Treating an atypical protein kinase C enzyme abnormality
Inventors
Farese, Robert Vito • Sajan, Mini Paliyath
Assignees
Office of General Counsel of VA • University of South Florida St Petersburg
Publication Number
US-9795584-B2
Publication Date
2017-10-24
Expiration Date
2034-07-30
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Abstract
Provided herein are compounds, compositions, pharmaceutical formulations, methods of treating and methods of using aPKC inhibitors for treating and/or preventing of aPKC abnormalities.
Core Innovation
Provided herein are compounds, compositions, pharmaceutical formulations, methods of treating and methods of using aPKC (atypical protein kinase C) inhibitors for treating and/or preventing aPKC abnormalities. The invention includes a method of treating or preventing an aPKC abnormality by administering effective amounts of aPKC inhibitors or their derivatives to subjects in need, where the inhibitors have a specific chemical formula (Formula I) with defined substituents R1 and R2, encompassing a range of possible chemical groups and ring formations. The aPKC inhibitor or its derivatives may be administered via various routes and dosage forms, covering doses ranging roughly from 0.001 mg to 1,000 mg. The aPKC abnormalities treated encompass diverse conditions including obesity, glucose intolerance, metabolic syndrome, hyperinsulinemia, hepatosteatosis, non-alcoholic cirrhosis, hypertriglyceridemia, hypercholesterolemia, polycystic ovary disease, and Alzheimer's disease.
The problem addressed arises from the pandemic of insulin-resistant states such as obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM), which remain significant public health issues globally and lack cures beyond lifestyle interventions or treatments with side effects. Insulin resistance involves impaired glucose metabolism which increases insulin secretion, contributing to various comorbidities. The role of protein kinase C enzymes, specifically aPKCs, is pivotal in regulating gluconeogenesis and lipogenesis affecting insulin sensitivity and glucose metabolism. In dietary-induced obesity, aPKC is activated by lipid mediators, leading to dysregulated pathways that increase glucose output and lipid production, establishing a cycle exacerbating insulin resistance. Current understanding highlights a need for treatments addressing underlying aPKC abnormalities.
The core innovation thus provides chemically-defined aPKC inhibitors that selectively inhibit the activity of aPKC isoforms, offering a therapeutic approach to correct the dysregulated insulin signaling pathways characteristic of obesity and related metabolic disorders. The compounds act by modulating aPKC function thereby mitigating insulin resistance and associated metabolic abnormalities. The disclosure also includes pharmaceutical formulations, methods of administration, and kits with instructions for treating the described conditions. Experimental examples demonstrate the specificity and efficacy of compounds such as 2-acetylcyclopentane-1,3-dione (ACPD) in inhibiting aPKC activity without affecting other PKC isoforms, reducing lipogenic and gluconeogenic factors, improving glucose tolerance, and reversing markers of metabolic syndrome in animal and human cell models.
Claims Coverage
The patent presents one independent claim covering a therapeutic method and related inventive features involving a specific compound for treating insulin resistance.
Method of treating insulin resistance using ACPD
A method of treating insulin resistance by administering an effective amount of 2-acetylcyclopentane-1,3-dione (ACPD) to a subject in need thereof.
Effective dosage range for ACPD
The effective amount of ACPD administered ranges broadly from about 0.001 mg to about 1,000 mg.
Multiple administration routes
The effective amount can be administered via various dosage forms formulated for oral, vaginal, intravenous, transdermal, subcutaneous, intraperitoneal, or intramuscular routes.
Refined effective dosage for treatment
An embodiment where the effective amount of ACPD ranges from about 0.001 mg to about 100 mg for treating insulin resistance.
The independent claim defines a therapeutic method for insulin resistance focused on administration of the compound ACPD in effective amounts with flexibility in dosage and administration routes. The main inventive features include the use of ACPD as the active agent, defined dosage ranges, and the inclusion of various administration modes.
Stated Advantages
ACPD selectively inhibits aPKC isoforms PKC-ι and PKC-ζ without affecting other PKC enzymes, suggesting specificity and potentially reduced off-target effects.
Treatment with ACPD or related aPKC inhibitors results in reduction of obesity-associated metabolic abnormalities, such as improved glucose tolerance, decreased hepatic lipid content, and normalization of lipogenic and gluconeogenic enzyme expression.
The aPKC inhibitors can be administered via multiple routes and formulations, enhancing versatility in therapeutic application.
Inhibiting aPKC corrects dysregulated signaling pathways that contribute to systemic insulin resistance, breaking the cycle of lipid-mediated aPKC activation and metabolic dysfunction.
Documented Applications
Treatment and prevention of insulin resistance and related metabolic disorders including obesity, glucose intolerance, metabolic syndrome, hyperinsulinemia, hepatosteatosis, non-alcoholic cirrhosis, hypertriglyceridemia, hypercholesterolemia, polycystic ovary disease, and Alzheimer's disease.
Use in therapeutic methods to improve hepatic and peripheral insulin sensitivity through modulation of aPKC activity.
Pharmaceutical formulations and kit preparations for administration of aPKC inhibitors in subjects having aPKC abnormalities.
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