Compounds, compositions, and methods for the treatment of disease
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Publication Number
US-11707531-B2
Publication Date
2023-07-25
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 compounds of Formula (II) and pharmaceutically acceptable salts or stereoisomers thereof, wherein Tm is a targeting moiety and B1 and B2 are purinyl nucleobase and pyrimidinyl nucleobase, or vice versa. The compound includes variable heteroatom selections across X1/X2, Y1/Y2, and Z1, and defines Z2, Z3, and Z4, including that Z4 is a self-immolative group or absent.
The disclosed scaffold further specifies linker architecture through T, L1-L4, Q1, and variable R groups. T is absent or a spacer group, L1 and L2 are absent or C1-C6 alkylene or C1-C6 heteroalkylene, L3 is an oligiopeptide-containing linker or a C1-C40 alkylene, C1-C40 heteroalkylene, C1-C40 alkenylene, or C1-C40 alkynylene, and L4 is absent or a linker connecting Z3 and Z4.
The patent also describes Formula (II) embodiments with specific targeting moiety types and additional structural options for the substituent variables, including R1-R8, R9, and R14. The document includes stereochemical scope such as racemates, enantiomers, and diastereomers, and describes compositions and uses associated with compounds of Formula (I) and/or Formula (II).
At the biological level, the document proposes host PRR activation, including STING, RIG-I, and NOD2, to induce type I IFNs, including IFN-α and IFN-β, and downstream immune effects. The document describes inducing PRR expression in targeted manners by administering the compounds to subjects having viral, bacterial, or cancer conditions, and discusses type I IFN signature formation.
Claims Coverage
The independent claim coverage centers on a compound of Formula (II) with one targeting moiety (Tm), two nucleobase units, and extensive structural variability across X1/X2, Y1/Y2, Z1/Z2/Z3/Z4, T, L1-L4, Q1, and R substituents. Across the provided claim content, the main inventive features are the Formula (II) scaffold, the selectable linker/self-immolative architecture, and the specified targeting moiety selections.
Compound of Formula (II) with targeting moiety and nucleobase units
A compound of Formula (II) including a targeting moiety (Tm), wherein B1 and B2 are purinyl and pyrimidinyl nucleobases in either order, and the compound is provided as a pharmaceutically acceptable salt or stereoisomer thereof.
Heteroatom-defined variable groups
Each of X1 and X2 is independently O or S, each of Y1 and Y2 is independently O, S, or N(R5), and each of Z1 is independently O or S.
Self-immolative group and linker architecture
Z2 is selected from defined oxygen, sulfur, carbonyl, sulfoxide, sulfone, amino-carbonyl, aryl, and heteroaryl options; Z3 is absent or selected from defined heterocyclyl, alkylene, hydroxyl, amino, carbonyl, aryl, heteroaryl, and related groups; and Z4 is a self-immolative group or absent, with T absent or a spacer group and L1-L4 defining the linker arrangement.
Oligiopeptide-linked linker unit and variable Q1
L3 is an oligiopeptide-containing linker or a C1-C40 alkylene, heteroalkylene, alkenylene, or alkynylene segment, optionally substituted by R14, and Q1 is C(O), C(S), or CH2.
Targeting moiety selection
Tm is a targeting moiety selected from an antibody, a hormone, a hormone derivative, folic acid, a folic acid derivative, biotin, a small molecule, an oligopeptide, a sigma-2 ligand, or a sugar.
The claims define a Formula (II) compound built around a targeting moiety, paired nucleobase units, and a highly variable linker/self-immolative framework. The scope is further shaped by defined heteroatom selections and substituent sets, with dependent claim content narrowing Tm to specific targeting classes.
Stated Advantages
Induces host pattern-recognition receptor (PRR) expression, including STING.
Activates innate immune response leading to type I interferon (IFN) production.
Promotes controlled apoptosis of virus-infected hepatocytes.
Provides immune-modulating antiviral activity.
Promotes type I IFN-linked antigen presentation and T-cell priming, including CD8+ T cells, for cancer immunotherapy.
Documented Applications
Treating microbial infection by inducing and/or activating innate immune pattern recognition receptors (PRRs) including STING and RIG-I/MDA5.
Treating cancer by inducing PRR expression and/or inducing and/or activating innate immune PRRs including STING and RIG-I/MDA5.
Vaccine and vaccine adjuvant compositions incorporating compounds of Formula (I) and/or Formula (II).
Treatment of viral infections via targeted PRR (STING) induction and innate immune activation leading to type I IFN production.
Treatment of bacterial infections via PRR activation involving nucleic acids/cyclic dinucleotides and peptidoglycan-related pathway components such as NOD2 and STING.
Cancer immunotherapy, including promoting type I IFN-linked antigen presentation and T-cell priming in the tumor microenvironment.
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