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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 (IC(50)) 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 (IC(50) = 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 (K(i) < 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 (IC(50) ≤ 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.

ABT-299 is an aqueous soluble prodrug that is converted rapidly in vivo to A-85783, a novel, highly potent, specific platelet activating factor (PAF) antagonist. The K, for inhibiting PAF binding to rabbit platelet membranes is 3.9 and 0.3 nM for human platelets. Inhibition is selective and reversible and is correlated with functional antagonism of PAF-mediated cellular responses (calcium mobilization, priming of superoxide generation, aggregation and degranulation). The in vivo generation of A-85783 from ABT-299 leads to potent inhibition of PAF-induced inflammatory responses (increased vascular permeability, hypotension and edema) and PAF-induced lethality. When administered i.v., the potency (ED50) of ABT-299 for inhibiting PAF responses was between 6 to 10 micrograms/kg in the rat and mouse and 100 micrograms/kg in the guinea pig. A dose of 100 micrograms/kg in the rat provided greater than 60% protection for 8 to 16 hr against cutaneous and systemic PAF challenge. This duration was also evidenced by ex vivo inhibition of platelet aggregation in guinea pig and sheep. In addition to being active parenterally, ABT-299 exhibited p.o. activity in the rat and mouse (ED50 = 100 micrograms/kg in both species). Pharmacokinetic studies in the rat revealed that ABT-299 was converted rapidly to A-85783 and, in turn, metabolized to the corresponding pyridine-N-oxide and sulfoxide metabolites. These metabolites exhibited significant potency in vitro and in vivo and thus may contribute to the activity observed after administration of ABT-299.