TAK-960 is an investigational, orally bioavailable, potent, and selective PLK1 inhibitor (IC50=1.5 nM) that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1).
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 is a potent PLK1 inhibitor with a mean IC50 of 1.5 nmol/L against the kinase domain of PLK1 at 3 μmol/L ATP. Treatment of HT-29 colorectal cancer cells with TAK-960 for 48 hours resulted in concentration-dependent accumulation of cells in G2–M phase. Accumulation of aberrant spindles was observed following treatment with TAK-960 at 10 or 30 nmol/L. TAK-960 inhibited the proliferation of human cancer cell lines in a concentration-dependent manner, with mean EC50 values ranging from 8.4 to 46.9 nmol/L. To confirm that TAK-960 inhibited PLK1 activity in vivo, mice bearing established HT-29 colorectal tumors were administered a single oral dose (5, 10, or 30 mg/kg) of TAK-960. Plasma exposure to TAK-960 increased in an approximately dose-proportional manner and was partitioned preferentially into the tumor. To further evaluate relationship between PD (pharmacodynamic) response and antitumor activity, TAK-960 was evaluated in mice bearing established HT-29 colorectal tumor xenografts using various regimens. All TAK-960 treatment schedules inhibited tumor growth in a dose-dependent manner without obvious body weight loss. In the subcutaneously implanted MV4-11 human leukemia model, treatment with TAK-960 at 7.5 mg/kg orally once daily for 9 days showed a significant increase in median survival compared with vehicle (39.5 vs. 25 days, respectively; P = 0.0055, Log-rank (Mantel–Cox) test) [2].
作用机制
TAK-960 binds to the ATP-binding pocket of PLK1[2].
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