Biological characterization of TAK-901, an investigational, novel, multitargeted Aurora B kinase inhibitor.
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.
Discovery Biology, Takeda San Diego, Inc. 10410 Science Center Drive, San Diego, CA 92121, USA.
Pamela
P
Farrell
Lihong
L
Shi
Jennifer
J
Matuszkiewicz
Deepika
D
Balakrishna
Takashi
T
Hoshino
Lilly
L
Zhang
Sarah
S
Elliott
Robyn
R
Fabrey
Bumsup
B
Lee
Petro
P
Halkowycz
BiChing
B
Sang
Seigo
S
Ishino
Toshiyuki
T
Nomura
Mika
M
Teratani
Yoshikazu
Y
Ohta
Charles
C
Grimshaw
Bheema
B
Paraselli
Takashi
T
Satou
Ron
R
de Jong
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D015415:Biomarkers; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D015415:Biomarkers; D002243:Carbolines; D006657:Histones; D047428:Protein Kinase Inhibitors; D013450:Sulfones; C583854:TAK-901; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576920:Aurka protein, rat; C576924:Aurkb protein, mouse; C576925:Aurkb protein, rat; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases