FBXO3 inhibitors
Inventors
Chen, Beibei • Mallampalli, Rama K.
Assignees
University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-10307423-B2
Publication Date
2019-06-04
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 discloses compounds, including benzathine analogs, that inhibit the activity of the E3 ubiquitin ligase component FBXO3. These FBXO3 inhibitors function by targeting a unique bacterial-like ApaG domain within the FBXO3 protein, blocking its interaction with the ubiquitin ligase substrate FBXL2. By inhibiting FBXO3, these compounds prevent FBXO3-induced ubiquitination and proteasomal degradation of FBXL2, leading to decreased levels of TRAF proteins and a subsequent reduction in pro-inflammatory cytokine release.
The problem addressed arises from the role of inflammatory disorders characterized by excessive pro-inflammatory cytokine release, often termed a 'cytokine storm,' which contributes to pathology in diseases such as sepsis, pneumonia, arthritis, and autoimmune conditions. Prior treatments targeting single cytokines or receptors have limited success, partly because systemic inflammation involves multiple mediators and complex signaling pathways. Moreover, current therapies like corticosteroids have broad off-target effects and limited effectiveness in reducing mortality during sepsis.
The invention solves this problem by discovering and targeting FBXO3, a key E3 ligase subunit that ubiquitinates and degrades FBXL2, which itself mediates degradation of TRAF family adaptor proteins involved in inflammatory cytokine signaling. FBXO3 possesses a unique ApaG domain structure not found in mammalian proteins, offering a selective molecular target. FBXO3 inhibitors developed herein block this pathway, reduce TRAF protein levels, suppress a broad spectrum of cytokines, and attenuate inflammation and tissue injury in various animal models of infection and inflammatory disease.
Claims Coverage
The patent includes multiple independent claims directed to methods of inhibiting cytokine release, treating inflammatory disorders and FBXO3-mediated diseases, inhibiting FBXO3-induced ubiquitination, inhibiting bacterial growth, and inhibiting FBXO3 bioactivity using specific benzathine-based FBXO3 inhibitors.
Use of N-heterocyclic-substituted benzathine as an FBXO3 inhibitor to inhibit pro-inflammatory cytokine release
A method of inhibiting pro-inflammatory cytokine release in a subject by administering an FBXO3 inhibitor that is an N-heterocyclic-substituted benzathine, wherein the N-heterocyclic substituent is selected from a specific list of heterocycles including pyrrolyl, pyridyl, morpholinyl, and others.
Use of N-heterocyclic-substituted benzathine to treat inflammatory disorders
A method of treating an inflammatory disorder in a subject by administering a therapeutically effective amount of an FBXO3 inhibitor of the specified benzathine class, with inflammation caused by a wide range of diseases including asthma, pneumonia, sepsis, autoimmune diseases, and viral or influenza-induced inflammation.
Specific structural features of benzathine FBXO3 inhibitors
Use of benzathine compounds having a divalent diamine core moiety with terminal aryl-containing moieties substituted by N-heterocyclic groups. The compounds conform to specified general formulae with defined substituents (R groups) and linking moieties, especially where R3 and R8 are 6-membered N-heterocycles.
Targeting the ApaG domain cavity of FBXO3 protein
Use of the FBXO3 inhibitor occupying the ApaG domain cavity of the FBXO3 protein, interacting with amino acid residues Y308, N335, E341, T368, and S370 to inhibit FBXO3 activity.
Treatment of FBXO3-mediated disorders with N-heterocyclic-substituted benzathine compounds
Methods of treating FBXO3-mediated disorders or injuries including malaria, toxic lung exposure, cancer (various types), Alzheimer's, or burn injuries by administering benzathine-based FBXO3 inhibitors as described.
Inhibition of FBXO3-induced ubiquitination and degradation of FBXL2
Methods of inhibiting FBXO3-induced ubiquitination and degradation of FBXL2 in tissues or cells by contacting with defined benzathine FBXO3 inhibitors.
Inhibition of bacterial growth by FBXO3 inhibitors
Methods for inhibiting bacterial growth in a subject or on surfaces by administering effective amounts of the FBXO3 inhibitors.
Inhibition of FBXO3 bioactivity by compounds interacting with specific residues
Method for inhibiting FBXO3 bioactivity by using compounds that interact with FBXO3 ApaG domain amino acid residues Y308, N335, E341, T368, and S370.
The independent claims focus on methods using specific N-heterocyclic-substituted benzathine compounds as FBXO3 inhibitors to inhibit pro-inflammatory cytokine release, treat inflammatory and FBXO3-mediated diseases, inhibit FBXL2 degradation, inhibit bacterial growth, and directly inhibit FBXO3 by targeting its ApaG domain.
Stated Advantages
FBXO3 inhibitors provide broad spectrum inhibition of multiple pro-inflammatory cytokines rather than targeting a single mediator.
The inhibitors target a unique bacterial-like ApaG domain of FBXO3, ensuring high selectivity and potentially limited off-target effects.
They suppress inflammation and prevent tissue damage in models of sepsis, pneumonia, influenza, and other inflammatory disorders.
The compounds exhibit low toxicity and demonstrate efficacy at doses well below predicted toxic levels in vivo.
FBXO3 inhibitors show activity independent of pathways targeted by corticosteroids and NSAIDs, potentially offering improved safety profiles.
Some compounds exhibit antibacterial activity by interacting with bacterial ApaG proteins, offering dual anti-inflammatory and antibacterial effects.
Documented Applications
Treatment of inflammatory disorders characterized by cytokine storms including sepsis, pneumonia, influenza-induced inflammation, arthritis, colitis, systemic lupus erythematosis, and various autoimmune diseases.
Treatment of bacterial infections or infections causing inflammatory injury, specifically infections with Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenza, and Escherichia coli.
Use as antibacterial agents to inhibit bacterial growth on surfaces or within subjects, possibly via interaction with bacterial ApaG proteins.
Treatment of FBXO3-mediated disorders and injuries such as malaria, toxic lung exposure, cancer (including leukemia, lymphoma, breast, colon, and other carcinomas), Alzheimer's disease, and burn-related injuries.
Use in treating lung injury, edema, and other manifestations of inflammatory conditions in animal models, demonstrating broad anti-inflammatory effects.
Topical treatment of dermatologic inflammatory disorders as shown in TPA-induced ear edema models.
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