Compounds, compositions, and methods for the treatment of disease
Inventors
Iyer, Radhakrishnan P. • Meher, Geeta • Sheri, Anjaneyulu • Zhou, Shenghua • Challa, Sreerupa • Gimi, Rayomand H. • Padmanabhan, Seetharamaiyer • Cleary, Dillon
Assignees
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Publication Number
US-11584774-B2
Publication Date
2023-02-21
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 provides compounds of Formula (II), or pharmaceutically acceptable salts or stereoisomers thereof, with a targeting moiety (Tm) and defined nucleobase units B1 and B2, where each is independently a purinyl nucleobase or a pyrimidinyl nucleobase. The scaffold includes heteroatom and linker elements X1/X2, Y1/Y2, Z1/Z2/Z3, T, L1-L5, Q1, and an oligopeptide L4 optionally substituted by one or more R16, together with defined substituent options R1-R16.
The Formula (II) scaffold defines connectivity through self-immolative group-containing Z4 and Z5 elements, spacer and linker groups, and a broad set of allowed alkylene, heteroalkylene, cycloalkylene, heterocyclyl, aryl, heteroaryl, and oligopeptide linkages. The disclosure also includes multiple defined terminal and substituent possibilities such as -OH, -N(R5)2, SR5, -CHO, -C(O)N(R5)2, and -OC(O)N(R5)2 within the structure framework.
The invention is directed to small molecules based on Formula (I)/(II) that are described as having antiviral activity and immune-modulating activity by stimulating innate immune pattern recognition receptors, including RIG-I, NOD2, and STING. The disclosure describes induction of endogenous type I interferons, including IFN-α and IFN-β, PRR expression including STING expression, and downstream signaling involving the cGAS-STING-IFN cascade, TBK1, and IRF3.
The disclosure further describes therapeutic methods in which administering the compounds results in immune modulation through inducing PRR expression in a targeted manner, including via an ADC framework as described in the document. The stated therapeutic scope includes viral infections, bacterial infections, and cancer, with use cases grounded in innate immune sensing, PRR expression induction, and type I interferon signaling.
Claims Coverage
The provided independent claim content centers on one compound claim for a Formula (II) scaffold. It combines a targeting moiety, defined nucleobase and heteroatom/linker elements, an oligopeptide L4, self-immolative group definitions, and extensive allowed substituent options across the scaffold.
Formula (II) targeted scaffold
A compound of Formula (II) (or a pharmaceutically acceptable salt or stereoisomer thereof) wherein Tm is a targeting moiety and the scaffold includes defined nucleobase and linker elements.
Nucleobase and heteroatom framework
B1 and B2 are independently a purinyl nucleobase or a pyrimidinyl nucleobase; X1 and X2 are independently O or S; Y1 and Y2 are independently O, S, or N(R5); and Z1 is independently O or S, with Z2 and Z3 independently absent or selected from specified connecting groups.
Self-immolative group and spacer architecture
Z4 and Z5 are defined as self-immolative group-containing or related moieties, T is a spacer group or absent, and L1, L2, L3, and L5 are absent or selected from specified alkylene, heteroalkylene, and related connectivity patterns.
Oligopeptide L4 optionally substituted by R16
L4 is an oligopeptide optionally substituted by one or more R16, and the claim includes L5 as a linker connecting Z4 and Z5 or absent.
Extensive substituent scope R1-R16
The claim defines allowed substituent sets for R1 through R16, including hydrogen, halo, CN, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and related functional groups within the Formula (II) structure.
The inventive coverage centers on a Formula (II) compound with a targeting moiety, defined nucleobase/heteroatom/linker components, an optionally substituted oligopeptide, self-immolative/linker moieties, and broad substituent chemistry, including salts and stereoisomers.
Stated Advantages
Antiviral activity.
Immune-modulating activity by stimulating innate immune pattern recognition receptors, including RIG-I, NOD2, and STING.
Induction of endogenous type I interferons, including IFN-α and IFN-β.
Induction of PRR expression, including STING expression.
Induction of PRR expression for immune modulation.
Activating host PRR pathways including STING, RIG-I, NOD2, and MDA5.
Inducing type I interferons (IFN-α and IFN-β) as an innate immune response.
Inducing controlled apoptosis of virus-infected cells.
Treatment of cancer using compounds of the stated formulae.
Providing vaccine-adjuvant compositions using Formula (I′) and Formula (II′) variants.
Immune responses including antitumoral immunity.
Documented Applications
Therapeutic use for viral infections across multiple virus classes.
Therapeutic use for bacterial infections.
Therapeutic use for cancer.
Immune modulation through inducing PRR expression in a targeted manner, including via an ADC framework as described in the document.
Methods of use for inducing PRR expression in a subject by administering a compound of Formula (I) or (II), including pharmaceutically acceptable salts, for viral conditions.
Methods of use for inducing PRR expression in a subject by administering a compound of Formula (I) or (II), including pharmaceutically acceptable salts, for bacterial conditions.
Methods of use for inducing PRR expression in a subject by administering a compound of Formula (I) or (II), including pharmaceutically acceptable salts, for cancer, including solid tumors.
An ADC (antibody drug conjugate) targeted delivery concept in connection with PRR expression and immune modulation for the listed therapeutic settings.
Vaccine-adjuvant use of compositions associated with Formula (I′) and Formula (II′) variants.
Therapeutic use in cancer through inducing PRR-mediated therapeutic responses.
Treatment aimed at inducing immune responses including antitumoral immunity.
In vitro immune-stimulation evaluation using THP1 dual reporter cells, measuring IRF and NF-κB induction with SEAP and Lucia reporter readouts.
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