Small molecule BET bromodomain inhibitors and uses thereof
Inventors
Strovel, Jeffrey William • Yoshioka, Makoto • Maloney, David J. • Yang, Shyh • Jadhav, Ajit • Urban, Daniel Jason
Assignees
Convergene LLC • ConverGene LLC • US Department of Health and Human Services
Publication Number
US-11028079-B2
Publication Date
2021-06-08
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 present invention relates to compounds that bind to and modulate the activity of bromodomain-containing proteins, particularly compounds of Formula I and their pharmaceutically acceptable salts, solvates, polymorphs, isomers, and prodrugs. These compounds inhibit bromodomain-containing proteins from binding acetylated proteins, including acetylated histones involved in the regulation or dysregulation of gene expression. The invention also encompasses pharmaceutical compositions containing these compounds and methods of using them to treat a variety of medical conditions, diseases, or disorders.
The background identifies the problem that bromodomain-containing proteins, especially BET family proteins such as BRD2, BRD3, BRD4, and BRDT, bind acetylated lysine residues on histones and thereby facilitate open chromatin structure and transcription initiation. Dysregulation of bromodomain-containing proteins is implicated in cancers, inflammation, metabolic, cardiovascular, neurodegenerative, psychiatric and infectious diseases. Existing cancer treatments like histone deacetylase (HDAC) inhibitors address some epigenetic changes but lack compounds directly antagonizing proteins encoded by MYC genes, which are often overexpressed in cancers and indirectly regulated by BET proteins. Thus, there is a need for pharmacological inhibition of bromodomain-containing proteins, specifically BET proteins, to indirectly suppress oncogenes such as MYC and provide effective treatment for various diseases.
Claims Coverage
There are multiple inventive features claimed in the patent covering compounds, pharmaceutical compositions, and therapeutic methods involving bromodomain-containing protein modulation.
Compounds of Formula I
Compounds of Formula I or pharmaceutically acceptable salts or isomers thereof that inhibit bromodomain-containing proteins' binding to acetylated proteins.
Heterocyclic ring system formation by R1 and R2
In some compounds, R1 and R2 together with the included nitrogen atom and linker L1 form a 4-, 5-, 6- or 7-membered heterocyclic or heteroaryl ring system optionally substituted with one or more R8 groups.
Variable functional groups on Y
The substituent Y in compounds of Formula I is selected from groups including NR6R7, —C(O)R11, —C(O)NR11R12, heterocycloalkyl, heteroaryl, and other substituents as defined, optionally substituted by one or more R8.
Substituents R3 and R4 variations
R3 and R4 in compounds of Formula I are independently selected from various functional groups including hydrogen, alkyl, heterocycloalkyl, heteroaryl, aryl, cycloalkyl and other defined groups, optionally substituted by one or more R8.
Pharmaceutical compositions
Pharmaceutical compositions comprising a compound of Formula I or pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.
Therapeutic methods for treating diseases involving bromodomain proteins
Methods for treating diseases or conditions associated with bromodomain-containing proteins by administering compounds of Formula I or their salts, wherein the compounds inhibit the activity of bromodomain-containing proteins by preventing their binding to acetylated proteins.
Treatment methods for various diseases
Methods wherein the disease or condition treated is selected from 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, ovarian cancer, chordoma, neuroendocrine tumors, Merkel cell carcinoma, prostate cancer, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, HIV infection, and fibrotic conditions including idiopathic pulmonary fibrosis, renal fibrosis, and cardiac fibrosis.
The claims cover compounds characterized by specific substituents and ring systems that inhibit bromodomain-containing proteins binding to acetylated proteins, their pharmaceutical formulations, and methods for treating multiple diseases mediated by such proteins using these compounds.
Stated Advantages
The compounds provide a new mode of pharmacological intervention for diseases involving bromodomain-containing proteins.
They offer an effective means for indirect suppression of MYC gene expression by inhibiting BET bromodomains.
They can be used to treat a wide variety of conditions including cancers, inflammation, fibrotic disorders, autoimmune diseases, infectious diseases, and neurodegenerative diseases.
Documented Applications
Treatment or prevention of cancers including 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, ovarian cancer, chordoma, neuroendocrine tumors, Merkel cell carcinoma, and prostate cancer.
Treatment or prevention of autoimmune and inflammatory diseases such as osteoarthritis and rheumatoid arthritis (including juvenile rheumatoid arthritis).
Treatment or prevention of neurodegenerative diseases including Alzheimer's disease.
Treatment or prevention of infectious diseases including HIV infection and viral infections such as herpes virus, human papilloma virus, adenovirus, and poxvirus.
Treatment or prevention of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, cardiac fibrosis, cystic fibrosis lung inflammation, and liver fibrosis.
Treatment or prevention of systemic inflammatory response syndrome and related conditions including sepsis, burns, pancreatitis, and major trauma.
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