin
Cancer cell, 2002•cell.comConstitutively 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
FLT3 tyrosine kinase inhibitor PKC412, which selectively induced G1 arrest and apoptosis of
Ba/F3 cell lines expressing mutant FLT3 (IC 50< 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 …
acute myeloblastic leukemia (AML). Here we report the identification of a small molecule
FLT3 tyrosine kinase inhibitor PKC412, which selectively induced G1 arrest and apoptosis of
Ba/F3 cell lines expressing mutant FLT3 (IC 50< 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 …
Abstract
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 FLT3 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 FLT3 and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors.
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