AKI-001 [8-ethyl-3,10,10-trimethyl-4,5,6,6a,8,10-hexahydropyrazolo[4',3':6,7] cyclohepta[1,2-b]pyrrolo[2,3-f]indol-9(3aH)-one]
a pentacycle represents a new class of pan-Aurora kinase inhibitors (IC50
AURKA, AURKB = 0.004, 0.005 uM) with excellent oral availability and high
potency against tumor xenografts in mouse. These properties compare favorably
with those of other reported Aurora kinase inhibitors. Cellular studies support
Aurora kinase inhibition (IC50 HCT116, HT29, MCF7 = 0.070, 0.070,
0.10 uM) as the mechanism of antiproliferative activity and, presumably, of
tumor growth inhibition [1].
Researchers assayed AKI-001 in a panel of kinase assays.
Importantly, there is little inhibition of non-Aurora kinases important for
cell cycle progression (for example, IC50 CDK2, CHK1 = 15, 0.085 uM).
However, AKI-001 does show off-target activities, most notably against receptor
tyrosine kinases and Src family members as has been reported for other Aurora
kinase inhibitors (IC50 SRC, FLT3, KDR = 0.25, 0.002, 0.012 uM).
The activity of AKI-001 is as follows:
IC50 (AURKA enzyme assay) = 0.004 uM
IC50 (AURKB enzyme assay) = 0.005 uM
Common Name: AKI-001
Synonyms: AKI-001; AKI 001; AKI001
IUPAC Name: N 8-ethyl-3,10,10-trimethyl-4,5,6,6a,8,10-hexahydropyrazolo[4',3':6,7] cyclohepta[1,2-b]pyrrolo[2,3-f]indol-9(3aH)-one
CAS Number: 925218-37-7
SMILES: -
Mechanism of Action: Kinase Inhibitor; pan-Aurora Inhibitor
Indication: Various Cancers; Anti-tumor Therapy
Development Stage: Investigational
Company: Genentech/Roche
Eidogen Sertanty Inc Provides Kinase
Knowledge Base (KKB): a Collection of nearly 1.6 M Kinase Inhibitors.
|
Aurora
kinases are a family of mitotic serine/threonine kinases conserved from yeast
to humans, and they have received significant recent attention as new targets
for anticancer therapy. The two major Aurora kinases, Aurora A and Aurora B,
have distinct functions in mitosis. The third Aurora kinase, Aurora C, has a
kinase domain most similar in sequence to that of Aurora B,and Aurora C appears
to have functions that overlap with those of Aurora B.
Despite
uncertainty surrounding the role of Aurora kinases in tumorigenesis, it is
clear that both Aurora A and Aurora B are critical for completion of mitosis
and for accurate cell cycle progression. As such, drugs targeting these kinases
might be expected to have potent antimitotic and antitumor activity [1].
References:
1. Rawson, T. E.; et. al. A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability. J Med Chem 2008, 51(15), 4465-4475.
AKI-001 showed excellent antiproliferative activity against several tumor
cell lines. This antiproliferative effect coincided with the compound
concentration required to produce a G2/M block (24 h assay), as measured by
flow cytometry. Researchers used several more specific cellular assays to judge
whether the observed antiproliferative effect was driven by inhibition of
Aurora A, Aurora B, or both. Overall, AKI-001 is approximately equipotent
in cellular inhibition of Aurora A and Aurora B (consistent with the equivalent
enzymatic IC50 values), and the compound concentrations required to
produce these effects are fairly close to the antiproliferative IC50
values. This suggests that the antiproliferative effect is likely to be a
consequence of Aurora inhibition [1].
References:
1. Rawson, T. E.; et. al. A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability. J Med Chem 2008, 51(15), 4465-4475.
