Chemoproteomic approaches for Epigenetic drug targets

Chemoproteomics has been successfully developed in the recent years as an alternative drug discovery tool to more traditional approaches using often isolated recombinant drug targets. It combines affinity-based capturing of compound targets and proteomics analysis in close-to-physiological conditions aiming at preserving protein complexes and post-translational modifications (PTMs). These features are particularly of importance when studying epigenetic drug targets that are most often part of large protein complexes which composition and function are regulated by the presence of a variety of PTMs.This presentation is aiming at presenting different complementary chemoproteomic strategies that have been used in epigenetic programs. In the first example, we report how the discovery of BET inhibitors has paved the way to demonstrate that members of the family of BROMO domain containing proteins are genuine drug targets. In a second example, taken this time from the HDAC family of deacetylases, we take advantage of chemoproteomics to show that some HDAC inhibitors display target and protein complex selectivity. In the case of slow-binding inhibitors, this selectivity is dependent on duration and dosing