Interrogating the Druggability of the 2-Oxoglutarate-Dependent Dioxygenase Target Class by Chemical Proteomics.

摘要: The 2-oxoglutarate-dependent dioxygenase target class comprises around 60 enzymes including several subfamilies with relevance to human disease, such as the prolyl hydroxylases and Jumonji-type lysine demethylases. Current drug discovery approaches are largely based on small molecule inhibitors targeting iron/2-oxoglutarate cofactor binding site. We have devised a chemoproteomics approach combination of unselective active-site ligands tethered beads, enabling affinity capturing 40 different from cells. Mass-spectrometry-based quantification bead-bound using free-ligand competition-binding format enabled comprehensive determination affinities for cosubstrate 2-oxoglutarate oncometabolites 2-hydroxyglutarate. also profiled set representative drug-like inhibitor compounds. results indicate that intracellular competition by endogenous cofactors high active site similarity present substantial chall...