Non-catalytic substrate-selective, p38α-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-11357781-B2
Publication Date
2022-06-14
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 generally to compounds that are inhibitors of p38 Mitogen-Activated Protein Kinases (MAPKs) proteins, with particular focus on compounds that inhibit the p38α MAPK protein by binding to a pocket near the ED substrate-docking site of p38α MAPK. Methods of using such compounds as treatments for diseases are also described.
The problem being solved stems from limitations of currently available p38 catalytic inhibitors, which are ineffective and cause toxicity due to non-selective activity against p38 isoforms and loss of p38α-dependent counterregulatory responses. These inhibitors block all p38α signaling through targeting the catalytic site, leading to adverse effects and lack of efficacy. Therefore, there is a need for therapeutics that can selectively inhibit p38α MAPK, selectively block certain p38α functions, and preserve critical counterregulatory and homeostatic functions, with applications for treating inflammatory and oncologic diseases.
The invention addresses this by identifying compounds that bind non-catalytically near the ED substrate-docking site of p38α MAPK, a region distinct from the catalytic site. Computer-aided drug design (CADD) was used to target a pocket near the ED site, which is required for phosphorylation of certain substrates such as MK2. Lead compounds such as UM101 were identified, which selectively bind p38α but not p38β, stabilize endothelial barrier function, inhibit proinflammatory gene expression, and mitigate experimental acute lung injury more potently and with better tolerability than existing catalytic inhibitors such as SB203580.
Claims Coverage
The patent contains independent claims directed to methods of treating inflammatory diseases by administering specific compounds and pharmaceutical compositions.
Methods of treating inflammatory diseases with compounds binding near the ED substrate-docking site of p38α MAPK
Methods comprising administering to a patient a therapeutically effective amount of compounds having defined structures that bind a pocket near the ED substrate-docking site of p38α MAPK.
Selective inhibition of p38α MAPK
Compounds selectively bind p38α MAPK over other isoforms, targeting the ED substrate-docking pocket defined by specific residues, for example R49, H107, L108, and K165.
Pharmaceutical compositions and administration forms
Pharmaceutical compositions comprising the compounds, including oral dosage forms, controlled-release, sustained-release or extended-release forms, and methods of administering these compositions orally with specified dose ranges.
Treatment of acute respiratory distress syndrome (ARDS)
Methods of treating ARDS by administering the compounds or compositions capable of selectively inhibiting p38α MAPK via the ED binding pocket.
The claims comprehensively cover methods of treating inflammatory diseases, particularly ARDS, by administering pharmaceutical compositions comprising compounds that selectively bind a pocket near the ED substrate-docking site of p38α MAPK, exhibiting selective inhibition and improved therapeutic effects.
Stated Advantages
The compounds selectively inhibit p38α MAPK, sparing other isoforms and thus potentially reducing toxicity compared to catalytic inhibitors.
They stabilize endothelial barrier function, reducing endothelial permeability and neutrophil transmigration.
They reduce inflammation by modulating cytokine expression without loss of p38α-dependent counterregulatory responses.
They are more potent and better tolerated than existing catalytic inhibitors in mitigating experimental acute lung injury (ALI).
Non-catalytic mode of action allows preservation of anti-inflammatory pathways such as those mediated by MSK1/2.
Documented Applications
Treatment or prevention of diseases alleviated by inhibiting p38α MAPK, notably cancer and inflammatory diseases.
Specific inflammatory diseases include rheumatoid arthritis, cardiovascular disease, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI).
Various cancers including but not limited to 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, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, skin cancer, stomach cancer, testicular cancer, blood cancers such as leukemia, lymphoma, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphoma.
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