Abstract
Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. TAK-960 [4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-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 G(2)-M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibited proliferation of multiple cancer cell lines, with mean EC(50) values ranging from 8.4 to 46.9 nmol/L, but not in nondividing normal cells (EC(50) >1,000 nmol/L). The mutation status of TP53 or KRAS and MDR1 expression did not correlate with the potency of TAK-960 in the cell lines tested. In animal models, oral administration of TAK-960 increased pHH3 in a dose-dependent manner 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 leukemia model. TAK-960 has entered clinical evaluation in patients with advanced cancers.
Highlights
The polo-like kinases (PLK) are evolutionarily conserved serine/threonine kinases that were first described in the so-called polo mutants of Drosophila melanogaster that failed to undergo normal mitotic progression [1]
Ó2011 American Association for Cancer Research. Addition to these general cellular functions, human Polo-like kinase 1 (PLK1) is overexpressed in various human cancers, including head and neck squamous cell carcinoma, non-small cell lung cancer, oropharyngeal carcinoma, melanoma, ovarian and endometrial carcinoma, and prostate cancer; elevated PLK1 has been associated with poor prognosis [2, 5, 6]
Several reports have shown that PLK1 depletion by short interfering RNA or PLK1 inhibition by smallmolecule inhibitors resulted in cell-cycle arrest at mitosis and induced apoptosis in cancer cell lines, but not in normal diploid cells or nondividing cells [7,8,9,10]
Summary
The polo-like kinases (PLK) are evolutionarily conserved serine/threonine kinases that were first described in the so-called polo mutants of Drosophila melanogaster that failed to undergo normal mitotic progression [1]. Many important functions of PLK1 have been discovered, such as activation of cell division cycle 2, chromosome segregation, centrosome maturation, bipolar spindle formation, regulation of the anaphase-promoting complex, and execution of cytokinesis [2,3,4]. Several reports have shown that PLK1 depletion by short interfering RNA or PLK1 inhibition by smallmolecule inhibitors resulted in cell-cycle arrest at mitosis and induced apoptosis in cancer cell lines, but not in normal diploid cells or nondividing cells [7,8,9,10]. PLK1 inhibitors are being evaluated in registered clinical trials [4]. Clinical responses have been reported with intravenous volasertib [11]
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