A Pentacyclic Aurora Kinase Inhibitor (AKI-001) with High in Vivo Potency and Oral Bioavailability
1区 · 医学
作者: Rawson, Thomas E. ; Ruth, 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 ; Ruger, Petra ; Cochran, Andrea G.
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.