GAS5 binding compounds, formulations, and uses thereof
Inventors
Patel, Niketa A. • Cai, Jianfeng
Assignees
Office of General Counsel of VA • University of South Florida St Petersburg
Publication Number
US-11278521-B2
Publication Date
2022-03-22
Expiration Date
2036-12-15
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Abstract
Provided herein are compounds that can bind GAS5 long non-coding RNA, compositions thereof, and uses thereof.
Core Innovation
Diabetes mellitus is a complex and costly disease with increasing prevalence worldwide, causing significant health issues and mortality. Despite awareness and existing treatments, diabetes remains a leading cause of death in the United States, imposing substantial economic costs and highlighting the need for improved diagnostic and therapeutic methods.
Recent studies have shown that the long non-coding RNA (IncRNA) GAS5 is reduced in serum from diabetic patients, and knockdown of GAS5 reduces PPARA expression in adipocytes. Dysregulation of GAS5 has also been reported in other diseases including various cancers, obesity, and neurodegenerative diseases, indicating its broad clinical relevance.
The invention provides compounds capable of binding GAS5 IncRNA to modulate its interaction with enzymes and compounds, thereby altering the amount and/or activity of GAS5 from normal or baseline states. Specifically, these compounds can either inhibit or facilitate enzyme binding to GAS5, affecting its stability and degradation, thus influencing GAS5 levels in cells or subjects.
The disclosed compounds have defined chemical structures (e.g., Formula 1 and derivatives), with specific substituents, and can bind GAS5 IncRNA sequences approximately 90%-100% identical to SEQ ID NO: 1. These compounds can be formulated pharmaceutically and administered to subjects to treat diseases, including diabetes and various cancers, by modulating GAS5 levels.
Claims Coverage
The patent includes six independent claims covering compounds with defined structures, their ability to bind GAS5 long non-coding RNA, pharmaceutical formulations comprising such compounds, and specific compound structures.
Compounds having a structure according to Formula 1
Compounds characterized by a structure according to Formula 1 with specified substituents R1 to R7, capable of binding GAS5 long non-coding RNA.
Capability of binding GAS5 long non-coding RNA
The compounds are capable of binding GAS5 long non-coding RNA, which has a sequence about 90%-100% identical to SEQ ID NO. 1.
Pharmaceutical formulations comprising compounds of Formula 1
Pharmaceutical compositions comprising a compound having a structure according to Formula 1, capable of binding GAS5 long non-coding RNA with sequence 90%-100% identical to SEQ ID NO.1.
Inclusion of auxiliary agents in pharmaceutical formulations
Pharmaceutical formulations further comprising agents selected from antisense or RNA interference molecules, chemotherapeutics, antineoplasic agents, hormones, antibiotics, antivirals, immunomodulating agents, antinausea agents, pain modifying agents, anti-inflammatory agents, antipyretics, antibiotics, and/or antibodies or fragments thereof.
Specific compounds having structure of Formula 3
Compounds specifically having the chemical structure of Formula 3 as defined in the patent.
Specific compounds having structure of Formula 14
Compounds specifically having the chemical structure of Formula 14 as defined in the patent.
The independent claims encompass compounds with defined chemical structures binding to GAS5 IncRNA, pharmaceutical formulations containing such compounds optionally with additional therapeutic agents, and embodiments specifying compounds of Formulas 3 and 14.
Stated Advantages
The compounds can increase GAS5 levels by disrupting its turnover mediated by UPF1, addressing a molecular mechanism relevant to diseases such as diabetes.
The compounds can modulate GAS5 stability and activity without inhibiting UPF1 globally, avoiding adverse effects associated with UPF1 inhibition.
The compounds demonstrated the ability to bind GAS5 RNA specifically and increase GAS5 levels in diabetic adipocytes without causing cell toxicity.
Documented Applications
Treatment of diabetes.
Treatment of various cancers including breast cancer, renal clear cell cancer, bladder cancer, hepatocellular cancer, gastric cancer, cervical cancer, non-small-cell lung cancer, pancreatic cancer, malignant pleural mesothelioma, and colorectal cancer.
Treatment of obesity.
Treatment of neurodegenerative diseases.
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