Conformationally Restricted Macrocycles as Improved FKBP51 Inhibitors Enabled by Systematic Linker Derivatization.

Macrocycles are increasingly considered as promising modalities to target challenging intracellular proteins. However, strategies for transitioning from active linear starting points to improved macrocycles are still underdeveloped. Here we explored the derivatization of linkers as an approach for macrocycle optimization.

Conformational Plasticity and Binding Affinity Enhancement Controlled by Linker Derivatization in Macrocycles.

Macrocycles are abundantly used by nature to enable cell-permeable bioactive molecules. Synthetic non-peptidic macrocycles are also increasingly considered as modalities for difficult-to-bind proteins but guidelines for macrocyclization are only beginning to emerge. Macrocycles are thought to constrain the available conformations but also to allow for residual flexibility, the latter being poorly understood.

Structure-Based Design of Ultrapotent Tricyclic Ligands for FK506-Binding Proteins.

Access to small, rigid, and sp-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.