PT  - JOURNAL ARTICLE
AU  - Glaser, Keith B.
AU  - Li, Junling
AU  - Marcotte, Patrick A.
AU  - Magoc, Terrance J.
AU  - Guo, Jun
AU  - Reuter, David R.
AU  - Tapang, Paul
AU  - Wei, Ru-Qi
AU  - Pease, Lori J.
AU  - Bui, Mai H.
AU  - Chen, Zehan
AU  - Frey, Robin R.
AU  - Johnson, Eric F.
AU  - Osterling, Donald J.
AU  - Olson, Amanda M.
AU  - Bouska, Jennifer J.
AU  - Luo, Yanping
AU  - Curtin, Michael L.
AU  - Donawho, Cherrie K.
AU  - Michaelides, Michael R.
AU  - Tse, Chris
AU  - Davidsen, Steven K.
AU  - Albert, Daniel H.
TI  - 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
AID  - 10.1124/jpet.112.197087
DP  - 2012 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 617--627
VI  - 343
IP  - 3
4099  - http://jpet.aspetjournals.org/content/343/3/617.short
4100  - http://jpet.aspetjournals.org/content/343/3/617.full
SO  - J Pharmacol Exp Ther2012 Dec 01; 343
AB  - 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.