C1-inh polymers in the plasma of HAE patients, and not on the specific events leading to this observation. Therefore it can only be speculated whether the polymers are assembled in the blood stream, or if they accumulate intracellularly prior to secretion into the blood stream. Additional experiments involving recombinant expression of the polymerogenic mutants are needed to elucidate this question. The present series of experiments demonstrate that at least six of 75 HAE patients carrying SERPING1 mutations have C1-inh polymers in plasma. The specific role of C1-inh polymers in the pathophysiology of HAE is still not clear. In addition to the inability of polymers to control target proteases it has been demonstrated that misfolded proteins are potent activators of the kallikrein kinin system. Further experiments are needed to elucidate whether C1-inh polymers present in the plasma from HAE patients, can potentiate formation of bradykinin through activation of the kallikrein kinin system. The Polo-like kinase family of serine/threonine kinases are critical regulators of the cell cycle that are evolutionarily VE-822 conserved from yeast to humans. Plks are characterized by an N-terminal catalytic domain and one or two C-terminal regions of similarity, termed polo-box domains. PBDs are unique to Plks and are essential for regulating Plk phosphorylation activity through intramolecular interactions with the catalytic domain, binding to substrates and controlling Plk subcellular localization in a spatial-temporal manner. These features make PBDs amenable to inhibition and are an ideal domain to explore the feasibility of inhibiting kinase phosphorylation activity by interfering with its intracellular localization and/ or ability to bind substrates rather than targeting the conserved ATP binding site. Humans express four Plk FDA-approved Compound Library inhibitor isoforms with apparently distinct expression patterns and physiological functions. Plk1 is a mitotic kinase that regulates centrosome maturation and separation, mitotic exit and cytokinesis, Plk1 has been the focus of extensive studies due to its strong association with oncogenic transformation of human cells. Plk1 is overexpressed in many types of human cancers and plays a critical role in cellular proliferation from yeast to mammals. Depletion or inhibition of Plk1 in cancer cells leads to mitotic arrest and subsequent apoptotic cell death. Thus, Plk1 is an attractive target for anticancer therapy. Over the years, efforts have been made to generate anti-Plk1 inhibitors, yielding several ATP-competitive inhibitors that inhibit Plk1 kinase activity. These include BI2536 and GSK461364A, which are currently being evaluated for their anti-proliferative properties in clinical trials and numerous others that are in preclinical development. However, their specificity and limited in vivo efficacy remain major concerns. The Plk1-PBD plays a critical role in Plk1 subcellular localization, substrate binding and phosphorylation and is required for proper cell division. Thus the Plk1-PBD has emerged as a candidate for therapeutic intervention and an alternative to targeting the Plk1 ATPase domain. The Plk1-PBD consists of two conserved polo boxes, each of which exhibits folds based on a six-stranded b sandwich and an a helix, which associate to form a 12-stranded b sandwich domain. Phosphoserine/phosphothreonine containing peptides comprising an S– motif bind along a positively charged cleft formed between PB1 and PB2. The negatively charged phosphate groups of phospho-Ser/Thr residues interact with key amino acid residues at the PB1 and PB2 interface that include His538 and Lys540 from PB2 to form pivotal electrostatic interactions. The unique physical properties of the Plk1-PBD make it an attractive target for designing inhibitors with great specificity and potency.