Quinolinones as inhibitors of translation initiation complex
Inventors
Ronai, Ze'ev • Pinkerton, Anthony B. • FENG, Yongmei • TOPISIROVIC, Ivan • Brown, Kevin • Hassig, Christian A.
Assignees
Royal Institution for the Advancement of Learning • Sanford Burnham Prebys Medical Discovery Institute • US Department of Health and Human Services
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Publication Number
US-10577349-B2
Publication Date
2020-03-03
Expiration Date
2036-03-01
Abstract
Provided herein are compounds and pharmaceutical compositions comprising quinolinones. The quinolinones and compositions thereof are useful as eukaryotic translation initiation factor 4F (eIF4F) complex modulators.
Core Innovation
The invention provides compounds and pharmaceutical compositions comprising quinolinones that function as modulators of the eukaryotic translation initiation factor 4F (eIF4F) complex. These compounds and compositions are useful for treating diseases mediated by altered translation initiation, specifically targeting eIF4G within the eIF4F complex. The disclosure includes methods of treating cancer, especially resistant cancers, using these compounds alone or in combination with BRAF or MEK inhibitors.
The problem addressed by this invention is the deregulation of cap-dependent translation associated with cancer initiation and progression. Specifically, the rate-limiting step of protein synthesis involves the loading of ribosomes onto mRNA templates stimulated by the eIF4F complex, which is a pivotal target for anticancer drug discovery due to its role in the TOR signaling pathway. Existing cancer therapies, such as BRAF or MEK inhibitors, often face issues with resistance. Thus, disrupting the eIF4F complex, particularly eIF4G, provides a strategy to potentiate existing therapies and overcome drug resistance, addressing significant unmet clinical needs in cancer treatment.
Claims Coverage
The patent includes one independent claim that covers compounds of Formula (Ia-1′) or Formula (Ia-1″), pharmaceutical compositions containing these compounds, and methods of treating cancer using these compounds.
Compound of Formula (Ia-1′) or (Ia-1″)
Claims a compound of Formula (Ia-1′) or Formula (Ia-1″), or pharmaceutically acceptable salt, solvate, tautomer, or N-oxide thereof, characterized by specific structural features including variations in moieties A, B, R1, R2, and heteroatoms in defined positions.
Specific structural substitutions
Includes embodiments where B is —C(═O)—, A is —CH═CH—, and R2 is halogen, specifically chloro, defining chemical modifications that distinguish the compound.
Pharmaceutical composition comprising Formula (Ia-1′) or (Ia-1″) compound
Composition comprising the compound of Formula (Ia-1′) or (Ia-1″), or a pharmaceutically acceptable salt, solvate, tautomer, or N-oxide thereof, along with pharmaceutically acceptable excipients.
Method of treating cancer
Method comprising administering the compound of Formula (Ia-1′) or Formula (Ia-1″), or pharmaceutically acceptable derivatives thereof, to a subject in need thereof for cancer treatment.
Treatment of resistant cancer types
The method includes treatment of resistant cancers, particularly melanoma, prostate cancer, pancreatic cancer, and colorectal cancer, indicative of targeted clinical use.
The independent claims cover synthesis and pharmaceutical compositions of defined quinolinone compounds targeting eIF4G in the eIF4F complex, and methods of treating cancer, particularly resistant forms, with these compounds, alone or in combination with other inhibitors.
Stated Advantages
Disrupting the eIF4F complex offers an appealing strategy to potentiate the effectiveness of existing cancer therapies and to overcome resistance to drugs such as BRAF or MEK inhibitors.
Documented Applications
Treatment of cancer mediated by altered translation initiation via targeting of eIF4G.
Treatment of resistant cancers, including melanoma, prostate cancer, pancreatic cancer, and colorectal cancer.
Combination therapy with BRAF or MEK inhibitors to enhance treatment effectiveness.
Treatment of cancer mediated by inhibition of AKT, NFκB, or mTOR components.
Treatment of cancer mediated by inhibition of DNA damage response and DNA repair activities.
Treatment of cancer mediated by inhibition of cell growth and induction of cell death.
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