{Reference Type}: Journal Article
{Title}: Structure-Based Design of Ultrapotent Tricyclic Ligands for FK506-Binding Proteins.
{Author}: Krajczy P;Meyners C;Repity ML;Hausch F;
{Journal}: Chemistry
{Volume}: 30
{Issue}: 45
{Year}: 2024 Aug 12
{Factor}: 5.02
{DOI}: 10.1002/chem.202401405
{Abstract}: Access to small, rigid, and sp3-rich molecules is a major limitation in the drug discovery for challenging protein targets. FK506-binding proteins hold high potential as drug targets or enablers of molecular glues but are fastidious in the chemotypes accepted as ligands. We here report an enantioselective synthesis of a highly rigidified pipecolate-mimicking tricyclic scaffold that precisely positions functional groups for interacting with FKBPs. This was enabled by a 14-step gram-scale synthesis featuring anodic oxidation, stereospecific vinylation, and N-acyl iminium cyclization. Structure-based optimization resulted in the discovery of FKBP inhibitors with picomolar biochemical and subnanomolar cellular activity that represent the most potent FKBP ligands known to date.