PLK1 INHIBITION · Inhibition of Cancer by Disrupting Interaction Between Polo-like Kinase 1 Polo-box Domain and Spindle Targets
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2006-03-01 → 2008-02-29
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- IRG
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Results in brief
Final Activity Report Summary - PLK1 INHIBITION (Inhibition of Cancer by Disrupting Interaction Between Polo-like Kinase 1 Polo-box Domain and Spindle Targets)
The main goal of this project was to attract and retain a young scientist working in United States to return and establish a research facility in Lithuania. As a result of the project, the Facility of Molecular and Cell Biology was established at the Laboratory of Biothermodynamics and Drug Design at the Institute of Biotechnology, Vilnius, Lithuania. The scientist, Jurgita Matuliene, has returned to Europe, brought extensive experience from her work at the University of Minnesota. The Marie Curie grant enabled the researcher to start a new research theme - active compound testing in live mammalian cells and determination of therapeutic methods during drug design at the laboratory. The institute did not carry out research in this field prior to the scientist's return. Together with the help of EU structural funds and Lithuanian Science and Studies Foundation, new equipment and research reagents were purchased. Four permanent staff positions were established and supported by Lithuanian state budget. The scientist taught a number of personnel and students the methods of cell biology. One of the main tasks of the scientist was to produce proteins-drug targets in prokaryotic and eukaryotic systems for the design of novel inhibitors that could become drug candidates with anticancer activities. As a result of the project, a group of novel inhibitors were designed, synthesised, and tested to be active against human cancerous cells. Two patent applications were submitted. Though numerous testing will be necessary before a drug candidate may be made, the beginning was successful, largely due to Marie Curie International Reintegration grant.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- INSTITUTE OF BIOTECHNOLOGY · VILNIUSCoordinatorLithuania
Links
Data: CORDIS, © European Union