Discovery of a Potent Proteolysis Targeting Chimera Enables Targeting the Scaffolding Functions of FK506‐Binding Protein 51 (FKBP51)

to related objects

Abstract: The FK506‐binding protein 51 (FKBP51) is a promising target in a variety of disorders including depression, chronic pain, and obesity. Previous FKBP51‐targeting strategies were restricted to occupation of the FK506‐binding site, which does not affect core functions of FKBP51. Here, we report the discovery of the first FKBP51 proteolysis targeting chimera (PROTAC) that enables degradation of FKBP51 abolishing its scaffolding function. Initial synthesis of 220 FKBP‐focused PROTACs yielded a plethora of active PROTACs for FKBP12, six for FKBP51, and none for FKBP52. Structural analysis of a binary FKBP12:PROTAC complex revealed the molecular basis for negative cooperativity. Linker‐based optimization of first generation FKBP51 PROTACs led to the PROTAC SelDeg51 with improved cellular activity, selectivity, and high cooperativity. The structure of the ternary FKBP51:SelDeg51:VCB complex revealed how SelDeg51 establishes cooperativity by dimerizing FKBP51 and the von Hippel‐Lindau protein (VHL) in a glue‐like fashion. SelDeg51 efficiently depletes FKBP51 and reactivates glucocorticoid receptor (GR)‐signalling, highlighting the enhanced efficacy of full protein degradation compared to classical FKBP51 binding.

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Bibliographic citation: Discovery of a Potent Proteolysis Targeting Chimera Enables Targeting the Scaffolding Functions of FK506‐Binding Protein 51 (FKBP51) ; day:14 ; month:12 ; year:2023 ; extent:8
Angewandte Chemie / International edition. International edition ; (14.12.2023) (gesamt 8)

Creator: Geiger, Thomas M.
Walz, Michael
Meyners, Christian
Kuehn, Angela
Dreizler, Johannes
Sugiarto, Wisely O.
Maciel, Edvaldo V. S.
Zheng, Min
Lermyte, Frederik
Hausch, Felix

DOI: 10.1002/anie.202309706

URN: urn:nbn:de:101:1-2023121514211248654545

Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 15.08.2025, 7:38 AM CEST

Data provider

This object is provided by:
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.

Show original at data provider

Associated

Other Objects (12)

Discovery of a Potent Proteolysis Targeting Chimera Enables Targeting the Scaffolding Functions of FK506‐Binding Protein 51 (FKBP51)

Discovery of a Potent Proteolysis Targeting Chimera Enables Targeting the Scaffolding Functions of FK506‐Binding Protein 51 (FKBP51)

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors

Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors

Development of the first selective proteolysis targeting chimera for the FK506-binding protein 51

Development of the first selective proteolysis targeting chimera for the FK506-binding protein 51

Degradation of neurodegenerative disease-associated TDP-43 aggregates and oligomers via a proteolysis-targeting chimera

Degradation of neurodegenerative disease-associated TDP-43 aggregates and oligomers via a proteolysis-targeting chimera

A proteolysis-targeting chimera molecule selectively degrades ENL and inhibits malignant gene expression and tumor growth

A proteolysis-targeting chimera molecule selectively degrades ENL and inhibits malignant gene expression and tumor growth

Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Proteolysis targeting chimeras (PROTACs) for epigenetics research

Proteolysis targeting chimeras (PROTACs) for epigenetics research

Targeting proteolysis in viral cardiac inflammatory disease

Targeting proteolysis in viral cardiac inflammatory disease

Proteolysis targeting chimeras (PROTACs) in cancer therapy

Proteolysis targeting chimeras (PROTACs) in cancer therapy

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Discovery of a Potent Proteolysis Targeting Chimera Enables Targeting the Scaffolding Functions of FK506‐Binding Protein 51 (FKBP51)

Discovery of a Potent Proteolysis Targeting Chimera Enables Targeting the Scaffolding Functions of FK506‐Binding Protein 51 (FKBP51)

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors

Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors

Development of the first selective proteolysis targeting chimera for the FK506-binding protein 51

Development of the first selective proteolysis targeting chimera for the FK506-binding protein 51

Degradation of neurodegenerative disease-associated TDP-43 aggregates and oligomers via a proteolysis-targeting chimera

Degradation of neurodegenerative disease-associated TDP-43 aggregates and oligomers via a proteolysis-targeting chimera

A proteolysis-targeting chimera molecule selectively degrades ENL and inhibits malignant gene expression and tumor growth

A proteolysis-targeting chimera molecule selectively degrades ENL and inhibits malignant gene expression and tumor growth

Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Proteolysis targeting chimeras (PROTACs) for epigenetics research

Proteolysis targeting chimeras (PROTACs) for epigenetics research

Targeting proteolysis in viral cardiac inflammatory disease

Targeting proteolysis in viral cardiac inflammatory disease

Proteolysis targeting chimeras (PROTACs) in cancer therapy

Proteolysis targeting chimeras (PROTACs) in cancer therapy

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Discovery of a Potent Proteolysis Targeting Chimera Enables Targeting the Scaffolding Functions of FK506‐Binding Protein 51 (FKBP51)

Discovery of a Potent Proteolysis Targeting Chimera Enables Targeting the Scaffolding Functions of FK506‐Binding Protein 51 (FKBP51)

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors

Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors

Development of the first selective proteolysis targeting chimera for the FK506-binding protein 51

Development of the first selective proteolysis targeting chimera for the FK506-binding protein 51

Degradation of neurodegenerative disease-associated TDP-43 aggregates and oligomers via a proteolysis-targeting chimera

Degradation of neurodegenerative disease-associated TDP-43 aggregates and oligomers via a proteolysis-targeting chimera

A proteolysis-targeting chimera molecule selectively degrades ENL and inhibits malignant gene expression and tumor growth

A proteolysis-targeting chimera molecule selectively degrades ENL and inhibits malignant gene expression and tumor growth

Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Proteolysis targeting chimeras (PROTACs) for epigenetics research

Proteolysis targeting chimeras (PROTACs) for epigenetics research

Targeting proteolysis in viral cardiac inflammatory disease

Targeting proteolysis in viral cardiac inflammatory disease

Proteolysis targeting chimeras (PROTACs) in cancer therapy

Proteolysis targeting chimeras (PROTACs) in cancer therapy

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Cultural heritage institutions wishing to register will find more information here.

Fields marked * need to be filled in.

Username*

Please enter your username

Email*

Please enter your email address

Please do not fill this field

First name

Last name

Password*

Please enter your password

Confirm password*

Please enter the same password

I have read the terms of use and the privacy policy for the collection of personal data and accept them. *

This field is required.

I would like to subscribe to the newsletter of the Deutsche Digitale Bibliothek. See newsletter subscription info.

Account created

Your "My DDB" account has been successfully created. Before you can log in to your account, you must click the confirmation link in the message we just sent to the email address you provided.