Mutant IDH1 inhibitors useful for treating cancer
Inventors
Boxer, Matthew Brian • Rohde, Jason Matthew • Pragani, Rajan • Liu, Li • Davis, Mindy Irene Emily • Brimacombe, Kyle Ryan • Shen, Min • Simeonov, Anton • Karavadhi, Surendra • Urban, Daniel Jason • Jadhav, Ajit • Wang, Xiaodong • McIver, Andrew Louis
Assignees
University of North Carolina at Chapel Hill • US Department of Health and Human Services
Publication Number
US-10703746-B2
Publication Date
2020-07-07
Expiration Date
2035-12-22
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Abstract
Compounds of Formula I and Formula II and the pharmaceutically acceptable salts thereof are disclosed The variables A, B, Y, Z, X1, X2, R1-4 and R13-18 are disclosed herein. The compounds are useful for treating cancer disorders, especially those involving mutant IDH1 enzymes. Pharmaceutical compositions containing compounds of Formula I or Formula II and methods of treatment comprising administering compounds of Formula I and Formula II are also disclosed.
Core Innovation
The invention discloses compounds of Formula I and Formula II and their pharmaceutically acceptable salts which act as mutant IDH1 inhibitors. These compounds, pharmaceutical compositions containing them, and methods of treatment comprising the administration of such compounds are provided. The compounds are specifically useful for treating cancer disorders associated with mutant IDH1 enzymes, especially those with mutations such as IDH1 R132H and R132C, which confer a gain-of-function to catalyze the NADPH-dependent reduction of α-ketoglutarate to the oncometabolite R-2-hydroxyglutarate (2HG).
Mutant IDH1 enzymes are involved in various cancers including glioma, acute myelogenous leukemia, sarcoma, and others. The elevated levels of 2HG resulting from the mutant enzymes contribute to tumor development by mechanisms such as histone hypermethylation, inhibition of cell differentiation, and increased cancerous cell development. The invention addresses the need for inhibitors of mutant IDH1 that can reduce 2HG production, thereby potentially reducing the population of undifferentiated tumor cells and treating the associated cancers.
Claims Coverage
This patent includes multiple independent claims focusing on novel compounds of Formula IA, their specific molecular substitutions, pharmaceutical compositions containing these compounds, and methods of treating cancers characterized by IDH1 mutations. The main inventive features center on the chemical structure of the compounds and their use as targeted cancer therapeutics.
Compounds of Formula IA with defined substitution patterns
The invention provides compounds of Formula IA characterized by specific substituents where R1 is a phenyl or pyridyl group substituted with 0-3 groups selected from hydroxyl, halogen, cyano, nitro, various alkyl, haloalkyl, cycloalkyl, phenyl, oxyphenyl, and amide groups. R2 is an alkyl, alkenyl, alkynyl, or cycloalkyl group. R3 is a carboxamide substituent and R4 is hydrogen or an alkyl group. The ring systems A and B have detailed heteroaryl or phenyl substitution patterns including halogen, cyano, alkyl, alkoxy, haloalkyl and more.
Pharmaceutical compositions containing compounds of Formula IA
The invention covers pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt of Formula IA together with a pharmaceutically acceptable carrier suitable for administration to patients.
Methods of treating cancers with mutant IDH1 inhibitors
Methods of treating cancers characterized by presence of mutant IDH1 enzyme with the ability to catalyze NADPH-dependent reduction of α-ketoglutarate to R-2-hydroxyglutarate by administering compounds or pharmaceutically acceptable salts of Formula IA. Specific embodiments include treatment of cancers such as glioma, acute myelogenous leukemia, non-Hodgkin lymphoma, melanoma, and others using these inhibitors. The compounds are indicated to target mutated forms like IDH1 R132H and R132C.
The claims collectively cover novel mutant IDH1 inhibitor compounds with detailed structural definitions, pharmaceutical formulations containing these compounds, and therapeutic methods employing these compounds to treat a range of cancers characterized by mutant IDH1 enzymatic activity.
Stated Advantages
Inhibition of mutant IDH1 reduces levels of the oncometabolite 2HG, which is linked to elevated cancer risk, thus potentially reducing undifferentiated cancer cell populations.
Targeting mutant IDH1 is expected to have little effect on non-cancerous cells, resulting in lower toxicity compared to typical cytotoxic anticancer agents.
Documented Applications
Treatment of cancers characterized by mutant IDH1 enzyme activity resulting in production of 2HG.
Therapeutic use in cancers including glioma (glioblastoma), acute myelogenous leukemia, acute myeloid leukemia, myelodysplastic/myeloproliferative neoplasms, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin lymphoma, astrocytoma, melanoma, non-small cell lung cancer, cholangiocarcinomas, chondrosarcoma, and colon cancer.
Use in veterinary applications for treatment of various mammals, including companion animals and livestock.
Diagnostic and research applications utilizing detection of 2HG in biological samples to assess treatment efficacy and cancer presence.
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