Saturday, May 30, 2015

Drugs in Clinical Pipeline: AKI-001

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
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].

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].

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.