Chemical inhibition of the E3 ligase subunit FBXO7 confers neuroprotection and anti-inflammatory activity by stabilizing mitochondria
Inventors
Mallampalli, Rama K. • Chen, Beibei • Chu, Charleen T. • Liu, Yuan
Assignees
University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-11242339-B2
Publication Date
2022-02-08
Expiration Date
2038-06-25
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Abstract
A method for treating a neurodegenerative disease or an inflammatory disorder in a subject, comprising administering to the subject in need thereof, a compound, or a pharmaceutically acceptable salt thereof, of formula II: wherein each of R3-R7 is independently H, halogen, optionally-substituted alkyl, amino, alkoxy or hydroxy; R8 is an optionally-substituted heterocycloalkyl; anda is 0 to 3.
Core Innovation
The invention provides compounds, or pharmaceutically acceptable salts thereof, of formula II, which are used in methods for treating neurodegenerative diseases or inflammatory disorders in subjects. The compounds are characterized by substituents R3-R7 each being independently H, halogen, optionally-substituted alkyl, amino, alkoxy or hydroxy; R8 as an optionally-substituted heterocycloalkyl; and a being 0 to 3. These compounds, including a specific inhibitor BC1464, act by disrupting the interaction between the F box protein Fbxo7 and the mitochondrial kinase Pink1, thereby stabilizing Pink1 protein levels in cells.
The problem addressed by the invention arises from the role of Pink1 in maintaining mitochondrial quality through its involvement in dynamics, function, and selective degradation of damaged mitochondria. Loss-of-function mutations in Pink1 cause mitochondrial dysfunction leading to neurodegenerative diseases like familial Parkinson's disease and enhanced inflammatory responses. Fbxo7, an E3 ligase subunit, targets Pink1 for polyubiquitylation and proteasomal degradation, reducing Pink1 levels and thereby contributing to mitochondrial injury and inflammation. Prior to this invention, no chemical entities that increase Pink1 levels were known, representing an unmet need for therapeutic agents that protect mitochondrial function by modulating Pink1 stability.
The invention reveals that Fbxo7 mediates Pink1 degradation, and overexpression of Fbxo7 induces mitochondrial injury and lung inflammation. The disclosed compounds inhibit the Fbxo7-Pink1 interaction, preventing Pink1 degradation, leading to neuroprotection and anti-inflammatory effects through maintained mitochondrial integrity. Experimental evidence in cellular and animal models shows that Fbxo7 inhibition by compounds like BC1464 stabilizes Pink1 and attenuates mitochondrial dysfunction, neurotoxicity, and inflammatory injury, addressing both neurodegenerative and inflammatory pathologies.
Claims Coverage
The patent claims include one independent claim focusing on a treatment method using specific compounds of formula II, with multiple dependent claims elaborating on substituents and specific compound structures.
Method for treating neurodegenerative and inflammatory disorders using formula II compounds
A method comprising administering to a subject in need a compound of formula II, characterized by substituents R3-R7 that can be H, halogen, optionally-substituted alkyl, amino, alkoxy, or hydroxy; R8 as an optionally-substituted heterocycloalkyl; and a from 0 to 3.
Use of compounds with defined substituents for treatment of specific mitochondrial and muscle diseases
Methods for treating frontotemporal dementia, mitochondrial diseases caused by mutations in nuclear DNA or mtDNA, and diseases of skeletal or cardiac muscle by administering compounds of formula II with the stated substitution patterns.
Compounds with specified aminoalkyl and heterocycloalkyl substituents as therapeutic agents
Compounds where at least one of R3-R7 is an aminoalkyl (—(CH2)b—NR9R10), amino, or alkoxy group, where R8 is a heterocycloalkyl including oxygen heteroatoms (such as oxetanyl, oxolanyl, oxanyl), used for treating neurodegenerative or inflammatory diseases.
The claims cover methods of treating neurodegenerative and inflammatory disorders by administering compounds of formula II designed to inhibit Fbxo7-mediated Pink1 degradation, with various structural specifications on substituents that modulate therapeutic activity.
Stated Advantages
Disruption of the Fbxo7-Pink1 interaction stabilizes Pink1 protein levels in cells.
The compounds lessen the severity of neurotoxicity and inflammatory injury in multiple cellular and in vivo models.
Chemical inhibition of Fbxo7 supports mitochondrial integrity and function by preserving Pink1.
Documented Applications
Treatment of neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, and other dementias, tauopathies, Amyotrophic lateral sclerosis, Huntington's disease, and related neurodegenerative conditions.
Treatment of inflammatory disorders such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pneumonitis, pneumonia, arthritis, autoimmune diseases, and sepsis.
Treatment of pulmonary diseases including acute lung injury, acute respiratory distress syndrome, pulmonary hypertension, and lung cancer.
Treatment of diseases involving mitochondrial dysfunction like frontotemporal dementia, mitochondrial diseases caused by mutations in nuclear or mitochondrial DNA, and diseases of skeletal or cardiac muscle.
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