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

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ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia by Deepa B. Shankar, Junling Li, Paul Tapang, J. Owen McCall, Lori J. Pease, Yujia Dai, Ru-Qi Wei, Daniel H. Albert, Jennifer J. Bouska, Donald J. Osterling, Jun Guo, Patrick A. Marcotte, Eric F. Johnson, Niru Soni, Kresna Hartandi, Michael R. Michaelides, Steven K. Davidsen, Saul J. Priceman, Jenny C. Chang, Katrin Rhodes, Neil Shah, Theodore B. Moore, Kathleen M. Sakamoto, and Keith B. Glaser Blood Volume 109(8):3400-3408 April 15, 2007 ©2007 by American Society of Hematology

Chemical structure of ABT-869 (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea). Chemical structure of ABT-869 (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea). Deepa B. Shankar et al. Blood 2007;109:3400-3408 ©2007 by American Society of Hematology

ABT-869 inhibits phosphorylation of FLT3, STAT5, and ERK in MV-411 cells. ABT-869 inhibits phosphorylation of FLT3, STAT5, and ERK in MV-411 cells. MV-4-11 cells were cultured in the presence of varying concentrations of ABT-869 or vehicle control (0.1% DMSO) for 2 hours. Cells were lysed and lysates analyzed by Western blot using (A) anti–phospho-FLT3, (B) anti–phospho-STAT5, (C) anti–phospho-ERK for MV-4-11 cells, and (D) anti–phospho-STAT5 and anti–Pim-1 for MOLM-13 cells. For cell culture, β-actin was used as the load control for FLT3 and STAT5, whereas total ERK was used for ERK. The results from at least 2 independent experiments demonstrate similar inhibition of FLT3, STAT5, and ERK phosphorylation with ABT-869, a representative blot is shown. Deepa B. Shankar et al. Blood 2007;109:3400-3408 ©2007 by American Society of Hematology

ABT-869 induces apoptosis of MV-411 cells. ABT-869 induces apoptosis of MV-411 cells. (A) MV-4-11 cells were treated for 72 hours with ABT-869, stained with propidium iodide (50 mg/mL), and analyzed on a FACS Calibur flow cytometer. Sub-G0/G1 population was determined by CellQuest software and designated as apoptotic cells (% apoptotic cells ± SEM). (B) MV-4-11 cells (1 × 106) were harvested at 48 hours after treatment with various drug concentrations. Cells were stained with anti–annexin V–FITC antibody and propidium iodide and analyzed by flow cytometry. Increase in apoptosis was observed with increasing concentrations of ABT-869. Percentages in bottom right quadrants are cells in early apoptosis; annexin V+ and PI−. Percentages in bottom right quadrants are cells in late apoptosis: annexin V+ and PI−. (C) Western blot analysis for PARP cleavage and caspase-3 to assess apoptosis. (D) Representative Western blot analysis of caspase-3 and caspase-9 activation and PARP cleavage in MOLM-13 cells treated with ABT-869. The results from 3 independent experiments show decrease in pro–caspase-3 levels and cleavage of PARP with increasing concentrations of ABT-869. Deepa B. Shankar et al. Blood 2007;109:3400-3408 ©2007 by American Society of Hematology

ABT-869 inhibits phosphorylation of FLT3, STAT5, and ERK in the human blood AML model. ABT-869 inhibits phosphorylation of FLT3, STAT5, and ERK in the human blood AML model. MV-4-11 cells were spiked into normal human blood, 1 × 107 cells/mL, and treated with varying concentrations of ABT-869 for 2 hours. For FLT3 phosphorylation (A), blood was lysed and the FLT3 was immunoprecipitated from 1 mL of lysate with anti-FLT3 (sc-480; 10 mg/mL) and analyzed by Western blot. The results from at least 3 independent experiments demonstrate similar inhibition of phosphorylation of FLT3 by ABT-869; a representative blot is shown. (B) STAT5 and (C) ERK phosphorylation was analyzed from PBMCs prepared from blood treated as described above. Phospho-STAT5 and -ERK were determined directly in cell lysates. (D) Phospho-STAT5 and Pim-1 expressions were analyzed from PBMCs prepared from blood treated as described in “Materials and methods,” with the exception of spiking with MOLM-13 cells. The results from 2 independent experiments demonstrate similar inhibition of the phosphorylation of STAT5 and ERK and decreased Pim-1 expression by ABT-869; a representative blot is shown. (E) Pharmacokinetic analysis of ABT-869 plasma concentration from orally dosed mice with 3 and 10 mg/kg/day in 2.5% ethanol, 5% Tween-80, and 25% PEG 400 in PBS, and the 40 mg/kg dose in pure refined corn oil. ABT-869 was analyzed from plasma that had been protein precipitated with acidified methanol and concentration determined using LC-MS as described in “Materials and methods.” Data are shown as μM ± SEM. Deepa B. Shankar et al. Blood 2007;109:3400-3408 ©2007 by American Society of Hematology

