Preclinical Development TAK-960, a Novel, Orally Available, Selective Inhibitor of Polo-Like Kinase 1, Shows Broad-spectrum Preclinical Antitumor Activity in Multiple Dosing Regimens

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. HumanPLK1has been shown to be overexpressed in various human cancers, and elevated levels of PLK1have been associated with poor prognosis, making it an attractive target for anticancer therapy. TAK-960 [4-[(9cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2fluoro-5-methoxy-N-(1-methylpiperidin-4-yl) benzamide] is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1). Consistent with PLK1 inhibition, TAK-960 treatment caused accumulation of G2–M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibited proliferation ofmultiple cancer cell lines,withmeanEC50 values ranging from8.4 to 46.9nmol/L, but not innondividingnormal cells (EC50>1,000nmol/L). Themutation status ofTP53 orKRAS andMDR1 expression did not correlatewith the potency of TAK-960 in the cell lines tested. In animalmodels, oral administration of TAK-960 increasedpHH3 in a dose-dependentmanner and significantly inhibited the growth of HT-29 colorectal cancer xenografts. Treatment with once daily TAK-960 exhibited significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemiamodel. TAK-960 has entered clinical evaluation in patientswith advanced cancers. Mol Cancer Ther; 11(3); 700–9. 2011 AACR.