Development of Novel Epigenetic Therapies: Identification of small molecule inhibitors of methyl-dependent protein-protein interactions

• Applicant: Dr. Astrid Spannhoff
• Subject Area: Pharmacy
• Term: from 2009 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 125193302

Screening and identifying small molecules that inhibit protein-protein interactions has recently been referred to as “the high-hanging fruit in drug discovery” [1]. We have developed a protein array platform to screen for protein-protein interactions [2], which lends itself to further development as a tool for screening for compounds that inhibit protein-protein interactions. Players in this field are potential targets for drug development. This area of epigenetic therapy has established applications for the treatment of cancer and neurological diseases [3, 4]. We have been involved in this field for a number of years. We have performed high-throughput screens to identify the first small molecule inhibitors of protein methyltransferases [5-7]. These initial studies in our laboratory focused on developing inhibitors of enzyme function. These enzymes often target many substrates, and thus regulate many arms of an epigenetic pathway. The methylation of these different substrates often generates docking sites for effector proteins that harbor domains (chromo, tudor, PHD and MBT). We hypothesize that by blocking specific protein-protein interactions, we will be able to develop compounds that block a single arm of an epigenetic pathway. The specificity attained by blocking a single protein-protein interaction will be far greater than that attained by blocking the enzyme that regulates one of many interactions. Here we plan to develop and perform screens to identify lead compounds that can block methyl-dependent protein-protein interactions, which may be developed into targeted epigenetic therapies.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Mark T. Bedford