Non-ATP/catalytic site p38 mitogen activated protein kinase inhibitors
Inventors
Shapiro, Paul S. • MacKerell, JR., Alexander D. • Hasday, Jeffrey D. • Fletcher, Steven
Assignees
University of Maryland Baltimore
Publication Number
US-12202810-B2
Publication Date
2025-01-21
Expiration Date
2039-12-06
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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 uniquely inhibit p38α mitogen-activated protein kinase (MAPK) by targeting a specific pocket near the ED substrate-docking site, rather than the ATP/catalytic binding site. These compounds, such as those of Formula A and related structures, are designed through computer-aided drug design (CADD) to bind selectively to the substrate binding groove defined by particular amino acid residues in p38α MAPK. This approach enables substrate- and isoform-selective inhibition of p38α MAPK activity.
Current p38 MAPK inhibitors often lack effectiveness and cause toxicity, primarily because they inhibit catalytic activity across multiple p38 isoforms, including both proinflammatory (p38α) and cytoprotective (p38β) forms, and block all signaling events, including critical counterregulatory and homeostatic functions. The invention addresses these limitations by offering new therapeutics and methods for selective p38α inhibition that can maintain essential regulatory pathways, thereby reducing undesirable side effects and improving efficacy in treating inflammatory and oncologic diseases.
The disclosed compounds, in some embodiments, selectively stabilize endothelial and epithelial barriers, modulate proinflammatory cytokine gene expression, and demonstrate favorable biological effects in both human cell culture and animal models of acute lung injury, inflammatory, and cancer-related diseases. Methods of using these compounds include treatment or prevention of diseases where inhibition of p38α MAPK is therapeutically beneficial, with specific mention of applications to cancer, rheumatoid arthritis, respiratory conditions such as ARDS and COPD, and other inflammatory disorders.
Claims Coverage
The patent contains independent claims covering the compositions of specific p38α MAPK inhibitors, their pharmaceutical compositions, and methods of use for treating inflammatory diseases.
Compound targeting a non-ATP/catalytic site of p38α MAPK
A compound of a defined chemical formula that binds to a pocket near the ED substrate-docking site of p38α MAPK, featuring: - Specific linkers L1 and L2 selected from groups including —CH2—, —NH—SO2—, —NHCH2—, —CH2NH—, —NHCO—, —CONH—, —SO2—NH— - Substituents R1a and R2a independently selected from hydrogen and C1-3 alkyl - Structure and chemical groups specified in the claims - Non-ATP/catalytic site mode of inhibition
Pharmaceutical composition containing the specific compound
A pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof, optionally formulated for oral administration and oral dosage forms.
Method of treating inflammatory diseases by administering the compound
A method of treating an inflammatory disease in a patient by administering a therapeutically effective amount of the specific compound or its pharmaceutically acceptable salt, where the inflammatory disease is selected from rheumatoid arthritis, cardiovascular disease, multiple sclerosis, inflammatory bowel disease, COPD, asthma, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI). - Includes administration routes such as oral administration and oral dosage forms - Dosage range specified as 0.1 mg/kg to 200 mg/kg
In summary, the patent claims cover a novel chemical entity designed to inhibit p38α MAPK at a non-catalytic substrate site, pharmaceutical compositions containing that entity, and the use of such compositions for oral or other administration in the treatment of a broad range of inflammatory diseases.
Stated Advantages
The compounds selectively inhibit p38α MAPK without broadly inhibiting other isoforms, reducing toxicity compared to existing inhibitors.
Inhibiting p38α MAPK using these compounds preserves essential p38α-dependent counterregulatory and homeostatic functions, avoiding adverse loss of anti-inflammatory signaling.
The inhibitors effectively stabilize endothelial and epithelial barrier functions, reduce inflammation, and mitigate lung injury.
The approach offers improved efficacy and safety for the treatment of inflammatory and oncologic diseases over conventional p38 catalytic inhibitors.
Documented Applications
Treatment or prevention of cancer, including a comprehensive list such as pancreatic cancer, breast cancer, prostate cancer, lymphoma, melanoma, brain cancer, colon cancer, ovarian cancer, lung cancer, and various leukemias.
Treatment or prevention of inflammatory diseases including 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).
Stabilization of endothelial or epithelial barrier function to reduce protein leakage and mitigate lung injury in acute lung injury or ARDS models.
Regulation of leukocyte trafficking and cytokine expression for controlling inflammation.
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