Non-catalytic substrate-selective p38alpha-specific MAPK inhibitors with endothelial-stabilizing and anti-inflammatory activity, and methods of use thereof
Inventors
Shapiro, Paul S. • MacKerell, JR., Alexander D. • Hasday, Jeffrey D.
Assignees
US Department of Veterans Affairs
Publication Number
US-11911393-B2
Publication Date
2024-02-27
Expiration Date
2037-06-22
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Abstract
Compounds that inhibit p38α MAPK protein, and methods of using the same, are provided for treating or preventing diseases such as cancer or inflammatory diseases.
Core Innovation
The invention relates to compounds that inhibit p38α MAPK protein by binding to a pocket near the ED substrate-docking site of p38α MAPK, providing pharmaceutical compositions and methods of using such compounds as treatments for disease. The p38α MAPK inhibitors described include compounds of various formulae, exemplified as Formula 1, Formula 2, Formula 11, Formula 12, Formula 13, Formula 14, Formulas 1001 to 1256, and compound UM101 and UM60, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. The binding pocket is defined by amino acid residues R49, H107, L108, M109, G110, A157, V158, E163, L164, and K165 in p38α MAPK.
The problem being solved is the limited efficacy and toxicity associated with conventional p38 catalytic inhibitors, which act by blocking the catalytic site of both p38α and p38β isoforms. These inhibitors cause toxicity potentially due to their lack of isoform selectivity and the suppression of p38α-dependent counterregulatory responses such as MSK1/2 activity. Thus, there is a need in the field for therapeutics that selectively inhibit p38α MAPK functions by targeting substrate-binding sites to preserve critical homeostatic functions, and to provide improved treatment of inflammatory and oncologic diseases.
Claims Coverage
The patent includes several independent claims covering compounds of specified formulae, pharmaceutical compositions, and methods of treating diseases using these compounds.
Selective p38α MAPK inhibitor compounds
Compounds having specific chemical structures that bind to a pocket near the ED substrate-docking site of p38α MAPK, characterized by defined residues and structural components such as variable groups (e.g., L1, R5), including specific compounds like 4-chloro-N-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)benzamide (UM101) and 4-chloro-N-(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)benzamide (UM60).
Pharmaceutical compositions containing the p38α MAPK inhibitors
Pharmaceutical compositions comprising a therapeutically effective amount of the claimed compounds optionally in oral dosage forms and with physiologically compatible carriers.
Methods of treating inflammatory and other diseases by administering the compounds
Methods of treating inflammatory diseases such as rheumatoid arthritis, cardiovascular diseases, multiple sclerosis, inflammatory bowel disease, COPD, asthma, acute respiratory distress syndrome, and acute lung injury, as well as other diseases including Alzheimer's, psoriasis, atherosclerosis, pain, and glomerulosclerosis, by administering therapeutically effective amounts of the claimed compounds or their pharmaceutical compositions, optionally orally.
The claims collectively cover novel p38α MAPK selective inhibitor compounds that bind near the ED substrate-docking site, corresponding pharmaceutical compositions, and therapeutic methods for treating various inflammatory and other diseases.
Stated Advantages
The compounds selectively inhibit p38α MAPK, sparing p38β and preserving p38α-dependent counterregulatory responses such as MSK1/2 activity.
They stabilize endothelial and epithelial barrier functions and reduce inflammation.
They exhibit superior efficacy and potency compared to conventional inhibitors in mitigating experimental acute lung injury with improved tolerability.
Documented Applications
Treatment or prevention of diseases alleviated by inhibiting p38α MAPK activities including cancer and inflammatory diseases.
Specifically rheumatoid arthritis, cardiovascular disease, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome, and acute lung injury.
Application to a wide range of cancers such as acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, colon cancer, colorectal cancer, glioma, head and neck cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer, stomach cancer, blood cancers including leukemias and lymphomas, among others.
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