PKC-Delta-I inhibitor formulations and uses thereof
Inventors
Patel, Niketa A. • Patel, Rekha S. • Sparks, Robert Pleasants • Guida, Wayne Charles
Assignees
US Department of Veterans Affairs • Office of General Counsel of VA • University of South Florida St Petersburg
Publication Number
US-11844779-B2
Publication Date
2023-12-19
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
The invention provides pharmaceutical formulations that include an effective amount of a PKCδI inhibitor, which is capable of inhibiting PKCδI activity in a subject. This inhibition can be achieved by administering compounds having specific chemical structures as detailed in Formulas 1 and 3-7, or structural analogues thereof, to individuals in need. The inhibitors can specifically reduce PKCδI activity in adipocytes and are tailored not to affect the activity of other PKC isoforms such as PKCα, PKCβ, PKCγ, PKCε, PKCθ, PKCI, PKCζ, PKCδII, or PKCδVIII.
The background identifies a key problem: diseases such as obesity, diabetes, cancer, osteoarthritis, hepatosteatosis, cardiovascular diseases, and metabolic syndrome are significant health issues with complex causes and limited therapeutic options. PKCδI upregulation has been implicated in these diseases, and it plays a central role in promoting apoptosis, especially in adipocytes, which contributes to disease pathology. Current inhibitors lack specificity and can have undesirable side effects, and no specific PKCδI inhibitors are known. Therefore, there is a need for specific inhibitors of PKCδI to treat and prevent these diseases effectively.
To address this need, the invention provides small molecule inhibitors that specifically target PKCδI by binding the DMQD amino acid sequence within its V3 hinge region and simultaneously the active site in the C2 domain, increasing specificity. The compounds inhibit the cleavage and catalytic activity of PKCδI without affecting other PKC isoforms, reduce adipocyte apoptosis, and show efficacy in reducing pathologies related to obesity, diabetes, cancer, and other inflammatory and metabolic diseases. The formulations can be administered through various pharmaceutical dosage forms at effective amounts ranging from micrograms to grams, tailored for therapeutic use.
Claims Coverage
The patent includes four independent claims focusing on methods of treating obesity or diseases associated with PKCδI by administering specific compounds.
Methods of treating PKCδI-related disease by administering specific PKCδI inhibitors
Claims methods for treating diseases or disorders, including obesity, by administering an effective amount of a compound that inhibits PKCδI activity, wherein the compound belongs to specified chemical structures shown in Formulas 1 and 3-7.
Specific chemical structures of PKCδI inhibitors used in treatment methods
Claims cover compounds having particular molecular structures selected from defined chemical formulas that are effective to inhibit PKCδI activity when administered in therapeutically effective amounts.
Methods for treating obesity using PKCδI inhibitor compounds
Claims specifically focus on methods of treating obesity by administering effective amounts of compounds with defined inhibitory activity toward PKCδI, with structures set forth in the specified chemical formula groups.
Chemical structural definitions of obesity treatment compounds
Claims defining particular chemical structures of compounds utilized for treating obesity through inhibition of PKCδI activity, referencing specified structural formulae in the application.
The independent claims encompass therapeutic methods employing defined small molecule compounds with specific structures for targeted inhibition of PKCδI activity to treat obesity and related disorders, emphasizing chemical specificity and effective dosage for clinical application.
Stated Advantages
The compounds selectively inhibit PKCδI activity without affecting other PKC isoforms, reducing potential off-target effects and undesirable side effects.
The inhibitors effectively reduce adipocyte apoptosis, which is implicated in obesity and metabolic disorders, thereby addressing disease pathology.
The formulations enable targeted treatment of diseases associated with PKCδI upregulation, such as diabetes, cancer, inflammatory diseases, obesity, insulin resistance, metabolic syndrome, hepatosteatosis, cardiovascular diseases, and neurodegenerative diseases.
Documented Applications
Treatment and prevention of obesity and obesity-associated diseases by inhibiting PKCδI activity in subjects in need.
Therapeutic intervention in diabetes, cancer, inflammatory diseases such as osteoarthritis, metabolic syndrome, hepatosteatosis, cardiovascular diseases, and neurodegenerative diseases through administration of PKCδI inhibitors.
Reduction of adipocyte apoptosis in subjects suffering from metabolic and inflammatory disorders via administration of PKCδI inhibitor pharmaceutical formulations.
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