ArticleAngewandte Chemie (International ed. in English)2021
Macrocyclic FKBP51 Ligands Define a Transient Binding Mode with Enhanced Selectivity.
Article in Angewandte Chemie (International ed. in English), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 29 citations in OpenAlex.
- Toward Dual Targeting of Catalytic and Gatekeeper Pockets in Cyclophilins Using a Macrocyclic Scaffold.ACS medicinal chemistry letters · 2024Article
- Use of Poly(vinyl alcohol) in Spray-Dried Dispersions: Enhancing Solubility and Stability of Proteolysis Targeting Chimeras.Pharmaceutics · 2024Article
- The Role of FKBPs in Complex Disorders: Neuropsychiatric Diseases, Cancer, and Type 2 Diabetes Mellitus.Cells · 2024Review
- Analysis of the Selective Antagonist SAFit2 as a Chemical Probe for the FK506-Binding Protein 51.ACS pharmacology & translational science · 2023Review
- FKBP12 is a major regulator of ALK2 activity in multiple myeloma cells.Cell communication and signaling : CCS · 2023Article
- Binding pocket stabilization by high-throughput screening of yeast display libraries.Frontiers in molecular biosciences · 2022Article
- Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides.Chemical science · 2021Article
- Fenton-Chemistry-Based Oxidative Modification of Proteins Reflects Their Conformation.International journal of molecular sciences · 2021Article
- Development of NanoBRET-Binding Assays for FKBP-Ligand Profiling in Living Cells.Chembiochem : a European journal of chemical biology · 2021Article
- Macrocyclic FKBP51 Ligands Define a Transient Binding Mode with Enhanced Selectivity.Angewandte Chemie (International ed. in English) · 2021Article
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.