Compounds,compositions, and methods for the treatment of disease
Inventors
Iyer, Radhakrishnan P. • Sheri, Anjaneyulu • Padmanabhan, Seetharamaiyer • Meher, Geeta • Zhou, Shenghua • Challa, Sreerupa • Gimi, Rayomand H. • Cleary, Dillon
Assignees
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Publication Number
US-11744845-B2
Publication Date
2023-09-05
Expiration Date
Abstract
Disclosed are compounds and compositions for the activation or induction of expression of a pattern recognition receptor (e.g., STING, RIG-I, MDA5), and methods of use thereof.
Core Innovation
The disclosure relates to cyclic dinucleotide compounds, including compounds of Formula (I) and Formula (I-a), subformulas, variants such as (I-b) through (I-g), and pharmaceutically acceptable salts and stereoisomers. The compounds comprise selectable substituents, structural definition parameters, nucleoside-linked compounds, variable linker and labile groups, nucleobase units, and diversified substituents, with modified nucleobases explicitly enumerated.
The disclosure relates to innate immune response pathways and immune modulators acting through PRR activation, including STING, RIG-I, MDA5, and NOD2. The cyclic dinucleotide compounds are described as inducing signaling pathways associated with TBK1, IRF3, NF-κB, and type I interferons (IFN-α/IFN-β), with immune signaling, apoptosis, and inhibition of tumor growth.
Methods are described for inducing PRR and immune responses in subjects with cancer, including solid tumors and broad cancer types, and the compounds are described in connection with cancer treatment, including PD-1 resistant tumor contexts. The disclosure further describes combination therapy with additional agents, including anti-cancer agents and immuno-oncology agents, and use as vaccine adjuvants for antitumoral immunity.
Claims Coverage
The merged claim coverage centers on selecting a compound from a disclosed group or formula, extending that coverage to pharmaceutically acceptable salts. Across the inputs, the independent claim scope also includes nucleoside-linked compound formulas and method-of-treatment uses; five recurring inventive features are present.
Selected cyclic dinucleotide compounds and pharmaceutically acceptable salts
A compound selected from the group consisting of the specified options, or a pharmaceutically acceptable salt thereof.
Nucleoside-linked compound formula
Nucleoside-linked compounds of Formula (I) and subformulas, with variable linker and labile groups, nucleobase units, and diversified substituents.
Depicted chemical structure for the selected compound
The compound is defined by the specific depicted chemical structure, together with a pharmaceutically acceptable salt thereof.
Cancer treatment by administering an effective amount
A method for treating cancer comprising administering an effective amount of the compound or a pharmaceutically acceptable salt thereof.
Pharmaceutically acceptable salt or non-salt embodiment using variable X
The compound is defined using variable X as any pharmaceutically acceptable counterion, including salt forms, with the compound also described as a free acid or free base in some embodiments.
Overall, the claim coverage centers on compounds selected from specified groups or depicted structures, nucleoside-linked compound formulas, pharmaceutically acceptable salts and counterion variable X embodiments, and methods of treating cancer by administering an effective amount, including colon cancer and breast cancer.
Stated Advantages
Immune modulation through PRR activation, including STING, RIG-I, MDA5, and NOD2.
Induction of PRR and immune responses in subjects with cancer.
Additive versus synergistic effects are evaluated for the combination therapy, including reduced effective concentrations and fold increases in activity.
Antiviral and innate immune response activation involving type I interferons (IFN-α/IFN-β).
The disclosure reports reduced minimum inhibitory concentration (MIC) in the combined-use evaluation.
Documented Applications
Cancer treatment, including methods for treating colon cancer and breast cancer.
Cancer treatment by administering an effective amount of the compound or a pharmaceutically acceptable salt, including acute monocytic leukemia, lymphoma, melanoma, colon cancer, and breast cancer.
Use as vaccine adjuvants for antitumoral immunity.
Use in contexts described as PD-1 resistant tumor.
Combination therapy of a compound of Formula (I-a) or a pharmaceutically acceptable salt with an additional agent.
Anti-cancer use cases explicitly described for additional agents, including immuno-oncology agents such as immune checkpoint inhibitors, PD-1/PD-L1 and anti-CTLA4 antibodies, and CAR-T therapy.
Inducing PRR and immune responses by administering compounds of Formula (I) or Formula (I-a), including immune response components involving STING and other PRRs such as RIG-I and MDA5.
Antitumoral immunity associated with administering the disclosed compounds.
Tumor growth inhibition in a 4T1.luc2 breast carcinoma model.
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