Abstract
Subtype selectivity represents a challenge in many drug discovery campaigns. A typical example is the FK506 binding protein 51 (FKBP51), which has emerged as an attractive drug target. The most advanced FKBP51 ligands of the SAFit class are highly selective vs. FKBP52 but poorly discriminate against the homologs and off‐targets FKBP12 and FKBP12.6. During a macrocyclization pilot study, we observed that many of these macrocyclic analogs have unanticipated and unprecedented preference for FKBP51 over FKBP12 and FKBP12.6. Structural studies revealed that these macrocycles bind with a new binding mode featuring a transient conformation, which is disfavored for the small FKBPs. Using a conformation‐sensitive assay we show that this binding mode occurs in solution and is characteristic for this new class of compounds. The discovered macrocycles are non‐immunosuppressive, engage FKBP51 in cells, and block the cellular effect of FKBP51 on IKKα. Our findings provide a new chemical scaffold for improved FKBP51 ligands and the structural basis for enhanced selectivity.
Highlights
Proteins often cluster in families with similar structure
The dihydroxylated derivative 9 g of the larger macrocycle bound to FK506 binding protein 51 (FKBP51) with a Ki of 1.2 mm, whereas for 9 a–f no Scheme 1
We explored if the macrocyclic ligands could interfere with the cellular functions of FKBP51
Summary
Proteins often cluster in families with similar structure. The discovery of selective ligands that can discriminate between these close homologs remains a formidable challenge in chemical biology as well as in drug development. Macrocyclization is a popular approach to improve druglike properties for compounds outside the rule-of-five space[12] and is thought to be crucial for the unusually beneficial properties of the clinically used natural products FK506 (Figure 1 B), Rapamycin and Cyclosporin.[13] Macrocyclization was key to enhance the affinities or physicochemical properties of synthetic ligands for FKBP12[14] and cyclophilins.[15] In a pilot study on the macrocyclization of SAFit analogs,[16] we surprisingly observed a rearrangement of the FKBP51 binding pocket, which in turn allowed an unprecedented selectivity against the off-targets FKBP12 and FKBP12.6. Angewandte Chemie International Edition published by Wiley-VCH GmbH
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