A Pentacyclic Aurora Kinase Inhibitor (AKI-001) With High in Vivo Potency And Oral Bioavailability
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 (IC{sub 50} < 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.
- Research Organization:
- Stanford Linear Accelerator Center (SLAC)
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- AC02-76SF00515
- OSTI ID:
- 953057
- Report Number(s):
- SLAC-REPRINT-2009-227
- Journal Information:
- J. Med. Chem.51:4465,2008, Journal Name: J. Med. Chem.51:4465,2008 Journal Issue: 15 Vol. 51; ISSN JMCMAR; ISSN 0022-2623
- Country of Publication:
- United States
- Language:
- English
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