Fragment-based hit discovery and characterization of RNA Binding proteins with KH domain

Abstract

Chemical fragment-based Hit Discovery (FBHD) is an effective tool for the discovery of lead molecules and was responsible for the development of several FDA-approved drugs. In our group, we study RNA binding proteins containing the KH domain, which allows a protein to bind to a specific set of mRNAs in the cell and to control processes as transport of RNAs from the nucleus and RNA splicing. This class of proteins is related to diseases, including cancer and neurology. In this project we will study three proteins of this family: BICC1, FUBP2 and NOVA1, which have similar structural features and have no chemical inhibitor molecules. Here, we will employ fragment screening by weak affinity chromatography coupled to mass spectrometry (WAC-MS) to find ligands for KH-proteins. The aim is to elucidate the binding mode and to investigate whether it is possible to find common ligands for the KH-domain. From there, we will understand how selectivity between KH-proteins can be achieved. The initial findings will guide the growth of chemical fragments into larger, drug-like lead candidates via organic synthesis. By screening libraries of very small molecules, we can cover a vast chemical space with fewer compounds, leading to faster and cheaper guidance for drug design. Thus, we expect the have the identification of kinetics of chemical groups at low concentrations while maintaining high sensitivity. By combining these approaches, we will establish an effective tool for screening ligands and for advancing to leads for understudied targets as RNA binding proteins. (AU)