A Pentacyclic Aurora Kinase Inhibitor (AKI-001) with High in Vivo Potency and Oral Bioavailability

• Published in: Journal of medicinal chemistry 2008-08, Vol.51 (15), p.4465-4475
• Main Authors: Rawson, Thomas E, Rüth, Matthias, Blackwood, Elizabeth, Burdick, Dan, Corson, Laura, Dotson, Jenna, Drummond, Jason, Fields, Carter, Georges, Guy J, Goller, Bernhard, Halladay, Jason, Hunsaker, Thomas, Kleinheinz, Tracy, Krell, Hans-Willi, Li, Jun, Liang, Jun, Limberg, Anja, McNutt, Angela, Moffat, John, Phillips, Gail, Ran, Yingqing, Safina, Brian, Ultsch, Mark, Walker, Leslie, Wiesmann, Christian, Zhang, Birong, Zhou, Aihe, Zhu, Bing-Yan, Rüger, Petra, Cochran, Andrea G
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antineoplastic agents; Aurora Kinase A; Aurora Kinase B; Aurora Kinases; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Biological and medical sciences; Biological Availability; Cell Line, Tumor; Crystallography, X-Ray; Dogs; General aspects; Heterocyclic Compounds, 4 or More Rings - administration & dosage; Heterocyclic Compounds, 4 or More Rings - chemical synthesis; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - pharmacokinetics; Humans; Lactams - chemistry; Medical sciences; Mice; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Rats
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800052b

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.