Development of EPAC-specific small molecule modulators

EPAC proteins play essential role in a variety of biological functions and human diseases, including cancer, inflammation, cardiovascular diseases, CNS disorders, infections and diabetes. Therefore, huge efforts have been made to discover potent, small molecule EPAC modulators with high EPAC1 or EPAC2-isoform selectivity, that could serve as pharmacological probes and potential drug candidates for the development of new therapeutic strategies for various human diseases. Among the currently reported EPAC modulators we can distinguish two major categories: cAMP analogues which often exhibit EPAC agonist activity, and non-cyclic nucleotide small molecules, the majority of which tend to act as EPAC antagonists or EPAC inhibitors.
We have recently identified, using high throughput screening (HTS), a novel ligand (I942) which exhibits partial agonist properties against EPAC1, but not EPAC2. This is the first identified non-cyclic nucleotide small molecule with agonist properties towards EPAC1.