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-9730941-B2
Publication Date
2017-08-15
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 features compositions and methods for inhibiting the Pin1 protein using Table 1 Compounds. These compositions can be administered in therapeutically effective amounts to treat subjects, such as humans, who are suffering from or are at risk of immune disorders or proliferative disorders characterized by elevated Pin1 levels. The method includes determining the Pin1 marker expression level from biological samples and administering a Table 1 Compound if the Pin1 marker level is elevated. Monitoring Pin1 marker levels post-administration can also determine treatment efficacy and disease prognosis.
Pin1 is a protein that binds and regulates phosphorylated phosphoproteins, playing crucial roles in prolyl isomerization, cell cycle progression, and immune responses. Elevated Pin1 levels correlate with various cancers and poor clinical outcomes, and overexpression causes cell transformation and tumorigenesis. Pin1 inhibition suppresses oncogenic pathways and immune responses through selective inhibition of type I IFN mediated immunity. Therefore, there is a need for Pin1 inhibitors to treat immune and proliferative disorders by targeting multiple pathogenic pathways simultaneously.
Claims Coverage
The claims present two main inventive features related to methods of inhibiting Pin1 using specific chemical compounds.
Methods of inhibiting Pin1 with specific compounds
A method of inhibiting Pin1 by contacting Pin1 with compounds selected specifically from Compound 48 and Compound 49.
Inhibition of Pin1 within cells
The method wherein the Pin1 protein is inhibited within a cell, specifically including human cells.
The claims cover methods for inhibiting the Pin1 protein using precise compounds defined as Compound 48 or 49, including their application inside human cells.
Stated Advantages
Pin1 inhibitors provide a novel therapeutic approach to selectively inhibit type I interferon response while sparing proinflammatory cytokine production.
Pin1 inhibition can suppress numerous oncogenic pathways simultaneously for treating aggressive and/or drug-resistant cancers.
Co-administration with a Pin1 inhibitor may reduce the effective dose of other anti-inflammatory or anti-cancer agents, potentially lowering toxicity.
The methods enable monitoring of treatment efficacy by measuring Pin1 marker levels before and after administration.
Documented Applications
Treatment of a broad range of immune disorders such as multiple sclerosis, Crohn's disease, asthma, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, and various others characterized by elevated Pin1 activity.
Treatment of proliferative disorders including multiple types of leukemias, lymphomas, sarcomas, carcinomas, and solid tumors such as breast cancer, ovarian cancer, prostate cancer, lung carcinoma, melanoma, and neuroblastoma.
Combination therapies of Pin1 inhibitors with anti-inflammatory agents, antimicrobial agents, antiviral agents, or anti-cancer compounds to treat immune or proliferative disorders.
Use of Pin1 inhibitors in vitro for studying cell cycle regulation, mitosis, apoptosis, neurodegenerative diseases, and cancer-related pathways.
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