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J Med Chem. 2008 Aug 14;51(15):4465-75. doi: 10.1021/jm800052b. Epub 2008 Jul 17.

A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability.

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Departments of Small Molecule Drug DiscoVery, Cell Cycle and Global Regulators, Translational Oncology, and Protein Engineering, Genentech, Inc, 1 DNA Way, South San Francisco, California 94080, USA.


Aurora kinase inhibitors have attracted a great deal of interest as a new class of antimitotic agents. We report a novel class of Aurora inhibitors based on a pentacyclic scaffold. A prototype pentacyclic inhibitor 32 (AKI-001) derived from two early lead structures improves upon the best properties of each parent and compares favorably to a previously reported Aurora inhibitor, 39 (VX-680). The inhibitor exhibits low nanomolar potency against both Aurora A and Aurora B enzymes, excellent cellular potency (IC50 < 100 nM), and good oral bioavailability. Phenotypic cellular assays show that both Aurora A and Aurora B are inhibited at inhibitor concentrations sufficient to block proliferation. Importantly, the cellular activity translates to potent inhibition of tumor growth in vivo. An oral dose of 5 mg/kg QD is well tolerated and results in near stasis (92% TGI) in an HCT116 mouse xenograft model.

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