Benzathine analogs
Inventors
Chen, Beibei • Mallampalli, Rama K.
Assignees
University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-11857550-B2
Publication Date
2024-01-02
Expiration Date
2033-03-13
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Abstract
A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:wherein X is a divalent linking moiety; andR1-R10 are each individually H, optionally-substituted alkyl, optionally-substituted alkoxy, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted heterocyclic, halogen, amino, or hydroxy, provided that at least one of R3 or R8 is an optionally-substituted alkyl, a substituted alkoxy, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted heterocyclic, or halogen.
Core Innovation
The invention disclosed relates to compounds, including benzathine analogs and other small molecules, that serve as inhibitors of the ubiquitin E3 ligase subunit FBXO3. These compounds inhibit FBXO3 activity, thereby preventing FBXO3-induced ubiquitination and degradation of FBXL2, a related E3 ligase subunit. By maintaining FBXL2 levels, the compounds reduce levels of TRAF proteins, which are key mediators of cytokine release, thereby inhibiting the release of pro-inflammatory cytokines in inflammatory conditions.
The problem addressed involves inflammatory disorders characterized by excessive release of pro-inflammatory cytokines, known as a cytokine storm, leading to severe tissue injury and high morbidity and mortality. Existing anti-inflammatory strategies, including systemic corticosteroids and targeted anti-cytokine agents, have not improved mortality in conditions such as sepsis. Prior approaches focus on single molecular targets, but systemic inflammation involves many mediators released from multiple receptors. There is a need for novel therapeutic targets that regulate a broader spectrum of pro-inflammatory biomolecules with fewer side effects.
Claims Coverage
The patent includes seven independent claims covering methods of inhibiting pro-inflammatory cytokine release, treating inflammatory disorders, inhibiting FBXO3-mediated ubiquitination, and inhibiting bacterial growth using the disclosed compound.
Method for inhibiting pro-inflammatory cytokine release
Administering to a subject a therapeutically effective amount of a compound that inhibits FBXO3 activity, thereby reducing cytokine release.
Method for treating inflammatory disorders
Administering a therapeutically effective amount of a compound to treat inflammatory disorders including sepsis, pneumonia, chronic obstructive lung disease, inflammatory bowel disease, colitis, and disorders induced by specific bacterial infections.
Method for treating FBXO3-mediated disorders
Administering a therapeutically effective amount of a compound to a subject to treat disorders or injuries mediated by FBXO3 activity.
Method for inhibiting FBXO3-induced ubiquitination of FBXL2
Contacting FBXO3-containing tissue or cells with a compound that inhibits FBXO3 activity and prevents FBXL2 degradation.
Method for inhibiting bacterial growth
Administering to a subject or surface of an object an effective amount of the compound to inhibit bacterial growth.
Method for diminishing supraphysiological cytokine levels
Administering therapeutically effective amounts of the compound to reduce supraphysiological levels of TNFα, IL-1β, and IL-6 in subjects.
The independent claims cover the use of the disclosed compound for inhibiting cytokine release, treating multiple inflammatory and FBXO3-mediated disorders, preventing FBXL2 degradation, and inhibiting bacterial growth, reflecting the compound's multifunctional therapeutic utility.
Stated Advantages
Provide a novel small molecule anti-inflammatory therapeutic targeting a broad spectrum of pro-inflammatory cytokines by modulating FBXO3, rather than targeting single cytokines or receptors.
Target a unique bacterial-like molecular signature within FBXO3 (ApaG domain) conferring selectivity and potentially limited off-target effects.
Inhibit cytokine release effectively at doses below predicted toxic levels, indicating a favorable therapeutic index.
Demonstrated efficacy in multiple in vivo models of inflammation and infection, including sepsis, pneumonia, influenza-induced lung injury, colitis, and topical inflammation, indicating broad anti-inflammatory activity.
Potential as an antibacterial agent by inhibiting bacterial growth through interaction with bacterial ApaG proteins.
Documented Applications
Treatment of inflammatory disorders involving cytokine storm such as sepsis and pneumonia.
Treatment of inflammatory conditions induced by infections with bacteria including Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenza, and Escherichia coli.
Treatment of chronic inflammatory diseases including chronic obstructive lung disease, inflammatory bowel disease, Crohn's disease, colitis, arthritis, systemic lupus erythematosus, and other autoimmune diseases.
Use as antibacterial agents to inhibit bacterial proliferation either in subjects or on surfaces of objects.
Application for FBXO3-mediated disorders such as malaria, toxic lung exposure, cancer, Alzheimer's disease, and burn injuries.
Topical treatment of dermatologic inflammation and edema, such as ear edema.
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