Methods and compositions for modulating splicing
Inventors
Luzzio, Michael • McCarthy, Kathleen • Haney, William
Assignees
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Publication Number
US-11434489-B1
Publication Date
2022-09-06
Expiration Date
Abstract
Described herein are small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded by genes, and methods of use of the small molecule splicing modulator compounds for modulating splicing and treating diseases and conditions.
Core Innovation
The invention relates to a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, having stereochemical purity of at least 80%. The compound is defined by a substituted bicyclic aryl or substituted fused bicyclic heteroaryl ring Q, with X selected from —O—, —S—, or —NR3—, Z defined as —CR7— with R7 being H, and W defined as substituted or unsubstituted C1-C4 alkylene.
The structural definition further specifies R as H and broad substituent options for R3, R1, and R11-R17, together with R15 and R18 selected from H and —CH3. The disclosure also provides fixed structural parameters a and b as 0 and c and d as 1, and includes optional isotopically labeled variants.
The disclosed compounds are described as small molecule splicing modulators (SMSMs) and as stereochemically defined pyridazinyl phenol derivatives. Example embodiments and characterization data are described for stereodefined azabicyclic-containing, pyridazinyl-linked bicyclic amine, and related heteroaryl-substituted compounds, including fluorinated or deuterated substituent variants.
Claims Coverage
The independent claim is clm-00001. It defines one stereochemically pure Formula (IV) compound family with a substituted bicyclic aryl or substituted fused bicyclic heteroaryl ring Q, defined linkage components X, Z, and W, broad substituent sets, and a stereochemical purity requirement of at least 80%.
Stereochemically pure Formula (IV) compound
A compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, having stereochemical purity of at least 80%.
Substituted bicyclic aryl or substituted fused bicyclic heteroaryl ring Q
Ring Q is substituted bicyclic aryl or substituted fused bicyclic heteroaryl.
Defined linkage pattern X, Z, and W
X is —O—, —S—, or —NR3—; Z is —CR7—; R7 is H; and W is substituted or unsubstituted C1-C4 alkylene.
Broad substituent set for R3, R1, and R11-R17
R is H; R3 is H, —OR1, —N(R1)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R11, R12, R13, R14, R16, and R17 are each independently selected from H, F, —OR1, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, and substituted or unsubstituted C1-C6 heteroalkyl; and R15 and R18 are selected from H and —CH3.
Defined R1 options and fixed parameters
R1 is H, D, substituted or unsubstituted C1-C6 alkyl, —CD3, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; a and b are each 0; c and d are each 1.
Pharmaceutical composition including the compound
A pharmaceutical composition comprising a compound according to the compound claim, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier or excipient.
Across the independent claim, the inventive scope centers on stereochemically pure Formula (IV) compounds with a defined bicyclic or fused bicyclic heteroaryl ring Q, fixed linkage selections for X, Z, and W, broad but enumerated substituent options, and the minimum stereochemical purity threshold of at least 80%.
Stated Advantages
Stereochemical purity of at least 80%.
Restores aberrant RNA/protein isoform levels by modulating pre-mRNA/mRNA splicing for treating, preventing, or delaying cancer and non-cancer diseases.
Documented Applications
Pharmaceutical compositions comprising the stereochemically pure Formula (IV) compound together with a pharmaceutically acceptable carrier or excipient.
Treating, preventing, or delaying cancer and non-cancer diseases by modulating pre-mRNA/mRNA splicing and restoring aberrant RNA/protein isoform levels.
Measuring and detecting SMSM-induced changes in RNA transcript levels and splice variants in biological samples using gene expression assays, including RNASeq, RT-PCR, RT-qPCR, microarrays, and next-generation sequencing.
Splicing modulation assays for MAPTau (MAPT), MADD, FOXM1, SMN2, and IKBKAP using cell-based RT-qPCR readouts, including dose-response effects and viability/proliferation readouts.
In vivo tumor growth inhibition with summarized CNS brain/plasma exposure metrics.
Treating disease by modulating aberrant mRNA splicing at splice sites.
Therapeutic areas described include cancer.
Therapeutic areas described include neurodegenerative diseases.
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