Inhibitors of the FKBP51 protein from a high-throughput drug screen and methods of use
Inventors
Sabbagh, Jonathan Jacob • Dickey, Chad
Assignees
US Department of Veterans Affairs • University of South Florida St Petersburg
Publication Number
US-9962379-B2
Publication Date
2018-05-08
Expiration Date
2035-06-30
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Abstract
The subject invention concerns materials and methods for treating depression, stress disorders, such as PTSD, anxiety disorders, and/or a neurodegenerative disease or condition in a person or animal. In one embodiment, a person or animal in need of treatment is administered one or more compounds or drugs, or a composition comprising the one or more compounds or drugs, that inhibit FKBP51 activity or function. The subject invention also concerns a method for inhibiting activity of the FKBP51 protein in a cell. The subject invention also concerns methods of screening for compounds or drugs that inhibit the FKBP51 protein.
Core Innovation
The invention provides materials and methods for treating depression, stress disorders such as PTSD, anxiety disorders, and neurodegenerative diseases or conditions by administering compounds or drugs that inhibit FKBP51 activity or function. The invention includes the use of specific compounds, including benztropine, clonidine, pimozide, thioridazine, trifluoperazine, and triflupromazine, or their pharmaceutically acceptable salts, to achieve this inhibition. The invention also covers methods for inhibiting FKBP51 activity in cells and screening methods to identify such inhibitors.
The problem addressed by the invention stems from the role of FKBP51 as a co-chaperone of Hsp90 and its involvement in regulating stress hormone receptors, particularly the glucocorticoid receptor (GR). Elevated FKBP51 levels, associated with certain single nucleotide polymorphisms (SNPs) in the FKBP5 gene, increase susceptibility to major depression, PTSD, anxiety disorders, and neurodegenerative diseases like Alzheimer's disease. Prior to this invention, no treatments specifically targeting FKBP51 were available despite its recognized importance.
By providing compounds that attenuate the suppressive effects of FKBP51 on glucocorticoid receptor activity, the invention offers a therapeutic approach for conditions associated with elevated FKBP51. Moreover, the invention includes compositions comprising these compounds and methods of use that allow for treatment in both human and non-human mammals. Screening methods for new FKBP51 inhibitors are also encompassed, enabling discovery of additional therapeutics.
Claims Coverage
The patent discloses one independent claim focusing on a treatment method using FKBP51 inhibitors in combination with approved drugs, highlighting key inventive features related to compound selection, patient characteristics, and combinatorial treatments.
Method of treating neurodegenerative and psychiatric disorders using FKBP51 inhibitors and approved drugs
Administering to a person or animal having a neurodegenerative disease, depression, stress disorder, and/or anxiety disorder a therapeutically effective amount of one or more compounds or drugs, or compositions thereof, that inhibit FKBP51 activity or function, in combination with one or more approved drugs or compounds for treating these conditions, wherein the approved drugs include MDMA, propranolol, or ziprasidone.
Targeting subjects with elevated FKBP51 levels
Method includes treating individuals who exhibit increased levels of FKBP51 protein relative to controls, addressing the conditions associated with such elevated protein levels.
Use of compounds attenuating FKBP51 suppression of glucocorticoid receptor activity
The compounds or drugs used in the method are those that lessen or attenuate the suppressive effect of FKBP51 on glucocorticoid receptor (GR) activity.
Specific compounds included as FKBP51 inhibitors
The method employs specific compounds including benztropine, clonidine, pimozide, thioridazine, trifluoperazine, or triflupromazine, or their pharmaceutically or physiologically acceptable salts.
Inclusion of patients with FKBP5 gene SNPs linked to FKBP51 elevation
The method covers treating persons or animals exhibiting one or more SNPs in the FKBP5 gene associated with elevated FKBP51 protein levels.
Determination of FKBP51 protein levels and SNP status
The method further comprises determining whether the subject exhibits elevated FKBP51 protein levels and/or SNPs linked to such elevation prior to treatment.
Treatment of specific disorders including PTSD and Alzheimer's disease
The method explicitly includes post-traumatic stress disorder (PTSD) as the stress disorder and Alzheimer's disease as the neurodegenerative disease to be treated.
Combination therapy with various additional approved drugs
The method comprises further treating the subject with one or more additional approved drugs including donepezil, galantamine, memantine, MAO inhibitors, SSRIs, SNRIs, TCAs, risperidone, prazosin, mirtazapine, lithium, bupropion, trazodone, carbamazepine, and others as listed.
The claim covers a comprehensive method for treating neurodegenerative and psychiatric disorders by combining FKBP51 inhibitors with specific approved drugs, targeting patients with elevated FKBP51 levels or associated genetic markers, and optionally administering additional therapeutic agents.
Stated Advantages
Provides a novel therapeutic approach targeting FKBP51, an important protein linked to depression, stress disorders, anxiety, and neurodegenerative disease, which previously lacked targeted treatments.
Enables treatment of subjects identified by biomarkers such as elevated FKBP51 protein levels and genetic SNP markers, allowing for more personalized therapy.
Combining FKBP51 inhibitors with approved drugs enhances the scope of treatment options for complex neuropsychiatric and neurodegenerative conditions.
Covers pharmaceutical compositions and delivery methods facilitating effective administration and dosage control.
Documented Applications
Treatment of depression in persons or animals.
Treatment of stress disorders including post-traumatic stress disorder (PTSD).
Treatment of anxiety disorders.
Treatment of neurodegenerative diseases or conditions, explicitly including Alzheimer's disease.
Screening methods for compounds or drugs that inhibit FKBP51 protein activity.
Combination therapies involving FKBP51 inhibitors and other approved drugs for psychiatric and neurodegenerative disorders.
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