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
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11033569-B2
Publication Date
2021-06-15
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 invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, with structural choices for Z, B1 and B2, and variable heteroatom-containing linkers and substituents. Z is either S or O, with B1 being adeninyl and B2 being uracilyl, and the framework further specifies each of X1 and X2 as independently O or S, and Y1 and Y2 as S or NR5, with an alternative ordering option for Y1 and Y2.
The compounds include linker groups L1 and L2 that are independently absent, C1-C6 alkyl, or C1-C6 heteroalkyl, and substituent positions R1 through R9 are defined with allowed identities including hydrogen, halo, —CN, C1-C20 alkyl, OR7, oxo, cycloalkyl, heterocyclyl, aryl, heteroaryl, and multiple aryl/heteroaryl-linked variants. Optional substitution patterns are controlled by R8 and R9, and the description includes embodiment structures such as Formula (I-a) through Formula (I-g) with representative chemical structures and counterion or charge forms.
The disclosure frames these Formula (I) nucleoside-linked compound scaffolds in an immune-response context, including inducing immune responses associated with antitumoral immunity and PRR induction, including STING, RIG-I, and MDA5, together with related immune signaling markers such as IFN and NF-baB. The disclosure also describes therapeutic methods and immune-modulation methods in which the compounds are administered to induce PRR expression and related immune outcomes.
Claims Coverage
The independent claim coverage centers on a Formula (I) compound class with pharmaceutically acceptable salts and stereoisomers. The inventive features are expressed through a constrained nucleobase-like scaffold with defined heteroatom placements and extensive substituent variability, governed by Z, B1/B2, X1/X2, Y1/Y2, and the allowable substituent patterns for L1/L2 and R1-R9.
Formula (I) scaffold with adeninyl and uracilyl cores
A compound of Formula (I) wherein Z is either S or O, B1 is adeninyl, B2 is uracilyl, each of X1 and X2 is independently O or S, and Y1 and Y2 are defined as S or NR5 and O, S, or NR5 in the specified alternative pairing, including pharmaceutically acceptable salts or stereoisomers.
Linker selection by optional L1/L2 and R6 substitution
Each of L1 and L2 is independently absent, C1-C6 alkyl, or C1-C6 heteroalkyl, wherein each alkyl and heteroalkyl is optionally substituted with R6, with R6 defined as halo, —CN, C1-C20 alkyl, OR7, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
Substituent patterning via R1-R9 variability on the scaffold
R1 and R2 are each independently hydrogen, halo, —CN, C1-C20 alkyl, or OR7; R3 and R4 are each independently hydrogen, C1-C20 alkyl, OC(O)C1-C20 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R5 is hydrogen or C1-C20 alkyl; and R8 and R9 define optional substitution patterns over C1-C20 alkyl, heteroalkyl, carbonyl-linked, aryl, and heteroaryl variants.
Use for treating specific cancers by administering a therapeutically effective amount
A method of treating acute monocytic leukemia, lymphoma, melanoma, colon cancer, or breast cancer in a subject by administering a therapeutically effective amount of a compound of Formula (I).
Immune modulation by inducing pattern recognition receptor expression
A method of inducing expression of pattern recognition receptors (PRRs) for immune modulation in a subject by administering a therapeutically effective amount of a compound of Formula (I).
Overall claim coverage is directed to a structurally defined nucleobase-like compound class of Formula (I), characterized by adeninyl and uracilyl cores, S/O-controlled heteroatom positions, optional L1/L2 linkers bearing R6 substitution, and broad but enumerated substituent variability governed by R1-R9. The claim extends to pharmaceutically acceptable salts and stereoisomers, and also covers treatment of specified cancers and immune modulation by inducing PRR expression.
Stated Advantages
Inducing immune responses associated with antitumoral immunity and PRR induction, including STING, RIG-I, and MDA5.
Related immune signaling markers such as IFN and NF-baB are associated with the compounds.
Synergistic effects, including fold-activity improvements and/or reduced MIC or efficacious concentration when combined with an additional anticancer/immuno-oncology agent.
Additive effects when combined with additional anticancer/immuno-oncology agents.
Oral tolerability/maximum tolerated dose study reporting no adverse clinical signs.
Documented Applications
Treating acute monocytic leukemia, lymphoma, melanoma, colon cancer, or breast cancer in a subject.
Inducing expression of pattern recognition receptors (PRRs) for immune modulation in a subject.
Combination therapy use of a compound of Formula (I-a) together with an additional anticancer/immuno-oncology agent to achieve synergistic or additive effects, including immune checkpoint inhibitors such as PD-1/PD-L1 and anti-CTLA4, and CAR-T therapy.
Biological evaluation applications including ISG54 and NF-baB reporter assays in HEK293 cells, IRF-type I IFN activity evaluation in THP1-dual cells, STING binding readouts, IL-29 induction, gene expression of ISGs/PRR genes, tumor growth inhibition evaluation, and in vivo efficacy in a 4T1.luc2 murine breast carcinoma model with oral tolerability/maximum tolerated dose assessment with no adverse clinical signs.
Interested in licensing this patent?