Bicyclic BET bromodomain inhibitors and uses thereof
Inventors
Strovel, Jeffrey William • Yoshioka, Makoto • Maloney, David J. • Yang, Shyh Ming • Jadhav, Ajit • Urban, Daniel Jason
Assignees
ConverGene LLC • US Department of Health and Human Services • Government of the United States of America
Publication Number
US-10508106-B2
Publication Date
2019-12-17
Expiration Date
2036-11-23
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Abstract
The present invention relates to compounds that bind to and otherwise modulate the activity of bromodomain-containing proteins, to processes for preparing these compounds, to pharmaceutical compositions containing these compounds, and to methods of using these compounds for treating a wide variety of conditions and disorders.
Core Innovation
The invention relates to compounds that bind to and modulate the activity of bromodomain-containing proteins, particularly those that inhibit bromodomains from binding acetylated proteins. These compounds are described by a formula (Formula I) with various chemical substituents and are provided as pharmaceutically acceptable salts, solvates, polymorphs, isomers, and prodrugs.
The problem being solved involves the pharmacological modulation of epigenetic changes mediated by bromodomain-containing proteins, which play a central role in the regulation of gene expression through interaction with acetylated histones. Bromodomain-containing proteins, especially the BET family (BRD2, BRD3, BRD4, and BRDT), bind acetylated nucleosomes and facilitate gene transcription, including oncogene expression such as MYC. There is a need for effective compounds that inhibit these interactions to provide therapeutic benefit in diseases including cancer, inflammation, and others.
Claims Coverage
The patent includes one independent claim covering a specific compound and its pharmaceutically acceptable salts.
Specific bicyclic BET bromodomain inhibitor compound
The compound (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol or its pharmaceutically acceptable salts.
The claims focus on a specific bicyclic BET bromodomain inhibitor compound and its pharmaceutically acceptable salts.
Stated Advantages
The compounds provide a new mode of pharmacological intervention for diseases mediated or modulated by bromodomain-containing proteins such as cancer, inflammation, obesity, metabolic, cardiovascular, neurodegenerative, psychiatric, and infectious diseases.
The compounds exhibit binding affinity to bromodomain-containing proteins, supporting their utility as BET bromodomain inhibitors.
Documented Applications
Treatment or prevention of diseases or conditions mediated by bromodomain-containing proteins binding acetylated proteins, including various cancers such as human NUT midline carcinoma, multiple myeloma, Burkitt's lymphoma, myeloid leukemia, NPM1c mutant leukemia, T-cell lymphoblastic leukemia, hepatocellular carcinoma, glioblastoma, neuroblastoma, sarcoma, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, neuroendocrine tumors, Merkel cell carcinoma, prostate cancer, ovarian cancer, and chordoma.
Treatment or prevention of inflammatory and autoimmune diseases including osteoarthritis, rheumatoid arthritis (e.g., juvenile rheumatoid arthritis), Alzheimer's disease, and HIV infection.
Treatment or prevention of systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism disorders, fibrosis, viral infections such as herpes virus, human papilloma virus, and adenovirus, and diseases involving ischemia-reperfusion injury such as myocardial infarction and stroke.
Use in combination therapy with chemotherapy, radiation therapy, gene therapy, or immunotherapy for treatment of various conditions.
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