Anthranilic amides and the use thereof
Inventors
CHAKRABARTY, SURAVI • Flaherty, Patrick T. • Monlish, Darlene • Cavanaugh, Jane E. • Burow, Matthew E. • Elliott, Steven • HOANG, Van T.
Assignees
Tulane University • Duquesne University of the Holy Spirit
Publication Number
US-11465978-B2
Publication Date
2022-10-11
Expiration Date
2034-09-11
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Abstract
Disclosed are anthranilic amide derivatives having the formula. Compositions are disclosed that include the anthranilic amide derivatives and the use of the anthranilic amide derivatives for the manufacture of a medicament. Further disclosed are methods of inhibiting or treating cancer, inhibiting or reversing an epithelial to mesenchymal cellular transition, and/or inhibiting MEK1/2 and/or MEK 5 enzymatic activity in a subject by administering to the subject an effective amount of a disclosed anthranilic amide derivative.
Core Innovation
The invention discloses anthranilic amide derivatives of specified formulas, compositions comprising these derivatives, and their use for the manufacture of medicaments. The invention provides methods for inhibiting or treating cancer, inhibiting or reversing an epithelial to mesenchymal cellular transition, and/or inhibiting MEK1/2 and/or MEK5 enzymatic activity in a subject by administering an effective amount of a disclosed anthranilic amide derivative.
The problem addressed is the significant up-regulation and overexpression of MEK/ERK signaling pathways, particularly MEK5, in certain types of cancer, such as squamous cell carcinoma, prostate cancer, and breast cancer. These pathways contribute to cancer progression, proliferation, and the acquisition of more invasive cellular phenotypes through the process of epithelial to mesenchymal transition (EMT). There is a lack of selective small-molecule inhibitors that can effectively target MEK5 and modulate these pathways in cancer therapy.
The core innovation of the patent is the rational design, synthesis, and application of anthranilic amide derivatives that can selectively inhibit MEK1/2 and/or MEK5. These derivatives are effective in blocking, preventing, and even reversing EMT associated with tumor aggressiveness. Pharmaceutical compositions containing these derivatives, as well as methods for their administration to subjects with cancer or at risk of developing cancer, are disclosed for both prophylactic and therapeutic purposes.
Claims Coverage
The patent contains two independent claims covering the core inventive subject matter.
Anthranilic amide derivatives of a defined formula
This feature comprises compounds of a specific formula, where R1 is a primary or tertiary amine, OR11, or an amino acid, and R2 through R10 are each independently hydrogen, alkyl, alkene, alkyne, halogen, alkoxy, cyano group, or nitrile group, with further specification of possible substitutions. These compounds are structurally defined and include numerous explicitly listed examples with detailed substituents.
Pharmaceutical composition comprising anthranilic amide derivatives and pharmaceutically acceptable carrier
This feature is a composition that contains: - The anthranilic amide derivative described above. - A pharmaceutically acceptable carrier. Formulations are further defined for oral, intravenous, intradermal, intramuscular, and subcutaneous administration as well as for delivery in concentrate, dried powder, liquid, capsule, pellet, or pill forms.
Method for inhibiting MEK5 enzymatic activity in a subject
This inventive feature states administering an effective amount of the defined anthranilic amide compound to a subject, thereby inhibiting MEK5 enzymatic activity in the subject.
Collectively, these inventive features cover the compounds, compositions, and the method of inhibiting MEK5 in a subject by administering the described anthranilic amide derivatives.
Stated Advantages
The disclosed compounds selectively inhibit MEK5 and/or MEK1/2 and are effective against cancers in which these pathways are overexpressed or up-regulated.
The compounds can block, prevent, or reverse epithelial to mesenchymal transition, which is linked to tumor invasiveness and metastasis.
Some compounds selectively reverse the mesenchymal phenotype back to a more epithelial phenotype, a feature not previously achieved by small molecule compounds.
The compounds can be used both for treatment and prevention of various cancers and diseases involving MEK1/2 and/or MEK5 pathways.
Pharmaceutical compositions and methods allow for a variety of routes of administration and dosing regimens suitable for both prophylactic and therapeutic purposes.
Documented Applications
Treatment and/or prevention of various cancers, including solid tumors such as breast cancer, pancreatic cancer, squamous cell carcinoma, prostate cancer, and triple-negative breast cancer.
Inhibition or reversal of epithelial to mesenchymal transition in subjects, including cancer cells, to prevent or treat metastasis and aggressive cancer phenotypes.
Inhibition of MEK1/2 and/or MEK5 enzymatic activity in subjects through administration of anthranilic amide derivatives.
Use of anthranilic amide derivatives in in vitro and in vivo assays as models for MEK1/2 and/or MEK5 inhibition.
Manufacture of medicaments containing anthranilic amide derivatives for use in cancer therapy.
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