Abstract
PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and cross-reactivities with some receptor tyrosine kinases relevant for cancer. PHA-739358 inhibits all Aurora kinase family members and shows a dominant Aurora B kinase inhibition-related cellular phenotype and mechanism of action in cells in vitro and in vivo. p53 status-dependent endoreduplication is observed upon treatment of cells with PHA-739358, and phosphorylation of histone H3 in Ser(10) is inhibited. The compound has significant antitumor activity in different xenografts and spontaneous and transgenic animal tumor models and shows a favorable pharmacokinetic and safety profile. In vivo target modulation is observed as assessed by the inhibition of the phosphorylation of histone H3, which has been validated preclinically as a candidate biomarker for the clinical phase. Pharmacokinetics/pharmacodynamics modeling was used to define drug potency and to support the prediction of active clinical doses and schedules. We conclude that PHA-739358, which is currently tested in clinical trials, has great therapeutic potential in anticancer therapy in a wide range of cancers.
Highlights
A number of potential molecular targets for the identification of novel anticancer drugs interfere with the cell cycle [1, 2]
Aurora kinases play distinct roles during mitosis, with Aurora A being essential for centrosome maturation and spindle assembly and Aurora B functioning at kinetochores in chromosome attachment and at the end of mitosis in cytokinesis
Inhibition of Aurora kinases is emerging as a new strategy for anticancer therapy, and several small-molecule inhibitors have entered clinical trials
Summary
A number of potential molecular targets for the identification of novel anticancer drugs interfere with the cell cycle [1, 2]. Significant interest for Aurora kinases inhibition as an anticancer strategy was generated because some Aurora kinase family members are overexpressed in a variety of human cancers, and elevated expression has been correlated with chromosomal instability and clinically aggressive disease in some instances (5 – 9). Ectopic overexpression of one member of the family, Aurora A, was shown to induce oncogenic transformation in cells [10]. An oncogenic activity of Aurora B has not been shown, elevated Aurora B activity promotes Ras-mediated transformation by enhancing oncogenic signaling and by inducing aneuploidy [11]. A polymorphism (F31I) has been observed in the Aurora A gene and reported to be correlated with the degree of aneuploidy in human colon tumors and several other cancers [12]
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