Drugging the Undruggable: New Approaches to DNA-Protein Inferfacial Inhibition

Nearly every disease involves aberrant DNA-transcription and is driven by the disease-associated activation of transcription factors (TFs) that control the transcription of certain genes. Conventionally, these have been regarded as undruggable by small molecules due to the high-affinity nature of their protein-DNA interactions. To date, only very large molecules have been successfully employed in displacing/blocking TF-DNA interactions. The size of these molecules renders them unsuitable as drugs due to poor bioavailability, cell entry and solubility. In this project we seek to design novel small molecules that have a high affinity for specific TF-DNA interfaces and that disrupt their function, halting the disease process. Since displacement of the TF from the DNA is unnecessary, much smaller molecules can perform this role. Opening up the possibility of developing them into orally bioavailable drug therapies. This project focuses on developing a drug discovery platform directed to the discovery of novel TF-DNA interfacial inhibitors.