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

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. 7,8,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. Mol Cancer Ther; 11(3); 700-9. Ó2011 AACR.

Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy

“…18,19 This trial (BI 1230.4) was designed as a phase 1/2, open-label, multicenter trial of volasertib in patients with AML ineligible for intensive induction therapy. In the phase 1 part, dose escalation was performed in patients with relapsed/refractory AML.…”

Emerging therapeutic targets in bladder cancer

“…PLK1 is also being targeted through a lipid nanoparticle formulation of a small interfering RNA directed against PLK1 (TKM 080301) for advanced solid tumors and lymphoma with preliminary efficacy results in patients with colon cancer and carcinoid [87]. An ongoing phase I study is evaluating the compound in neuroendocrine tumors and adrenocortical carcinoma (NCT01262235), and other PLK1 inhibitors have shown promising preclinical activity [88]. Other preclinical studies based on the principle of synthetic lethality have identified cancer genes whose expression sensitizes tumors to the effects of PLK1 inhibitors [89].…”

Targeting polo-like kinase 1 in acute myeloid leukemia

“…TAK-960 is a potent orally bioavailable selective Plk1 inhibitor which was shown to have activity against a variety of tumor cell lines, including K562 leukemia cells in vitro. This agent also produced marked growth inhibition of AML MV4-11 cells in a mouse xenograft model [Hikichi et al 2012]. A phase I study has been completed in patients with advanced solid tumors, but has not yet been published.…”