Abstract A239: Preclinical characterization of ABT-348, a kinase inhibitor targeting the Aurora, VEGFR/PDGFR, and SRC kinase families

• Published in: Molecular cancer therapeutics 2011-11, Vol.10 (11_Supplement), p.A239-A239
• Main Authors: Glaser, Keith B., Li, Junling, Marcotte, Patrick A., Magoc, Terrance J., Guo, Jun, Reuter, David R., Tapang, Paul, Wei, Ru-Qi, Pease, Lori J., Bui, Mai H., Chen, Zehan, Frey, Robin R., Johnson, Eric F., Osterling, Donald J., Olson, Amanda M., Bouska, Jennifer J., Curtin, Michael L., Donawho, Cherrie K., Michaelides, Michael R., Tse, Chris, Davidsen, Steven K., Albert, Daniel H.
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-11-A239

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