In their latest publication in Chemistry, PROXIDRUGS project leader Felix Hausch and colleagues present the design of ultrapotent FKBP inhibitors. FK506-binding proteins (FKBPs) have great potential as drug targets and enablers of molecular glues, but have so far been difficult to target as they are picky with respect to chemotypes accepted as ligands. FK506 itself, a macrolide immunosuppressant, has been widely used for preventing organ rejection in transplant patients, but due to its characteristics, it is less suitable for broader drug design. Researchers have therefore been hunting for analogues of FK506, which overcome these current limitations.
The FKBP ligands Hausch and his team synthesized, are the most potent FKBP ligands known to date, with picomolar biochemical and subnanomolar cellular activity. This breakthrough was achieved by enantioselective synthesis of a rigid tricyclic scaffold, a molecule that closely mimics parts of FK506. The authors used a 14-step gram-scale synthesis process, which included techniques like anodic oxidation, precise vinylation, and a special type of cyclization called N-acyl iminium cyclization. Structure-based optimization then led to ultrapotent tricyclic ligands that are able to precisely position functional groups to interact with FKBPs. This advancement not only opens new avenues for drug development targeting FKBPs, but also sets a new benchmark for the design of highly specific and effective ligands.
Comments