Modified carbazoles as therapeutic agents
Inventors
Stella, Nephi • Diaz, Philippe
Assignees
University of Washington • University of Montana Missoula
Publication Number
US-11420967-B2
Publication Date
2022-08-23
Expiration Date
2039-06-12
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Abstract
This disclosure relates to compounds that target microtubules, pharmaceutical compositions comprising them, and methods of using the compounds and compositions for treating diseases. More particularly, this disclosure relates to modified carbazole compounds and pharmaceutical compositions thereof, methods of targeting microtubules with these compounds, and methods of treating diseases affected by microtubule disruption.
Core Innovation
The invention provides novel modified carbazole compounds that target microtubules by binding to the colchicine site of tubulin. These compounds include unique features such as a hydroxymethyl moiety linking the carbazole to an aromatic moiety, an ethyl group on the nitrogen atom of the carbazole, and specific chemical modifications in the second aromatic moiety. Detailed chemical structures and variations for these compounds are described, including pharmaceutically acceptable salts, prodrugs, and stereoisomers.
The problem being addressed is the lack of effective therapeutic options for devastating cancers such as glioblastoma multiforme (GBM) and cancers with BRAF mutations that are resistant to current treatments. Existing microtubule-targeting agents have shown only minimal therapeutic benefits in these cancers, which underscores the need for radically different approaches that circumvent the shortcomings of current therapies.
The compounds disclosed disrupt microtubule assembly and dynamics, thereby impairing mitosis and inducing cell death in cancer cells. The heterocyclic carbazole scaffold can be chemically modified in diverse ways, providing a versatile platform for optimizing therapeutic properties. These compounds demonstrate pronounced antitumor activity, especially in GBM and BRAF-mutant cancers, as well as an ability to kill different subtypes of patient-derived GBM cells, supporting their potential as next-generation microtubule-targeting agents.
Claims Coverage
There are several independent claims in this patent, each providing a distinct inventive feature related to compounds, compositions, and methods using modified carbazoles.
Compound of formula (I)
A compound of formula (I), as described in the patent, comprising: - A structure that binds to the colchicine site of tubulin. - Contains a hydroxymethyl moiety linking the carbazole to an aromatic moiety. - An ethyl moiety linked to the nitrogen atom of the carbazole. - Includes select chemical modifications in the second aromatic moiety. - Covers stereoisomers, pharmaceutically acceptable salts, and prodrugs thereof.
Pharmaceutical composition comprising one or more compounds of formula (I)
A pharmaceutical composition including one or more compounds of formula (I) and a pharmaceutically acceptable carrier, solvent, adjuvant, or diluent. - Suitable for various modes of administration as per the disclosure. - The composition may optionally contain one or more secondary therapeutic agents.
Method of treating cancer with compounds of formula (I)
A method of treating cancer by administering one or more compounds according to formula (I) to a subject in need thereof. - Applicable to cancers such as BRAF-mutant cancers, melanoma, brain cancer, colorectal cancers, lung cancer, breast cancer, head and neck tumors, and lymphoma. - Specific coverage for glioblastoma and cancers that develop in peripheral tissues and metastasize to the brain.
Method of treating cancer comprising co-administration of secondary therapeutic agents
A method as above, further comprising administering one or more secondary therapeutic agents selected from antimetabolites, nucleoside analogs, taxanes, vinca alkaloids, microtubule inhibitors, alkylating agents, and BRAF inhibitors. - Specifies combination therapies, with or without sequence or dosage limitations.
Method of disrupting microtubule function in a cell using compounds of formula (I)
A method of disrupting MT function in a cell by administering one or more compounds according to formula (I) to the cell. - Pertains to direct action on microtubules to alter cell division and induce cell death.
The claims broadly cover compounds with a defined chemical structure that target the colchicine site of tubulin, related pharmaceutical compositions, and a variety of methods for treating cancers and disrupting microtubule function using these compounds, including combination therapies.
Stated Advantages
The compounds display pronounced antitumor activity in multiple glioblastoma model systems and exhibit lower toxicity in non-cancerous liver cells, suggesting a promising therapeutic index.
The heterocyclic carbazole scaffold allows for versatile chemical modification using simple starting materials and established chemistry, supporting ease of medicinal optimization.
Compounds of the disclosure kill all major patient-derived glioblastoma subtypes regardless of genetic heterogeneity, addressing the issue of tumor heterogeneity in therapeutic targeting.
The compounds can be combined with a wide range of secondary therapeutic agents, potentially enabling synergistic effects and reduced dosages of standard treatments.
Documented Applications
Treatment of cancer, including BRAF-mutant cancers, melanoma, brain cancer, colorectal cancers, lung cancer, breast cancer, head and neck tumors, lymphoma, glioblastoma multiforme, and cancers that metastasize to the brain.
Combination therapy with secondary therapeutic agents, such as antimetabolites, microtubule inhibitors, alkylating agents, and BRAF inhibitors, for enhanced anti-cancer treatment.
Disrupting microtubule function in cells, including the induction of cell death in cancer cells via interference with microtubule assembly and dynamics.
Methods of treating diseases associated with cannabinoid CB1 and/or CB2 receptor, including ADHD/ADD, alcohol use disorder, ALS, Alzheimer's, autism, cancer pain, fibromyalgia, frontotemporal dementias, glioblastoma, Huntington's disease, IBD/IBS, migraine, multiple sclerosis, neuropathic pain, Parkinson's, Rett syndrome, rheumatoid arthritis, Tourette's, trigeminal neuralgia, and epilepsy.
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