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Papers of the Week

Papers: 15 Apr 2023 - 21 Apr 2023

Basic Science

Animal Studies, Molecular/Cellular, Pharmacology/Drug Development

Neuropathic Pain, Psychological/Comorbidities

2023 Apr 14

J Med Chem


Structure-Based Discovery of a New Selectivity-Enabling Motif for the FK506-Binding Protein 51.


Knaup FH, Meyners C, Sugiarto WO, Wedel S, Springer M, Walz C, Geiger TM, Schmidt M, Sisignano M, Hausch F


In recent years, the selective inhibition of FKBP51 has emerged as a possible treatment for chronic pain, obesity-induced diabetes, or depression. All currently known advanced FKBP51-selective inhibitors, including the widely used SAFit2, contain a cyclohexyl residue as a key motif for enabling selectivity over the closest homologue and anti-target FKBP52. During a structure-based SAR exploration, we surprisingly discovered thiophenes as highly efficient cyclohexyl replacement moieties that retain the strong selectivity of SAFit-type inhibitors for FKBP51 over FKBP52. Cocrystal structures revealed that the thiophene-containing moieties enable selectivity by stabilizing a flipped-out conformation of Phe of FKBP51. Our best compound, , potently binds to FKBP51 biochemically as well as in mammalian cells, desensitize TRPV1 in primary sensory neurons, and has an acceptable PK profile in mice, suggesting its use as a novel tool compound for studying FKBP51 in animal models of neuropathic pain.