Polo-like kinase 1 (Plk-1) is a serine / threonine protein kinase involved in the entry into, progression through and exit from mitosis with roles in centrosome maturation, bi-polar spindle formation, chromosome separation and cytokinesis. Plk-1 belongs to the PLK family, comprising the structurally related Plk-1, -2, -3 and -4 proteins, that are characterized by having an n-terminal kinase domain and a c-terminal “polo-box” domain involved in protein-protein interactions. Plk-1 is ubiquitously expressed in normal tissues and is over-expressed in a variety of human tumours including lung, colon, stomach, breast, ovary, head and neck, and melanomas and its over-expression often correlates with poor prognosis. Depletion of Plk-1 by siRNA in tumour cells leads to, amongst other things, the inhibition of centrosome maturation resulting in a mitotic block and eventually apoptosis. Further, interference with Plk-1 expression in mouse xenograph tumour models by injection of Plk-1 anti-sense oligonucleotide into the tail vein leads to tumour regression, with no observable animal toxicity. Taken together, these observations indicate that Plk-1 is potentially a target for cancer therapy. The strategy of developing ATP mimetic inhibitors as therapeutics for the inhibition of protein kinases in the treatment of cancer has recently had success with the approval of Gleevec for the treatment of AML. Further, ATP mimetic inhibitors directed towards several other protein kinases, including, Aurora, Cdk-1/2, EGFR, Raf, VEGFR1/2, IGFR, PDGFR/Kit, Flt-3 and PKCs are currently undergoing clinical evaluation in the cancer setting. In order to identify ATP-mimetic inhibitors of Plk-1, we screened a kinase-directed chemical library against recombinant Plk-1 and identified several chemical classes with good potency. The characterization of these compounds will be presented.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]