C-Abl tyrosine kinase inhibitory compound embodiments and methods of making and using the same
Inventors
Marugan, Juan J. • Ferrer, Marc • Southall, Noel T. • Dulcey, Andres E. • Hu, Xin • Dextras, Christopher R. • Talley, Daniel C. • Alvarez, Alejandra • Zanlungo, Silvana • Von Bernhardi, Rommy M.
Assignees
Pontificia Universidad Catolica de Chile • US Department of Health and Human Services
Publication Number
US-11649218-B2
Publication Date
2023-05-16
Expiration Date
2039-03-08
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Abstract
Disclosed herein are embodiments of a compound that inhibits c-Abl tyrosine kinase (also referred to herein as “c-Abl”). The compound embodiments described herein are novel c-Abl inhibitors that can bind to c-Abl at an allosteric site and inhibit its activity in various pathways. The compound embodiments also are capable of crossing the blood brain barrier and therefore are useful in inhibiting c-Abl activity as it affects pathways and/or proteins in the brain. The compound embodiments described herein are effective therapeutic agents for treating diseases involving c-Abl, such as cancers, motor neuron diseases, and neurodegenerative diseases. Also disclosed herein are embodiments of methods for making and using the c-Abl inhibitory compound embodiments.
Core Innovation
Disclosed herein are embodiments of novel compounds that inhibit c-Abl tyrosine kinase by binding to an allosteric site, specifically the myristate pocket, to inhibit its activity. These compounds are designed to cross the blood brain barrier, enabling effective inhibition of c-Abl activity in brain pathways, and are useful as therapeutic agents for diseases involving c-Abl, such as cancers, motor neuron diseases, and neurodegenerative diseases.
The problem being solved arises from diseases like Alzheimer's disease (AD), which involves neuronal dysfunction, cytoskeletal alterations, and abnormal protein phosphorylation, leading to neuronal loss and cognitive decline. Existing treatments for AD are ineffective, and there is a need for new therapeutic agents that can cross the blood brain barrier and target molecular pathways such as c-Abl involved in neurodegenerative diseases.
The disclosed compounds have a dibenzoazepinone core functionalized to promote blood brain barrier passage and potent binding to c-Abl tyrosine kinase. These compounds exhibit improved potency and brain penetration compared to conventional c-Abl inhibitors like Imatinib, Nilotinib, GNF-2, and GNF-5. Also disclosed are methods of making these compounds, compositions containing them, and methods of using the compounds to treat diseases involving c-Abl overexpression or over-activity.
Claims Coverage
The patent includes one independent claim related to compounds having specific chemical structures defined by Formulas IIA-IIF and their methods of making and using them. The claim coverage focuses on the novel structure, binding characteristics, and therapeutic uses of these compounds.
Compounds having structures satisfying Formulas IIA-IIF
Compounds characterized by a dibenzoazepinone core with specific substituents (R, X, Y groups) that bind allosterically to c-Abl, particularly at the myristate pocket, and that can cross the blood brain barrier.
Selective substitution patterns and chemical structures
Compounds with defined substituents including alkyl, heteroalkyl, aromatic, boronic acid, and halogen groups in specific positions, ensuring effective inhibition and brain penetration.
Methods of making compounds via coupling and cyclization
Methods comprising coupling aryl-containing compounds to form bis-aryl products, cyclizing to dibenzoazepinone cores, and further functionalizing or substituting to obtain the claimed compounds, including transition metal catalyzed couplings.
Pharmaceutical compositions including the compounds
Pharmaceutical formulations containing the disclosed compounds or their pharmaceutically acceptable salts, solvates, or prodrugs, along with pharmaceutically acceptable excipients for various modes of administration.
Methods of treating diseases involving c-Abl tyrosine kinase
Therapeutic methods involving administering efficacious amounts of the compounds or compositions to subjects with diseases associated with c-Abl activity or overexpression, including cancers, neurodegenerative diseases, lysosomal storage diseases, and infectious diseases.
The claims cover novel dibenzoazepinone-based compound structures that bind allosterically to c-Abl tyrosine kinase, their synthetic methods, pharmaceutical compositions, and methods of treatment for various diseases involving c-Abl, emphasizing structural features, brain penetration, and use in therapy.
Stated Advantages
The compounds exhibit the ability to bind c-Abl at an allosteric site (myristate pocket) with increased potency compared to existing c-Abl inhibitors.
The compounds are capable of crossing the blood brain barrier, allowing effective targeting of c-Abl activity in the brain.
Enhanced selectivity for c-Abl tyrosine kinase reduces off-target effects compared to conventional inhibitors.
The compounds protect neurons against amyloid-beta toxicity, reduce amyloid plaque burden, and improve cognitive function in Alzheimer's disease mouse models.
The compounds reduce cholesterol accumulation in Niemann-Pick C disease models at lower concentrations than current treatments.
They prevent neuronal death induced by excitotoxicity and improve survival and reduce seizures in an epilepsy mouse model.
The compounds show activity against leukemic cells and asexual malaria parasites, indicating broad therapeutic potential.
Documented Applications
Treatment of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, primary lateral sclerosis, Kennedy's syndrome, frontal temporal dementia associated with ALS, spinal muscular atrophy.
Treatment of cancers such as leukemia, glioma, glioblastoma, and neuroblastoma involving c-Abl overexpression or overactivity.
Treatment of lysosomal storage diseases including Farber disease, Krabbe disease, Fabry disease, Schindler disease, Sandhoff disease, Tay-Sachs disease, Gaucher disease, Niemann-Pick A, B, C, and D diseases, Hunter disease, Sanfilippo syndrome, and Sly syndrome.
Therapeutic intervention against bacterial infections (Shigella flexneri, Escherichia coli, Helicobacter pylori, Anaplasma phagocytophilum, Salmonella enterica) and viral infections (HIV).
Treatment of malaria caused by Plasmodium falciparum.
Reduction of cognitive decline and amyloid plaque burden in Alzheimer's disease animal models.
Protection against neuronal death caused by amyloid beta toxicity and oxidative stress.
Reduction of cholesterol accumulation in Niemann-Pick C cellular models.
Protection from neuronal excitotoxicity and prevention of seizures in temporal lobe epilepsy mouse models.
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