Fragment-based Ligand Discovery in Proteomes by Reversible Covalent Chemistry

• Applicant: Dr. Stephan Hacker
• Subject Area: Biological and Biomimetic Chemistry
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269068426

While the expenses paid by the pharmaceutical industry for research and development have tremendously increased in the recent years, the number of newly approved drugs has stagnated. This shows that the classical approach of identifying drugs by screening very large compound libraries is reaching its limits. Many novel cellular targets, like transcriptions factors, protein-protein interactions or structural proteins, are even viewed as being undruggable in this approach, although they play key roles in the development of many diseases such as cancer.Novel methods for the identification of drugs are very promising approaches to bridge the gap between expenses paid for research and development and the approval of novel drugs. The method of fragment-based drug discovery examines the ability of very small chemical fragments to bind to certain target proteins. The initial fragment-based hits are then combined and further elaborated into therapeutically applicable drugs. This method is very successful and has already provided one approved novel drug and several clinical candidates albeit it is only scarcely utilized so far.The main disadvantage of this approach is that binding of the fragments has to be examined individually for each target protein and that the exact molecular mode-of-action of the protein has to be known. During my postdoctoral project in the group of Prof. Benjamin Cravatt I want to work on a novel method to monitor the ability of fragments to bind to many different target proteins in a highly parallel fashion without having to know their exact molecular mode-of-action. For this purpose I will apply the method of activity-based protein profiling that has been developed by Prof. Benjamin Cravatt. In this context, I will modify fragments with chemically reactive groups that will allow monitoring the binding of these fragments to many different target proteins in parallel using a competitive approach. Using this method fragment-based drug discovery should become significantly faster, more efficient and more broadly applicable. Therefore, it should allow developing drugs against so far undruggable diseases.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Benjamin F. Cravatt, Ph.D.