Last update 19 Sep 2024

FKBP52

Last update 19 Sep 2024

Basic Info

Synonyms

51 kDa FK506-binding protein, 52 kDa FK506-binding protein, 52 kDa FKBP

+ [17]

Introduction

Immunophilin protein with PPIase and co-chaperone activities. Component of steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). May play a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors between cytoplasm and nuclear compartments. The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening. Acts also as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly. May have a protective role against oxidative stress in mitochondria.

Drugs associated with FKBP52

FK-1706

Target

FKBP52

Mechanism

FKBP52 agonists

Active Org.

Astellas Pharma, Inc. [+1]

Originator Org.

Astellas Pharma, Inc.

Active Indication

Nervous System Diseases [+2]

Inactive Indication-

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

ILS-920

Target

FKBP52

Mechanism

FKBP52 inhibitors

Active Org.-

Originator Org.

Pfizer Inc.

Active Indication-

Inactive Indication

Acute Ischemic Stroke

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with FKBP52

NCT00827190 / CompletedPhase 1

Ascending Single Dose Study Of The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of ILS-920 Administered Intravenously To Healthy Adult Subjects

This is a first-in-human study of ILS-920. This study will provide an initial assessment of the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ILS-920 after administration of ascending single intravenous (IV) doses to healthy adult subjects.

Start Date01 Feb 2009

Sponsor / Collaborator

Wyeth AB

100 Clinical Results associated with FKBP52

100 Translational Medicine associated with FKBP52

0 Patents (Medical) associated with FKBP52

641

Literatures (Medical) associated with FKBP52

02 Sep 2024·ChemMedChem

1,4‐Pyrazolyl‐Containing SAFit‐Analogues are Selective FKBP51 Inhibitors With Improved Ligand Efficiency and Drug‐Like Profile

Article

Author: Bauder, Michael ; Hausch, Felix ; Meyners, Christian ; Sugiarto, Wisely Oki ; Gaali, Steffen ; Buffa, Vanessa

AbstractThe FK506 binding protein 51 (FKBP51) is an appealing drug target due to its role in several diseases such as depression, anxiety, chronic pain and obesity. Towards this, selectivity versus the close homolog FKBP52 is essential. However, currently available FKBP51‐selective ligands such as SAFit2 are too large and lack drug‐like properties. Here, we present a structure activity relationship (SAR) analysis of the pipecolic ester moiety of SAFit1 and SAFit2, which culminated in the discovery of the 1,4‐pyrazolyl derivative 23 d, displaying a binding affinity of 0.077 μM for FKBP51, reduced molecular weight (541.7 g/mol), lower hydrophobicity (cLogP=3.72) and higher ligand efficiency (LE=0.25). Cocrystal structures revealed the importance of the 1,4‐ and 1,3,4‐ substitution patterns of the pyrazole ring versus the 1,4,5 arrangement.

01 Sep 2024·Journal of Psychiatric Research

Molecular evidence of altered stress responsivity related to neuroinflammation in the schizophrenia midbrain

Article

Author: Debs, Sophie R ; Weickert, Cynthia Shannon ; Purves-Tyson, Tertia D ; Zhu, Yunting ; Rothmond, Debora A

Stress and inflammation are risk factors for schizophrenia. Chronic psychosocial stress is associated with subcortical hyperdopaminergia, a core feature of schizophrenia. Hyperdopaminergia arises from midbrain neurons, leading us to hypothesise that changes in stress response pathways may occur in this region. To identify whether transcriptional changes in glucocorticoid and mineralocorticoid receptors (NR3C1/GR, NR3C2/MR) or other stress signalling molecules (FKBP4, FKBP5) exist in schizophrenia midbrain, we measured gene expression in the human brain (N = 56) using qRT-PCR. We assessed whether alterations in these mRNAs were related to previously identified high/low inflammatory status. We investigated relationships between stress-related transcripts themselves, and between FKBP5 mRNA, dopaminergic, and glial cell transcripts in diagnostic and inflammatory subgroups. Though unchanged by diagnosis, GR mRNA levels were reduced in high inflammatory compared to low inflammatory schizophrenia cases (p = 0.026). We found no effect of diagnosis or inflammation on MR mRNA. FKBP4 mRNA was decreased and FKBP5 mRNA was increased in schizophrenia (p < 0.05). FKBP5 changes occurred in high inflammatory (p < 0.001), whereas FKBP4 changes occurred in low inflammatory schizophrenia cases (p < 0.05). The decrease in mRNA encoding the main stress receptor (GR), as well as increased transcript levels of the stress-responsive negative regulator (FKBP5), may combine to blunt the midbrain response to stress in schizophrenia when neuroinflammation is present. Negative correlations between FKBP5 mRNA and dopaminergic transcripts in the low inflammatory subgroup suggest higher levels of FKBP5 mRNA may also attenuate dopaminergic neurotransmission in schizophrenia even when inflammation is absent. We report alterations in GR-mediated stress signalling in the midbrain in schizophrenia.

08 Aug 2024·The Journal of Physical Chemistry B

Cooperative Protein Dynamics of Heterotetrameric Hemoglobin from Scapharca inaequivalvis

Article

Author: Gao, Xiang ; Mizuno, Misao ; Ishikawa, Haruto ; Mizutani, Yasuhisa

Hemoglobins achieve cooperative oxygen binding by diverse strategies based on different assemblies of globin subunits. Heterotetrameric hemoglobin from Scapharca inaequivalvis (HbII) consists of two AB-dimers, whose structure closely resembles that of homodimeric hemoglobin from the same organism (HbI). Herein, we investigated the structural dynamics of HbII following carbon monoxide (CO) dissociation using time-resolved resonance Raman (RR) spectroscopy. The observed spectra showed that the heme structure of the transient dissociated form of HbII was similar to that of HbI; however, the transition from the transient dissociated form to the equilibrium unligated form was faster for HbII than for HbI. Furthermore, the dependence of the time-resolved spectra on the yield of CO dissociation revealed that the transition became faster as the number of dissociated ligands increased from one to four. The positive correlation between the rate constants and number of dissociated ligands indicates that the structural transition of HbII following CO dissociation is cooperative.

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FKBP52

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