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

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Rawson TE,Rüth M,Blackwood E,Burdick D,Corson L,Dotson J,Drummond J,Fields C,Georges GJ,Goller B,Halladay J,Hunsaker T,Kleinheinz T,Krell HW,Li J,Liang J,Limberg A,McNutt A,Moffat J,Phillips G,Ran Y,Safina B,U

doi

10.1021/jm800052b

subject

Has Abstract

pub_date

2008-08-14 00:00:00

pages

4465-75

issue

15

eissn

0022-2623

issn

1520-4804

journal_volume

51

pub_type

杂志文章

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