Recent Advances and New Strategies in Targeting Plk1 for Anticancer Therapy

Polo-like kinase 1 (Plk1) plays key roles in regulating mitotic processes that are crucial for cellular proliferation. Overexpression of Plk1 is tightly associated with the development of particular cancers in humans, and a large body of evidence suggests that Plk1 is an attractive target for anticancer therapeutic development. Drugs targeting Plk1 can potentially be directed at two distinct sites: the N-terminal catalytic kinase domain (KD), which phosphorylates substrates, and the C-terminal polo-box domain (PBD) which is essential for protein–protein interactions. In this review we summarize recent advances and new challenges in the development of Plk1 inhibitors targeting these two domains. We also discuss novel strategies for designing and developing next-generation inhibitors to effectively treat Plk1-associated human disorders.

TrendsA large body of evidence suggests that Plk1 is an attractive anticancer drug target. Plk1 inhibition appears to be particularly promising in cancer cells bearing inactivating TP53 or activating RAS mutations because of their addiction to a high level of Plk1.Plk1 offers two biochemically distinct drug targets – the N-terminal KD and the C-terminal protein–protein interaction domain (PBD).A remarkable progress has been made in generating KD inhibitors, yielding several ATP-competitive analogs currently in clinical trials. However, these inhibitors commonly exhibit dose-limiting toxicities by inhibiting other structurally similar kinases.The PBD has emerged as an alternative target for developing a new class of Plk1 inhibitors. Although PBD inhibitors could confer superb binding affinity and specificity, currently available inhibitors are still at an early stage of development.