ABT-348 is a novel ATP-competitive inhibitor of Aurora kinases (Aurora B, C and A, IC50 values of 7, 1 and 120 nM, respectively). The activity against Aurora B is reflected in cellular assays of inhibition of histone H3 phosphorylation (IC50 value of 21 nM), induction of polyploidy (IC15 value of 12 nM) and inhibition of colony formation of human pancreatic carcinoma cells (MiaPaCa, IC50 value of 4 nM). Consistent with enzyme inhibition, ABT-348 inhibited the autophosphorylation of the respective enzyme in nocodazole-arrested cells (IC50 values of 13, 13 and 189 nM for Aurora B, C and A). Potency (IC50 values) in the cellular assays also correlated with inhibition of proliferation of cell lines derived from leukemia (0.3 nM, MV-4–11), lymphoma (4 nM, DOHH2), and solid tumors (MiaPaCa, 4 nM; SW620, 6 nM; OVCAR5, 7 nM; and HCT-15, 6 nM). Inhibition of Aurora B activity in vivo by ABT-348 was confirmed by measuring phosphorylation of histone H3 in circulating tumor cells obtained from an engrafted leukemia model (RS4;11). Inhibition of histone H3 phosphorylation was observed 4 hours after dosing that persisted in a dose-dependent manner for at least 8 hours. The extent of inhibition at 4 hours was related to the plasma concentration of ABT-348 (IC50: 3.6 μM), which was in close agreement with the value determined for inhibition of histone H3 phosphorylation in cells in the presence of mouse plasma (3.3 μM). In addition to its Aurora enzyme activity, evaluation of ABT-348 for inhibitory activity across 128 kinases revealed a unique kinome profile “signature” by virtue of its potent binding activity (Ki values <30 nM) against the VEGFR/PDGFR families and the SRC family of cytoplasmic tyrosine kinases (LYN, BLK, LCK, ABL, FYN, and SRC). The potent VEGFR/PDGFR binding activity was reflected in enzyme assays (IC50 values <10 nM) performed at 1 mM ATP and also correlated with inhibition of RTK auto-phosphorylation in cells for KDR, FLT3, CSF-1R, KIT, PDGFR and. These activities translated into potent inhibition of VEGF-stimulated endothelial cell proliferation (IC50 value <0.3 nM). Evidence that ABT-348 blocked VEGF-mediated responses in vivo was provided by the molecule's potent activity (ED50 value of 0.2 mg/kg, IV) in blocking VEGF-mediated vascular permeability in the uterus and its ability to induce dose-dependent increases in plasma PIGF in mice. Activity against the Src kinase family was evident in the anti-proliferative activity of ABT-348 against BCR ABL expressing tumor cells and cells expressing the gleevec-resistant BCR-ABL T315I mutation (IC50 values of 47 and 260 nM). Based upon these favorable in vitro and in vivo activities, ABT-348 was evaluated and found to be effective in leukemia (RS4;11, regression) xenografts. These results provide the rationale for clinical assessment of ABT-348 as a therapeutic agent in the treatment of cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A239.