ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia

Identification of AKN-032, a novel 2-aminopyrazine tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia

“…In the third AML cell line tested HL-60, a cell line reported to be FLT3 negative [25], a full cytotoxic response was achieved, but at noticeably higher concentrations.…”

“…Inhibition of MV4-11 proliferation was chosen as the first cellular assay. This cell line has been used extensively when characterizing FLT3 enzyme A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 19 inhibitors both in cell-kill assays and in xenografts [25,38,39]. Compounds with an IC 50 below 400 nM in the MV4-11 cell line were then tested in another cellular assay, using the rapidly A c c e p t e d M a n u s c r i p t …”

Drug resistance in mutant FLT3-positive AML

“…Additional novel FLT3 inhibitors in early development include the N-(4-(3-amino-1H-indazol-4yl)phenyl-N1(2-fluoro-5-methylphenyl) urea ABT-869 (Albert et al, 2006;Shankar et al, 2007;Zhou et al, 2008), which is a multitargeted inhibitor with activity toward FLT3, PDGFR, KIT and KDR; the benzimidalzolequinoline CHIR-258 (TKI258; Chiron, Emeryville, CA, USA), which has among its targets FLT3, KIT, FMS, VEGFR and FGFR (Lopes de Menezes et al, 2005) and is a promising antimyeloma drug (Trudel et al, 2005) presently in Phase I clinical trials for multiple myeloma, mixed solid tumors and AML; the hydroxystyrylacrylonitrile LS104 (Kasper et al, 2008), which is in a Phase I clinical trial for patients with refractory/ relapsed hematological malignancies; and AP24534 (Ariad, Cambridge, MA, USA), a multitargeted kinase inhibitor with activity against FLT3, KIT and FGFR (Rivera et al, 2008), and which is in Phase I clinical trials for CML and other hematological malignancies. It is important to note that thus far, no selective FLT3 inhibitor has been developed that would allow the study of FLT3 exclusively as a target.…”

Synergistic antileukemic effects between ABT-869 and chemotherapy involve downregulation of cell cycle-regulated genes and c-Mos-mediated MAPK pathway

“…For in vitro and in vivo experiments, ABT-869 was prepared as published previously. 21 Clinical-grade Ara-C (100 mg ml À1 , Pharmacia, Sydney, WA, Australia) and Dox (2 mg ml À1 , Pharmacia) were diluted just before use. The MEK inhibitor U0126 was purchased from Promega and dissolved in dimethylsulfoxide at a concentration of 10 mM as stock.…”

“…19,21 However, considering the complexity of the disease, monotherapy with ABT-869 is unlikely to deliver complete or lasting responses in AML. Furthermore, resistance to TKIs has been well described in patients treated with imatinib mesylate monotherapy for chronic myelogenous leukemia.…”