Despite a significant progress in the therapy of various cancers, currently used medicines lack the necessary efficacy and selectivity. Conventional chemotherapy uses drugs that attack all dividing cells thus killing not only cancerous cells but also vitally important healthy dividing cells. There is an urgent need for novel approaches and methods to treat various cancers.
Polo-like kinase 1 (Plk1) is found to play a critical role in the development of ovarian, prostate, pancreatic, breast and other cancers. Plk1 has been validated as a mitotic cancer target for a number of years. However, the standard approach, inhibitor design for the ATP binding site of Plk1, turned out to be ineffective due to the lack of specificity. Plk kinases contain Polo-box domain ( PBD) that binds phosphopeptide motif present in many proteins, essential for mitotic progression. Since PBD is essential for Plk1 function and localization, drug design can be targeted specifically at Plk1 and not other proteins. We propose to analyse in several ways if the PBD can be validated as a drug target. First, analyse PBD function in mammalian cells using RNAi and genetic rescue approach. Second, design and synthesize inhibitors for PBD and analyse their effect on cancerous cells. Design will be carried out in silico using molecular modelling program written in collaboration with the software company.
Third, analyse other members of Plk family, namely, Plk2 and Plk3, which are quite different from Plk1 in terms of expression and function in mammalian cells and their role in cancer and the function of their PBDs is not yet established. The proposed research is highly interdisciplinary, combining the advanced knowledge of experimental molecular and cell biology. Research will be carried out in close collaboration with several scientists that apply biophysical techniques (calorimetry), organic chemistry, and computer simulation of molecular reactions, with the application of computer programming.
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