Chemical modifications that create an inhibitor with high affinity for Polo-like kinase-1 (Plk1), an important molecule for the regulation of cell growth and proliferation, are reported this week in Nature Chemical Biology. Since PlK1 is a potential target for cancer treatment, these finding could have important clinical application.
Specifically targeting Plk1 has proven challenging, as there are hundreds of human kinases and they all share similar structural features. In addition to features shared among kinases, Plk1 has some unique domains important for functional interaction with other proteins. One of these domains, called a polo-box domain (PBD), is necessary for the proper localization of Plk1 inside of a cell. Previous studies have shown that displacing Plk1 from its proper site is sufficient to interfere with cell proliferation.
Terrence Burke and colleagues identified an inhibitor for Plk1 that interferes with the protein-protein interactions with PBD. Structural analysis revealed that the inhibitor exposed a new binding channel on the kinase. Identification of this new channel could inspire the design of new inhibitors for cancer treatment that selectively target Plk1.