期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 6, 页码 3320-3349出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c02195
关键词
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资金
- DFG [HA5565-5/1]
- LOEWE cluster TRABITA
- Pioneer Fund (ENTEGA/TU Darmstadt)
The design and synthesis of macrocyclic FKBP51-selective ligands with high affinity and selectivity through incorporation of polar functionalities demonstrates a viable strategy to target the shallow FKBP51 binding site selectively. The high-resolution crystal structures of six macrocyclic inhibitors in complex with FKBP51 confirmed the desired selectivity-enabling binding mode, highlighting the potential of macrocyclization as an effective approach in drug development.
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.
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