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-11911392-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 generally to compounds that inhibit p38 Mitogen-Activated Protein Kinases (MAPKs) proteins, specifically to compounds that inhibit p38α MAPK protein by binding to a pocket near the ED substrate-docking site of p38α MAPK, and methods of using such compounds as treatments for disease. These compounds include pharmaceutical compositions comprising a therapeutically effective amount of a p38α MAPK inhibitor or its pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug, and a physiologically compatible carrier medium. The p38α MAPK inhibitor is capable of binding to a pocket defined at least by residues R49, H107, L108, and K165, or by residues R49, H107, L108, M109, G110, A157, V158, E163, L164, and K165 in p38α MAPK.
The problem being solved stems from the inadequacy of currently available p38 catalytic inhibitors, which have poor effectiveness and cause toxicity issues due to activity against non-inflammatory p38 isoforms like p38β and loss of p38α-dependent counterregulatory responses, such as those involving MSK1/2. The invention addresses the need for selective inhibition of p38α MAPK that blocks certain p38α functions while preserving critical homeostatic and counterregulatory mechanisms, which could offer therapeutic benefits for inflammatory and oncologic diseases.
The invention also provides new methods of inhibiting p38α MAPK by contacting the protein with compounds binding near the ED substrate-docking site, with specified chemical formulas (Formula 1, 2, 11, 12, 13, 14, and others) and includes compounds like UM101 and UM60. These compounds exhibit substrate-selectivity, stabilizing endothelial barrier functions, reducing inflammation and cytokine expression, and mitigating acute lung injury (ALI) in models. The compounds selectively inhibit p38α without loss of anti-inflammatory p38α-dependent counterregulatory signaling, unlike catalytic inhibitors.
Claims Coverage
The patent includes two independent claims directed to methods of treating diseases in a patient by administering therapeutically effective amounts of specific compounds with defined chemical structures.
Administration of compounds with specific chemical structures
The method involves administering compounds having specific chemical structures characterized by particular substituents (e.g., L1 as —CH2—, —C(CH3)2—, or —C(CH2CH2)—), exemplified by 4-chloro-N-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)benzamide, 4-chloro-N-(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)benzamide, or 4-chloro-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide, or their pharmaceutically acceptable salts.
Selective treatment of pain
The claimed method includes treating pain by administering the compounds described, indicating a therapeutic application for the compounds as p38α MAPK inhibitors.
Modes of administration and dosage forms
The method covers administering these compounds as pharmaceutical compositions, including oral dosage forms that can be controlled-release, sustained-release, or extended-release. Administration routes include oral administration with specified dosage ranges from 0.1 mg/kg to 200 mg/kg.
The claims focus on methods of treating diseases, including pain, by administering specific p38α MAPK inhibitor compounds with defined chemical structures via pharmaceutical compositions or oral dosage forms, emphasizing selective compound structures, dosage, and administration forms.
Stated Advantages
Compounds selectively inhibit p38α MAPK, thereby reducing toxicity associated with inhibition of other p38 isoforms such as p38β.
Inhibition of p38α MAPK does not result in loss of p38α-dependent counterregulatory responses, preserving anti-inflammatory signaling pathways such as those mediated by MSK1 and MSK2.
The compounds stabilize endothelial barrier function and more effectively mitigate acute lung injury compared to existing inhibitors like SB203580.
The substrate-selective inhibition results in reduced inflammation and modified cytokine expression, providing therapeutic benefits in inflammatory and oncologic diseases.
The compounds demonstrate selectivity and biological activity in human cell models and animal models with better tolerance and efficacy than current catalytic inhibitors.
Documented Applications
Treatment or prevention of diseases including cancer and inflammatory diseases such as 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).
Treatment of hyperproliferative disorders, specifically various forms of cancer including pancreatic, breast, prostate, lymphoma, skin, colon, melanoma, brain, ovarian, pancreatic, prostate, blood cancers and a broad list of cancer types stated explicitly.
Use of the p38α MAPK inhibitors to stabilize endothelial barrier function, reduce inflammation, regulate leukocyte trafficking and cytokine expression, mitigate LPS-induced lung injury, and provide anti-inflammatory therapeutic effects.
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