Abstract
Polo-like kinase 1 (Plk1) plays key roles in regulating various mitotic processes that are critical for cellular proliferation. A growing body of evidence suggests that Plk1 overexpression is tightly associated with the development of human cancers. Interestingly, various types of cancer cells are shown to be addicted to a high level of Plk1, and the reversal of Plk1 addiction appears to be an effective strategy for selectively killing cancer cells, but not normal cells. Therefore, Plk1 is considered an attractive anticancer drug target. Over the years, a large number of inhibitors that target the catalytic activity of Plk1 have been developed. However, these inhibitors exhibit significant levels of cross-reactivity with related kinases, including Plk2 and Plk3. Consequently, as an alternative approach for developing anti-Plk1 therapeutics, substantial effort is under way to develop inhibitors that target the C-terminal protein–protein interaction domain of Plk1, called the polo-box domain (PBD). In this communication, I will discuss the pros and cons of targeting the PBD in comparison to those of targeting the ATP-binding site within the kinase domain.
Highlights
Polo-like kinase 1 (Plk1) plays key roles in regulating various mitotic processes that are critical for cellular proliferation
Developing inhibitors that target the catalytic activity of a protein kinase has become a prevailing method, various efforts are under way to develop inhibitors that target a functionally critical protein–protein interaction domain of a kinase
Studies showed that inhibiting Plk1 catalytic activity potently induces early mitotic arrest (Sumara et al 2004; Hanisch et al 2006; Lenart et al 2007), whereas inhibiting Plk1 polo-box domain (PBD) function results in preanaphase arrest (Seong et al 2002; Hanisch et al 2006). These findings suggest that this Plk1 kinase activity-dependent process is essentially required from the early stage of mitosis, whereas the PBDdependent Plk1 function is essential only at a much later stage but prior to the metaphase/anaphase transition
Summary
Polo-like kinase 1 (Plk1) plays key roles in regulating various mitotic processes that are critical for cellular proliferation. As an alternative approach for developing anti-Plk1 therapeutics, substantial effort is under way to develop inhibitors that target the C-terminal protein–protein interaction domain of Plk1, called the polo-box domain (PBD).
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