Krajczy, Patryk ; Meyners, Christian ; Repity, Maximilian L. ; Hausch, Felix (2024)
Structure‐based design of ultrapotent tricyclic ligands for FK506‐binding proteins.
In: Chemistry – A European Journal, 30 (45)
doi: 10.1002/chem.202401405
Artikel, Bibliographie
Dies ist die neueste Version dieses Eintrags.
Kurzbeschreibung (Abstract)
Access to small, rigid, and sp³‐rich molecules is a major limitation in the drug discovery for challenging protein targets. FK506‐binding proteins hold high potential as drug targets or enablers of molecular glues but are fastidious in the chemotypes accepted as ligands. We here report an enantioselective synthesis of a highly rigidified pipecolate‐mimicking tricyclic scaffold that precisely positions functional groups for interacting with FKBPs. This was enabled by a 14‐step gram‐scale synthesis featuring anodic oxidation, stereospecific vinylation, and N‐acyl iminium cyclization. Structure‐based optimization resulted in the discovery of FKBP inhibitors with picomolar biochemical and subnanomolar cellular activity that represent the most potent FKBP ligands known to date.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2024 |
| Autor(en): | Krajczy, Patryk ; Meyners, Christian ; Repity, Maximilian L. ; Hausch, Felix |
| Art des Eintrags: | Bibliographie |
| Titel: | Structure‐based design of ultrapotent tricyclic ligands for FK506‐binding proteins |
| Sprache: | Englisch |
| Publikationsjahr: | 12 August 2024 |
| Ort: | Weinheim |
| Verlag: | Wiley-VCH |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Chemistry – A European Journal |
| Jahrgang/Volume einer Zeitschrift: | 30 |
| (Heft-)Nummer: | 45 |
| Kollation: | 7 Seiten |
| DOI: | 10.1002/chem.202401405 |
| Zugehörige Links: | |
| Kurzbeschreibung (Abstract): | Access to small, rigid, and sp³‐rich molecules is a major limitation in the drug discovery for challenging protein targets. FK506‐binding proteins hold high potential as drug targets or enablers of molecular glues but are fastidious in the chemotypes accepted as ligands. We here report an enantioselective synthesis of a highly rigidified pipecolate‐mimicking tricyclic scaffold that precisely positions functional groups for interacting with FKBPs. This was enabled by a 14‐step gram‐scale synthesis featuring anodic oxidation, stereospecific vinylation, and N‐acyl iminium cyclization. Structure‐based optimization resulted in the discovery of FKBP inhibitors with picomolar biochemical and subnanomolar cellular activity that represent the most potent FKBP ligands known to date. |
| Freie Schlagworte: | rigidification, structure-based drug design, prolines, fused ring systems, FK506-binding proteins |
| ID-Nummer: | Artikel-ID: e202401405 |
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 540 Chemie 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie |
| Fachbereich(e)/-gebiet(e): | 07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie > Strukturbasierte Wirkstoffforschung 07 Fachbereich Chemie > Clemens-Schöpf-Institut |
| Hinterlegungsdatum: | 13 Nov 2024 06:19 |
| Letzte Änderung: | 13 Nov 2024 13:41 |
| PPN: | 523504950 |
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| Suche nach Titel in: | TUfind oder in Google |
Verfügbare Versionen dieses Eintrags
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Structure‐Based Design of Ultrapotent Tricyclic Ligands for FK506‐Binding Proteins. (deposited 12 Nov 2024 13:27)
- Structure‐based design of ultrapotent tricyclic ligands for FK506‐binding proteins. (deposited 13 Nov 2024 06:19) [Gegenwärtig angezeigt]
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