Uses
A novel Aurora B kinase inhibitor with potential antineoplastic activity. It binds to and inhibits the activity of Aurora B, which may result in a decrease in the proliferation of tumor cells that overexpress Aurora B. Aurora B is a positive regulator of mitosis that functions in the attachment of the mitotic spindle to the centromere; the segregation of sister chromatids to each daughter cell; and the separation of daughter cells during cytokinesis.
Biological Activity
protein kinases aurora a, b, and c play crucial roles during mitosis and cell division, are frequently elevated in cancer, and represent attractive targets for therapeutic intervention. tak-901 is a novel, multitargeted aurora b kinase inhibitor derived from a novel azacarboline kinase hinge-binder chemotype.
in vitro
tak-901 exhibited time-dependent, tight-binding inhibition of aurora b, but not aurora a. consistently, tak-901 suppressed cellular histone h3 phosphorylation and induced polyploidy. in various human cancer cell lines, tak-901 inhibited cell proliferation with effective concentration values from 40 to 500 nmol/l. tak-901 potently inhibited only a few kinases other than aurora b in intact cells, including flt3 and fgfr2 [1].
in vivo
in rodent xenografts, tak-901 exhibited potent activity against multiple human solid tumor types, and complete regression was found in the ovarian cancer a2780 model. in vivo biomarker studies showed that tak-901 induced pd responses consistent with aurora b inhibition and correlating with retention of tak-901 in tumor tissue. [2].
IC 50
0.0017, 0.021 for aurora-b/incenp and aurora-a/tpx2, respectively
References
[1] farrell p, shi l, matuszkiewicz j, balakrishna d, hoshino t, zhang l, elliott s, fabrey r, lee b, halkowycz p, sang b, ishino s, nomura t, teratani m, ohta y, grimshaw c, paraselli b, satou t, de jong r. biological characterization of tak-901, an investigational, novel, multitargeted aurora b kinase inhibitor. mol cancer ther. 2013;12(4):460-70.
