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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 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.

The Aurora kinases are a family of serine/threonine kinases that mediate multiple events in cell division. Humans have three Aurora kinases, A, B and C, that are differentially localized and mediate distinct functions during mitosis. Because the Aurora kinases play a key role in mitosis and are overexpressed in multiple human tumor types, there has been considerable interest in developing Aurora kinase inhibitors as antitumor agents. A number of small-molecule Aurora kinase inhibitors have been reported and there are several compounds currently in Phase I/II clinical trials for cancer. ABT-348 is a novel, potent and orally bioavailable inhibitor of the Aurora kinases as well as the VEGF and PDGF families of receptor tyrosine kinases and is currently in Phase I clinical trials. Herein we describe the discovery and preparation of this molecule including the SAR work that provided improved Aurora kinase potency, aqueous solubility and oral bioavailability with reduced hERG and CYP liabilities relative to earlier analogs. 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 C202.

Reactions of thionyl chloride-dimethylformamide reagent at 58°C in deuteriochloroform with 1-triptycylcarbinol and ditriptycylcarbinol produced the sulfite ester and the interesting rearranged compound 1-chloro-2-(1-triptycyl) tribenzobicyclo [3.2.2] nonatriene (a triptycyl-substituted homotriptycene), respectively. The mechanistic differences that occur after initial formation of chlorosulfite intermediates are discussed. Molecular mechanics calculations were used to explore the exothermicity of this and related rearrangements