PKC-delta-I inhibitor formulations and uses thereof
Inventors
Patel, Niketa A. • Patel, Rekha S. • Sparks, Robert Pleasants • Guida, Wayne Charles
Assignees
Office of General Counsel of VA • University of South Florida St Petersburg
Publication Number
US-11129808-B2
Publication Date
2021-09-28
Expiration Date
2037-03-15
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Abstract
Provided herein are formulations that can contain an effective amount of a PKCδ inhibitor. Also provided herein are methods of inhibiting a PKCδ in a subject in need thereof, that can include the step of administering an effective amount of a compound that is capable of inhibiting a PKCδ.
Core Innovation
Obesity, diabetes, cancer, osteoarthritis, hepatosteatosis, cardiovascular diseases, and metabolic syndrome are significant health issues, especially in developed countries. Current therapeutic and preventative pharmaceuticals for these diseases are limited, creating a need for improved treatments.
The invention provides pharmaceutical formulations containing an effective amount of a PKCδI inhibitor, specifically compounds having structures according to any of Formulas 1 and 3-7 or their structural analogues. These inhibitors reduce PKCδI activity, particularly in adipocytes, without affecting other PKC isoforms such as PKCα, PKCβ, PKCγ, PKCε, PKCθ, PKCI, PKCζ, PKCδII, or PKCδVIII.
The PKCδI inhibitors can simultaneously bind the DMQD amino acid sequence within the V3 hinge region and the active site on the C2 domain of PKCδI. Methods are provided for treating diseases or disorders characterized by upregulation of PKCδI by administering these formulations. The diseases include diabetes, cancer, inflammatory diseases, obesity, insulin resistance, metabolic syndrome, hepatosteatosis, cardiovascular diseases, and neurodegenerative diseases.
Claims Coverage
The patent includes one primary independent claim directed to a method of treating a PKCδI disease or disorder using specific PKCδI inhibitors. The inventive features focus on the selection of the disease, the specificity of the inhibitor, and the mode of action of the inhibitor.
Method of treating obesity with PKCδI inhibitors
A method of treating a PKCδI disease or disorder in a subject with up-regulation of PKCδI in adipocytes where the disease is obesity.
Use of compounds according to Formulas 1 and 3-7 as inhibitors
Administering a formulation comprising an effective amount of a PKCδI inhibitor that is a compound having a structure as in any one of Formulas 1 and 3-7.
Use of compound according to Formula 1 as inhibitor
Administering a formulation comprising a PKCδI inhibitor that is a compound according to Formula 1.
Selective reduction of PKCδI activity
The PKCδI inhibitor effectively reduces PKCδI activity and is not effective to reduce activity of other PKC isoforms including PKCα, PKCβ, PKCγ, PKCε, PKCθ, PKCI, PKCζ, PKCδII, PKCδVIII, or combinations thereof.
Simultaneous binding to specific PKCδI regions
The PKCδI inhibitor simultaneously binds the DMQD amino acid sequence within the V3 hinge region and the active site on the C2 domain of PKCδI.
Effective dosage range
The effective amount of the PKCδI inhibitor ranges from about 0.001 micrograms to about 1 gram.
The claims cover methods of treating obesity via administration of specific PKCδI inhibitors with defined chemical structures. The inventive aspects include the molecule structures, their selective inhibition of PKCδI without affecting other PKC isoforms, simultaneous binding to key PKCδI sites, and defined dosage ranges for effectiveness.
Stated Advantages
The PKCδI inhibitors specifically reduce PKCδI activity without affecting other PKC isoforms, increasing specificity and reducing unwanted side effects.
The inhibitors reduce adipocyte apoptosis, which is relevant for diseases characterized by PKCδI upregulation.
Some compounds demonstrated over 85% inhibition of PKCδI cleavage and phosphorylation in pre-adipocytes and mature adipocytes, showing potent activity.
The compounds do not appear to cause cellular toxicity in treated adipocytes.
Documented Applications
Treatment or prevention of diseases or disorders characterized by PKCδI upregulation including diabetes, cancer, inflammatory diseases (such as osteoarthritis), obesity, insulin resistance, metabolic syndrome hepatosteatosis, cardiovascular diseases, and neurodegenerative diseases.
Reduction of adipocyte apoptosis in subjects with diseases related to PKCδI upregulation.
Use in pharmaceutical formulations for administering effective amounts of PKCδI inhibitors to subjects needing treatment for obesity and related PKCδI disorders.
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