Effect of ABT-869 on proliferation and differentiation of normal human bone marrow progenitors and AML patient samples. Effect of ABT-869 on proliferation and differentiation of normal human bone marrow progenitors and AML patient samples. (A) Methylcellulose-based colony assay was performed with normal human bone marrow cells treated with varying concentrations of ABT-869 and analyzed 14 days after treatment. The experiment is an average of 5 samples with triplicate platings. The inhibitor was not toxic to the bone marrow cells up to a concentration of 1 μM. (B) Methylcellulose-based colony assay performed on AML patient samples containing the FLT3-ITD gene. The experiment is an average of 2 patients with triplicate platings. (C) Methylcellulose-based colony assay performed on FLT3-ITD–negative AML patient samples. The experiment is an average of 5 samples with triplicate platings. All data are expressed as number of colonies ± SEM. All human samples were obtained through an approved protocol from the UCLA IRB and uphold the tenets of the Helsinki protocol. Deepa B. Shankar et al. Blood 2007;109:3400-3408 ©2007 by American Society of Hematology

ABT-869 exhibits dose-dependent efficacy and regression of established subcutaneous MV-4-11 tumors. ABT-869 exhibits dose-dependent efficacy and regression of established subcutaneous MV-4-11 tumors. (A) Daily oral administration of ABT-869 at concentrations of 5, 10, 20 and 40 mg/kg/day was initiated when the MV-411 tumors reached an average of 400 mm3 in volume. The graph shows the dosage response to the inhibitor compared with tumors treated with vehicle control (3 mice per group). (B). Mice injected with MV-411 cells were treated with 40 mg/kg/day ABT-869 or vehicle the day after the injection of cells. The graph shows that the mice receiving treatment never developed tumors in contrast to the vehicle control (3 mice per group). (C) After a single administration of ABT-869 (10 mg/kg), tumors were harvested 3 and 6 hours later, snap-frozen in liquid N2, homogenized in lysis buffer, immunoprecipitated with anti-PY20, and analyzed by Western blot with anti-FLT3. (D) H&E sections of tumors from day 12 of dosing treated with vehicle or 40 mg/kg/d of ABT-869 at low (× 10) and high (× 40) power. Vehicle control–treated tumors show increased mitotic activity (arrowheads, lower left panel). Treated tumors show areas of cell death and inflammatory cells (arrowheads, lower right panel). (E) Ki67 and TUNEL staining of tumor sections from day 12 of dosing were used to evaluate proliferation and apoptosis, respectively. Deepa B. Shankar et al. Blood 2007;109:3400-3408 ©2007 by American Society of Hematology

ABT-869 inhibits the growth of and prevents MOLM-13 tumor formation. ABT-869 inhibits the growth of and prevents MOLM-13 tumor formation. (A) Daily oral administration of ABT-869 at concentrations of 5, 10, 20, and 40 mg/kg/day was initiated when the MOLM-13 tumors reached an average of 400 mm3 in volume (1 mouse per dosage group). The graph shows the dosage response to the inhibitor compared with tumors treated with vehicle control. (B). Mice injected with MOLM-13 cells were treated with 40 mg/kg/day ABT-869 or vehicle the day after injection of cells (2 mice per dosage group). The graph shows that the mice receiving treatment developed tumors after 26 days of treatment in contrast to the vehicle control (tumor size ± SEM). (C) ABT-869 prolongs survival in MV-4-11 bone engraftment model. NOD-SCID mice were injected with 5 × 106 MV-4-11 cells after bone marrow ablation with cyclophosphamide. Treatment with ABT-869 began on day 40 after injection and continued for another 20 weeks. Survival was determined by observation when the animal demonstrated hind limb paralysis or became moribund. Deepa B. Shankar et al. Blood 2007;109:3400-3408 ©2007 by American Society of Hematology