Molecular Cancer apeutics apeutic Discovery overy and Characterization of Novel Mutant Ther 3 Kinase Inhibitors

nloaded a subpopulation of acute myeloid leukemia (AML) patients, the constitutively activated tyrosine , mutant FLT3, has emerged as a promising target for therapy. The development of drug resistance, er, is a growing concern for mutant FLT3 inhibitors, such as PKC412. Potential therapeutic benefit ise from the combination of two structurally diverse inhibitors that target—but bind differently to— me protein or from two inhibitors with completely different mechanisms of action. Thus, there is a need ntification and development of novel FLT3 inhibitors that have the ability to positively combine with 2 or standard chemotherapeutic agents used to treat AML as a way to suppress the development of esistance and consequently prolong disease remission. Here, we report the effects of the novel type II ompetitive inhibitors, HG-7-85-01 and HG-7-86-01, which potently and selectively target mutant FLT3 n kinase activity and inhibit the proliferation of cells harboring FLT3-ITD or FLT3 kinase domain point ts via induction of apoptosis and cell cycle inhibition. Antileukemic activity of HG-7-85-01 was shown to be comparable with that observed with PKC412 in a bioluminescence assay using NCr nude mice ring Ba/F3-FLT3-ITD-luc+ cells. HG-7-85-01 was also observed to override PKC412 resistance. Finally, 85-01 and HG-7-86-01 synergized with PKC412 and standard chemotherapeutic agents against mutant 2-sensitive and some PKC412-resistant, FLT3-positive cells. Thus, we present a structurally novel class PKC41 of FLT3 inhibitors that warrants consideration for clinical testing against drug-resistant disease in AML patients. Mol Cancer Ther; 9(9); 2468–77. ©2010 AACR.