Inhibitors of GLI1 as therapeutic agents
Inventors
Greenlee, William J. • van Drie, John • HUANG, Xinyan • SALZER, James • SHOHDY, Nadim
Assignees
Publication Number
US-12209092-B2
Publication Date
2025-01-28
Expiration Date
2039-11-19
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Abstract
This disclosure relates to compounds, pharmaceutical compositions comprising them, and methods of using the compounds and compositions for treating diseases related to glioma-associated oncogene (Gli) expression. More particularly, this disclosure relates to bicyclic compounds and pharmaceutical compositions thereof, methods of inhibiting Gli expression with these compounds, and methods of treating diseases related to Gli expression.
Core Innovation
This disclosure provides novel compounds, specifically bicyclic compounds of formula (I) and (II), and their pharmaceutically acceptable salts. These compounds function as inhibitors of the GLI1 transcription factor, which is part of the Hedgehog (Hh) signaling pathway. The patent also discloses pharmaceutical compositions containing these compounds and methods of inhibiting GLI1 expression through administration of these compositions or compounds.
The invention addresses the problem of diseases related to aberrant GLI1 expression, including cancers characterized by elevated GLI1 and neurological disorders associated with myelin loss or deficiency. The background explains that disruptions in the Hh/GLI pathway contribute to the initiation, proliferation, and maintenance of cancer stem cells, as well as to disorders of myelination in the nervous system such as multiple sclerosis and various inherited or acquired neuropathies.
The disclosed compounds are designed to inhibit GLI1 and/or GLI2 with low-micromolar to sub-micromolar IC50, offering new therapeutic agents for conditions involving upregulated GLI1 signaling. The disclosure includes the structure, preparation, and specific examples of these compounds, as well as pharmaceutical compositions and methods of their therapeutic use in diseases related to GLI expression.
Claims Coverage
The claims establish two main inventive features centered around novel compounds of formula (II) as GLI1 inhibitors and their pharmaceutical compositions.
Compounds of formula (II) with specific structural features
These are compounds of the formula (II): - The variable t is an integer (1 or 2). - R11 and R12 are defined as hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, heterocyclyl, hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), —OH, or oxetanyl. - Ring X represents an aryl or heteroaryl, optionally substituted with one or more R13. R13 is defined broadly and includes halogen, nitro, cyano, alkyl, haloalkyl, amino, various oxygen and sulfur-containing substituents, aryl, heteroaryl, heterocyclyl, and cycloalkyl groups, among others. - Rings Y and Z together form a bicyclic moiety (such as isoindolin-2-yl, 3,4-dihydroisoquinolin-2(1H)-yl, and related structures) optionally substituted with groups defined as R14, which may include halogen, nitro, cyano, alkyl, and other diverse residues. - The group also explicitly claims specific example compounds, including but not limited to: 8-chloro-2-(2-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-6-yl)-1,2,3,4-tetrahydroisoquinoline; 6-(4-chloroisoindolin-2-yl)-2-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole; and other listed chemical structures from claim 5. - The compounds may exist as pharmaceutically acceptable salts.
Pharmaceutical compositions containing the claimed compounds
This feature covers pharmaceutical compositions comprising one or more of the claimed compounds of formula (II) and a pharmaceutically acceptable carrier, solvent, adjuvant, or diluent.
In summary, the inventive features focus on new GLI1 inhibitor compounds with defined structural motifs and their use in pharmaceutical compositions, broadening potential therapeutic tools against diseases involving aberrant GLI1 activity.
Stated Advantages
The compounds inhibit GLI1 and/or GLI2 with low-micromolar and sub-micromolar IC50, allowing for potent GLI inhibition.
Compositions and methods provide improvements in the treatment of diseases or disorders associated with GLI1 and/or GLI2 expression.
The disclosure provides a method for enhancing remyelination and neuroprotection in the central and peripheral nervous systems.
Documented Applications
Treatment of neurological disorders characterized by myelin loss or myelin deficiency, including multiple sclerosis, central pontine myelinolysis, acute disseminated encephalomyelitis, progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis, post-infectious encephalomyelitis, chronic inflammatory demyelinating polyneuropathy, Devic's disease, Balo's concentric sclerosis, leukodystrophies, optic neuritis, transverse myelitis, cerebral palsy, spinal cord injury, age-associated myelin deficiency, Alzheimer's Disease, and acquired and inherited neuropathies in the peripheral nervous system.
Treatment of cancers, including those characterized by elevated GLI1, such as breast cancer, pancreatic cancer, colon cancer, lung cancer, rhabdomyosarcoma, basal-cell carcinoma, glioblastoma, medulloblastoma, leukemia, prostate cancer, skin cancer, lymphoma, esophageal cancer, ovarian cancer, thyroid cancer, osteosarcoma, liver cancer, multiple endocrine neoplasia, gastrointestinal cancer, and mesothelioma.
Treatment of non-CNS diseases such as cystic kidney disease, chronic liver disease, Hepatitis C, obstructive pulmonary disease, organ fibrosis (kidney, cardiac, pulmonary), and rheumatoid arthritis.
Inhibiting GLI1 expression in treated subjects.
Enhancing remyelination and neuroprotection of central nervous system or peripheral nervous system neurons.
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