Nuclear factor kappa B pathway inhibitor composition and use of same
Inventors
Henrich, Curtis J. • Kang, Moon-II • Bokesch, Heidi R. • Gustafson, Kirk R. • Colburn, Nancy H. • Young, Matthew R. • McMahon, James B.
Assignees
US Department of Health and Human Services
Publication Number
US-8729053-B2
Publication Date
2014-05-20
Expiration Date
2029-09-22
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Abstract
An embodiment of the invention provides a pharmaceutical composition comprising a compound of formula (I) a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. Another embodiment of the invention provides a method of treating or preventing a condition associated with increased expression and/or activity of an NFκB pathway using same compounds. A further embodiment of the invention provides a method of diagnosing a condition in an individual using same compounds.
Core Innovation
The invention provides a pharmaceutical composition comprising compound I, which can be in the form of a pharmaceutically acceptable salt, prodrug, hydrate, or solvate, together with a pharmaceutically acceptable carrier. The compound exists in Z (cis) or E (trans) configurations and may be administered to treat or prevent conditions associated with increased expression and/or activity of the nuclear factor kappa B (NFκB) pathway.
The invention also discloses methods of treating or preventing such conditions by administering an effective amount of compound I or its derivatives to individuals in need. Additionally, methods are described for diagnosing conditions suspected to be linked to increased NFκB pathway activity. This diagnostic method involves contacting a sample from the individual with compound I and assessing NFκB activity changes to identify if the condition is associated with NFκB upregulation.
The problem addressed by the invention is that increased expression and/or activity of NFκB pathways is associated with several diseases and conditions, including breast cancer and inflammation. Existing inhibitors of NFκB pathways lack sufficient specificity or have limitations. Therefore, there is a need for compositions and methods to inhibit NFκB pathways more effectively, which the invention aims to provide through compound I and its pharmaceutical compositions.
Claims Coverage
The patent includes several independent claims covering pharmaceutical compositions, methods of treatment, and methods of diagnosis involving compound I and its derivatives. The inventive features focus on the composition of matter, therapeutic use, and diagnostic applications related to NFκB pathway inhibition.
Pharmaceutical composition comprising compound I
A pharmaceutical composition comprising compound I of the specified formula or its pharmaceutically acceptable salt, prodrug, hydrate, or solvate, optionally including one or more additional NFκB pathway inhibitors such as ibuprofen, sulindac, curcumin, aspirin, sulfasalazine, SC-514, BMS-345541, MLN120B, or PS-1145.
Method of treating conditions associated with NFκB pathway
A method of treating a condition linked to increased expression and/or activity of the NFκB pathway by administering an effective amount of compound I or its derivatives, including treatment of cancer tumorigenesis or tumor progression (breast cancer, leukemia), inflammation, colitis, diabetes, prostatitis, pancreatitis, atherosclerosis, inflammatory bowel disease, rheumatoid arthritis, gastritis, or asthma. The compound can be coadministered with additional NFκB inhibitors either simultaneously or sequentially.
Method of diagnosing conditions via compound I
A method of diagnosing a condition suspected of being associated with increased NFκB pathway activity by contacting a biopsy (including breast tissue or blood cells) from an individual with compound I or derivatives and measuring changes in NFκB expression or activity, where a decrease indicates association with the condition.
The claims comprehensively cover the composition containing compound I, its use to treat various NFκB-related diseases including different cancers and inflammatory disorders, and diagnostic methods utilizing compound I to assess NFκB pathway activity in patient samples.
Stated Advantages
Compound I selectively inhibits the NFκB pathway with high potency, demonstrated by low micromolar IC50 values, and does so without cytotoxic or cytostatic effects on tested cells.
Compound I inhibits phosphorylation of IKKβ and IκBα, leading to blockage of NFκB activation, nuclear translocation, DNA binding, and transcriptional activity, thereby effectively repressing NFκB-dependent gene expression and tumor-promoting activities.
Unlike other NFκB inhibitors, compound I does not inhibit MAP kinases (JNK, ERK) or STAT3 phosphorylation, nor does it bind the ATP binding pocket of IKKβ, which may contribute to higher specificity and reduced off-target effects.
Compound I inhibits tumor promoter-induced cellular transformation and invasion in breast cancer cells, indicating potential therapeutic use in cancer progression and invasion.
Documented Applications
Treatment or prevention of conditions associated with increased expression and/or activity of the NFκB pathway including cancer tumorigenesis or tumor progression (especially breast cancer and leukemia), inflammation, colitis, diabetes, prostatitis, pancreatitis, atherosclerosis, inflammatory bowel disease, rheumatoid arthritis, gastritis, and asthma.
Diagnostic method for detecting conditions associated with increased NFκB pathway activity by analyzing biopsied tissues, such as breast tissue or blood cells, using compound I to measure NFκB pathway expression/activity changes.
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