Cancer Therapeutics Insights Biological Characterization of TAK-901, an Investigational, Novel, Multitargeted Aurora B Kinase Inhibitor

نویسندگان

  • 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
  • Charles Grimshaw
  • Takashi Satou
  • Ron de Jong
چکیده

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 varioushumancancer cell lines,TAK-901 inhibited cell proliferationwith effective concentrationvalues from40 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 thanAurora 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 correlatingwith 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.

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Biological characterization of TAK-901, an investigational, novel, multitargeted Aurora B kinase inhibitor.

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تاریخ انتشار 2013