TY - JOUR T1 - Preclinical Characterization of ABT-348, a Kinase Inhibitor Targeting the Aurora, Vascular Endothelial Growth Factor Receptor/Platelet-Derived Growth Factor Receptor, and Src Kinase Families JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 617 LP - 627 DO - 10.1124/jpet.112.197087 VL - 343 IS - 3 AU - Keith B. Glaser AU - Junling Li AU - Patrick A. Marcotte AU - Terrance J. Magoc AU - Jun Guo AU - David R. Reuter AU - Paul Tapang AU - Ru-Qi Wei AU - Lori J. Pease AU - Mai H. Bui AU - Zehan Chen AU - Robin R. Frey AU - Eric F. Johnson AU - Donald J. Osterling AU - Amanda M. Olson AU - Jennifer J. Bouska AU - Yanping Luo AU - Michael L. Curtin AU - Cherrie K. Donawho AU - Michael R. Michaelides AU - Chris Tse AU - Steven K. Davidsen AU - Daniel H. Albert Y1 - 2012/12/01 UR - http://jpet.aspetjournals.org/content/343/3/617.abstract N2 - ABT-348 [1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea] is a novel ATP-competitive multitargeted kinase inhibitor with nanomolar potency (IC50) for inhibiting binding and cellular autophosphorylation of Aurora B (7 and 13 nM), C (1 and 13 nM), and A (120 and 189 nM). Cellular activity against Aurora B is reflected by inhibition of phosphorylation of histone H3, induction of polyploidy, and inhibition of proliferation of a variety of leukemia, lymphoma, and solid tumor cell lines (IC50 = 0.3–21 nM). In vivo inhibition of Aurora B was confirmed in an engrafted leukemia model by observing a decrease in phosphorylation of histone H3 that persisted in a dose-dependent manner for 8 h and correlated with plasma concentration of ABT-348. Evaluation of ABT-348 across a panel of 128 kinases revealed additional potent binding activity (Ki < 30 nM) against vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) families and the Src family of cytoplasmic tyrosine kinases. VEGFR/PDGFR binding activity correlated with inhibition of autophosphorylation in cells and inhibition of vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation (IC50 ≤ 0.3 nM). Evidence of on-target activity in vivo was provided by the potency for blocking VEGF-mediated vascular permeability and inducing plasma placental growth factor. Activity against the Src kinase family was evident in antiproliferative activity against BCR-ABL chronic myeloid leukemia cells and cells expressing the gleevec-resistant BCR-ABL T315I mutation. On the basis of its unique spectrum of activity, ABT-348 was evaluated and found effective in representative solid tumor [HT1080 and pancreatic carcinoma (MiaPaCa), tumor stasis] and hematological malignancy (RS4;11, regression) xenografts. These results provide the rationale for clinical assessment of ABT-348 as a therapeutic agent in the treatment of cancer. ER -