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Papers of the Week

2021 Mar 05

J Med Chem

Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors.


Bauder M, Meyners C, Purder PL, Merz S, Sugiarto W O, Voll AM, Heymann T, Hausch F
J Med Chem. 2021 Mar 05.
PMID: 33666419.


The FK506-binding protein 51 (FKBP51) emerged as a key player in several diseases like stress-related disorders, chronic pain, and obesity. Linear analogues of FK506 called SAFit were shown to be highly selective for FKBP51 over its closest homologue FKBP52, allowing the proof-of-concept studies in animal models. Here, we designed and synthesized the first macrocyclic FKBP51-selective ligands to stabilize the active conformation. All macrocycles retained full FKBP51 affinity and selectivity over FKBP52 and the incorporation of polar functionalities further enhanced affinity. Six high-resolution crystal structures of macrocyclic inhibitors in complex with FKBP51 confirmed the desired selectivity-enabling binding mode. Our results show that macrocyclization is a viable strategy to target the shallow FKBP51 binding site selectively.