Methods and compositions for the inhibition of Pin1
Inventors
Lu, Kun Ping • Boxer, Matthew Brian • Davis, Mindy Irene Emily • Pragani, Rajan • Shen, Min • Simeonov, Anton Momtchilov • Wei, Shuo • Zhou, Xiao Zhen
Assignees
Beth Israel Deaconess Medical Center Inc • US Department of Health and Human Services
Publication Number
US-10413548-B2
Publication Date
2019-09-17
Expiration Date
2033-06-07
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Abstract
The invention features compositions and methods for inhibiting the Pin1 protein, and the treatment of disorders characterized by elevated Pin1 levels.
Core Innovation
The invention provides compositions and methods for inhibiting the Pin1 protein to treat disorders characterized by elevated Pin1 levels, such as immune disorders and proliferative disorders. The inhibition is achieved by contacting the Pin1 protein with compounds listed in Table 1, which can be administered in therapeutically effective amounts to subjects suffering from or at risk of such disorders. The methods include determining the Pin1 marker expression levels in subjects before and after administering the compounds to evaluate suitability and monitor treatment efficacy.
The problem addressed is the need for improved therapeutic agents and methods for treating diseases characterized by elevated Pin1 expression, especially immune disorders and cancers. Current treatments for immune disorders rely on immunosuppressive agents whose effectiveness varies and often cause adverse side effects. Moreover, cancer incidence is increasing, and there are limited treatments that lack guaranteed success. Pin1 is overexpressed in many cancers and activates multiple oncogenes while inhibiting tumor suppressors; thus, Pin1 inhibitors are needed to suppress oncogenic pathways simultaneously for treating aggressive or drug-resistant cancers.
Claims Coverage
The patent includes one independent claim defining a method of inhibiting Pin1 by contacting it with specific compounds. The claims focus on the particular compounds used for inhibition and the context of Pin1 within cells, especially human cells.
Method of inhibiting Pin1 with specific compounds
The invention covers a method for inhibiting Pin1 by contacting Pin1 with a compound having a structure selected from Compound 9 and Compound 10 as defined in the patent.
Inhibition of Pin1 in a cellular context
The method includes inhibiting Pin1 when Pin1 is present within a cell, allowing for intracellular targeting of Pin1 protein.
Inhibition of Pin1 in human cells
The method further specifies inhibition of Pin1 in human cells, enabling therapeutic applicability in human subjects.
The claims define methods for inhibiting Pin1 using specific compounds (Compound 9 and Compound 10), including the context of Pin1 within cells and particularly within human cells. The inventive aspects focus on these compounds as Pin1 inhibitors applied in cellular environments.
Stated Advantages
Inhibitors of Pin1 provide improved therapeutic agents and methods for treating immune disorders and proliferative disorders characterized by elevated Pin1 levels.
The compounds allow for simultaneous suppression of multiple oncogenic pathways, useful for treating aggressive and drug-resistant cancers.
Combination therapies with other anti-inflammatory, anti-microbial, anti-viral, or anti-cancer agents can enhance efficacy and potentially reduce dosage and side effects.
Documented Applications
Treatment of immune disorders including a wide range of diseases such as asthma, arthritis, multiple sclerosis, diabetes, lupus, Crohn's disease, psoriasis, and many others characterized by elevated Pin1 expression.
Treatment of proliferative disorders including acute and chronic leukemias, Hodgkin's and non-Hodgkin's disease, various sarcomas and carcinomas such as breast, ovarian, prostate, lung, and other cancers known to express elevated Pin1.
Use in diagnostic assays to measure Pin1 marker levels in biological samples to identify subjects who may benefit from Pin1 inhibitor treatment or to monitor treatment efficacy.
Combination therapies involving Pin1 inhibitors with anti-inflammatory agents, antimicrobial agents, antiviral agents, or chemotherapeutic anti-cancer agents for enhanced treatment outcomes.
Pharmacogenomic applications to tailor treatment regimens based on individual genetic profiles related to Pin1 expression and drug metabolism.
Use of Pin1 inhibitors in vitro for studying cell cycle, mitosis, apoptosis, neurodegenerative diseases, carcinogenesis, and in vivo for inhibiting cell growth in cancer, fungal, and parasitic infections.
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