ChemMedChem, 2018
Based on the similarity between the active sites of the deubiquitylating and deneddylating enzyme ChlaDub1 (Cdu1) and the evolutionary related protease adenain a target‐hopping approach screening on a focused set of adenain inhibitors has been pursued. The thereby identified cyano‐pyrimidine based inhibitors represent the first active‐site directed small molecule inhibitors for Cdu1. High‐resolution crystal structures of Cdu1 in complex with two covalently bound cyano‐pyrimidines as well as with its substrate ubiquitin have been obtained. These structural data were complemented by enzymatic assays and covalent docking studies to provide insight into Cdu1s substrate recognition, active site pocket flexibility and potential hotspots for ligand interaction. Combined, these data provide a strong foundation for future structure‐guided medicinal chemistry optimization of this cyano‐pyrimidine based scaffold towards more potent and specific Cdu1 inhibitors.
