The Polo-like kinases (PLKs) have been investigated as oncology targets for several years; however, only recently have potent inhibitors been described. Here, we report on progress in the clinical validation of the PLKs as antitumor drug targets as well as recent understanding gained regarding their synergistic roles in the context of other molecular defects occurring in tumors. Also relevant to the development of PLK inhibitors as therapeutics are the putative roles of other members of this family as tumor suppressors. The resulting potential drawbacks of non-isoform selective compounds are presented. As an alternative approach to achieving PLK1 specificity, we discuss prospects for developing small molecule inhibitors of the crucial regulatory and subcellular targeting domain containing the Polo-boxes.
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