9ey3

Publication Abstract from PubMed

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 position 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.

Structure-Based Design of Ultrapotent Tricyclic Ligands for FK506-Binding proteins.,Krajczy P, Meyners C, Repity M, Hausch F Chemistry. 2024 Jun 5:e202401405. doi: 10.1002/chem.202401405. PMID:38837733^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.