 |
PDBsum entry 3coh
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
A pentacyclic aurora kinase inhibitor (aki-001) with high in vivo potency and oral bioavailability.
|
|
|
Authors
|
|
T.E.Rawson,
M.Rüth,
E.Blackwood,
D.Burdick,
L.Corson,
J.Dotson,
J.Drummond,
C.Fields,
G.J.Georges,
B.Goller,
J.Halladay,
T.Hunsaker,
T.Kleinheinz,
H.W.Krell,
J.Li,
J.Liang,
A.Limberg,
A.Mcnutt,
J.Moffat,
G.Phillips,
Y.Ran,
B.Safina,
M.Ultsch,
L.Walker,
C.Wiesmann,
B.Zhang,
A.Zhou,
B.Y.Zhu,
P.Rüger,
A.G.Cochran.
|
|
|
Ref.
|
|
J Med Chem, 2008,
51,
4465-4475.
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
