Antineoplastic effect of a single oral dose of the novel Flt3 inhibitor KRN383 on xenografted human leukemic cells harboring Flt3-activating mutations

FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML

“…Reports of other FLT3 inhibitors in preclinical development include the quinoxaline AG1295 , which was specifically cytotoxic to FLT3-ITD-positive AML blasts (Levis et al, 2001); the quinoxaline AG1296 , selectively kills mutant FLT3-positive cell lines and primary AML cells, and inhibits FLT3-ITD autophosphorylation with an IC 50 of approximately 1 μM (Tse et al, 2001; Tse et al, 2002); the (5-hydroxy-1 H -2-indolyl)(1 H -2-indolyl)-methanone D64406 and the 5-butanoate-1 H -2-indolyl)(1 H -2-indolyl)-methanone D-65476 , which displays an IC 50 of around 0.2-0.3 μM against TEL-FLT3-transfected Ba/F3 cells (Teller et al, 2002); the tricyclic quinoxaline AGL2043 (Gazit et al, 2003); the 1-phenyl-3- H -8-oxa-2,3-diaza-cyclopenta[a]inden GTP-14564 , which inhibits FLT3-ITD-expressing Ba/F3 cells at a concentration of 1 μM (Murata et al, 2003); the quinoline urea Ki23819 , which has been shown to be effective against FLT3-ITD-expressing human cell lines (Komeno et al, 2005); KRN383 , which inhibits FLT3-ITD autophosphorylation with an IC 50 of less than 5.9 nM, D835Y autophosphorylation with an IC 50 of 43 nM, and proliferation of FLT3-ITD-positive cells with an IC 50 of less than 2.9 nM and shows in vivo activity against FLT3-ITD-positive leukemia (Nishiyama et al, 2006); the 2,4,5-trisubstituted pyrimidine, FI-700 , which inhibits FLT3 kinase activity with an IC 50 of 20 nM, inhibits the growth of MV4-11 cells with an IC 50 of 14 nM, and displays in vivo anti-leukemia activity (Kiyoi et al, 2007); the quinoline Ki11502 , which inhibits the proliferation of mutant FLT3-positive MV4-11 and MOLM13 with an IC 50 of 0.5-0.6 μM and an IC 50 of 37.54 nM against FLT3 kinase (Nishioka et al, 2008); 5-(1,3,4-oxadiazol-2-yl)pyrimidine derivatives , which show efficacy when administered orally in a MOLM-13 xenograft model (Ishida et al, 2008); the N,N′ -diphenyl urea NVP-AST487 , which selectively targets mutant FLT3 kinase activity, is able to override PKC412 resistance in vitro and synergizes with chemotherapeutic agents against mutant FLT3-positive cells, and inhibits the growth of FLT3-ITD-expressing cells in vivo (Weisberg et al, 2008b); the bis(1H-indol-2-yl)methanone compound102 , which overrides resistance to PKC412, including PKC412 resistance due to mutated residue N676 in FLT3, and which synergizes with chemotherapeutic agents (Mahboobi et al, 2006; Heidel et al, 2009). Other structural classes of FLT3 inhibitors include pyrimido-diazepines (Gracias et al, 2008), 4-amino-6-piperazin-1-yl-pyrimidine-5-carbaldehyde oximes (Gaul et al, 2007), and the 2-acylaminothiophene-3-carboxamides (Patch et al, 2006).…”