American Association for Cancer Research
15357163mct120657-sup-f2_pdf_1529k.pdf (1.49 MB)

Supplementary Figure 2 from Biological Characterization of TAK-901, an Investigational, Novel, Multitargeted Aurora B Kinase Inhibitor

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journal contribution
posted on 2023-04-03, 13:50 authored by Pamela Farrell, Lihong Shi, Jennifer Matuszkiewicz, Deepika Balakrishna, Takashi Hoshino, Lilly Zhang, Sarah Elliott, Robyn Fabrey, Bumsup Lee, Petro Halkowycz, BiChing Sang, Seigo Ishino, Toshiyuki Nomura, Mika Teratani, Yoshikazu Ohta, Charles Grimshaw, Bheema Paraselli, Takashi Satou, Ron de Jong

PDF file - 1.5 MB, TAK-901 is not a potent inhibitor of cellular JAK2, c-SRC or ABL. Inhibition of various cellular tyrosine kinases by TAK-901. The indicated cells were treated with various concentrations of TAK-901, DMSO or control (Ctrl) compounds for 4 hours and then were lysed. Gel electrophoresis was performed followed by immunoblotting using the antibodies indicated.



Protein kinases Aurora A, B, and C play essential roles during mitosis and cell division, are frequently elevated in cancer, and represent attractive targets for therapeutic intervention. TAK-901 is an investigational, multitargeted Aurora B kinase inhibitor derived from a novel azacarboline kinase hinge-binder chemotype. TAK-901 exhibited time-dependent, tight-binding inhibition of Aurora B, but not Aurora A. Consistent with Aurora B inhibition, 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. Examination of a broad panel of kinases in biochemical assays revealed inhibition of multiple kinases. However, TAK-901 potently inhibited only a few kinases other than Aurora B in intact cells, including FLT3 and FGFR2. In rodent xenografts, TAK-901 exhibited potent activity against multiple human solid tumor types, and complete regression was observed in the ovarian cancer A2780 model. TAK-901 also displayed potent activity against several leukemia models. In vivo biomarker studies showed that TAK-901 induced pharmacodynamic responses consistent with Aurora B inhibition and correlating with retention of TAK-901 in tumor tissue. These preclinical data highlight the therapeutic potential of TAK-901, which has entered phase I clinical trials in patients within a diverse range of cancers. Mol Cancer Ther; 12(4); 460–70. ©2013 AACR.