The project goal is to exploit diversity-oriented synthesis (DOS) to discover protein-protein interaction (PPI) inhibitors of gankyrin-S6 complex.
Vital cellular functions are all regulated by protein complexes. In order for a complex to work correctly, interactions among its subunits must have the right intensity. If they are too weak or too strong, the complex does not work well, causing disease. Thus, modulation of PPIs offers a strategy for therapy. Gankyrin is a protein that forms a complex with the S6 subunit of ATPase in 26S proteasome. This complex is overexpressed in hepatocellular and oesophageal cancers, so its inhibition would offer a strategy for the treatment of such diseases. Unfortunately, the development of PPI modulators is challenging, mainly because the libraries of compounds used for biological screening have a limited structural diversity and a low probability to contain an active compound. A new synthetic strategy is necessary to solve this problem.
DOS affords the highest structural diversity in compound libraries, maximising the chances to find an active molecule. PPI inhibitors of gankyrin could become the first drugs against oesophageal and hepatic cancers, for which no pharmacological treatment exist.
The project will involve four steps: 1) structure-guided design of gankyrin ligands; 2) their chemical synthesis; 3) test of their inhibitory properties on gankyrin and 4) structural characterization of the protein-inhibitor complex. The process will be iterative: based on biological results, new compounds will be designed and synthesized.
The development of drugs against two incurable diseases would have a benefit for millions of people. The fellowship will provide the researcher with new knowledge and skills in computational chemistry and biophysics, it will boost his academic career and will lead to a long-term collaboration between researcher and host institution.
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