Methods and compositions for modulating splicing
Inventors
Luzzio, Michael • McCarthy, Kathleen • Haney, William
Assignees
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Publication Number
US-11021708-B2
Publication Date
2021-06-01
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 modulating splicing of a pre-mRNA at a splice site sequence comprising a bulged nucleotide positioned at the -1 position relative to a splice site, or at the -21 or -1 position relative to a splice site. The method includes contacting the pre-mRNA or cells comprising the pre-mRNA with an agent that binds to the pre-mRNA and modulates splicing of the pre-mRNA.
The agent comprises a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof. The compound of Formula (IV) is defined by ring Q as substituted 2-hydroxy-phenyl or substituted bicyclic aryl or heteroaryl, X as -NR3-, R3 as unsubstituted C1-C2 alkyl or unsubstituted C3 cycloalkyl, Z as CR7, and R7 as H or D.
The Formula (IV) framework further defines W as unsubstituted C2-C3 alkylene or C2 heteroalkylene, R as H, R15 and R18 as each independently selected from H and methyl, R16 and R17 as each H, and parameters a = 0, b = 0, c = 1, and d = 1. The compound of Formula (IV) has a stereochemical purity of at least 80%, and dependent refinements specify bulged nucleotide identity, splice-site sequence variants, and modulation of NMD without inhibiting NMD.
Claims Coverage
The independent claim coverage centers on a method of modulating splicing at a splice site sequence containing a bulged nucleotide at the -1 position or the -21 or -1 position, using an agent that binds pre-mRNA. The agent is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate, with specified structural selections and a stereochemical purity of at least 80%. Dependent claims further refine the bulged nucleotide identity, splice-site sequence variants, splicing outcome, and NMD-associated modulation.
Bulged nucleotide splice-site splicing modulation at the -21 or -1 position
A method of modulating splicing of a pre-mRNA at a splice site sequence comprising a bulged nucleotide positioned at the -21 or -1 position relative to a splice site, by contacting the pre-mRNA or cells comprising the pre-mRNA with an agent that binds to the pre-mRNA and modulates splicing of the pre-mRNA.
Formula (IV) agent with defined ring and substituent framework
The agent comprises a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein ring Q is substituted 2-hydroxy-phenyl or substituted bicyclic aryl or heteroaryl, X is -NR3-, R3 is unsubstituted C1-C2 alkyl or unsubstituted C3 cycloalkyl, Z is CR7, R7 is H or D, W is unsubstituted C2-C3 alkylene or C2 heteroalkylene, R is H, R15 and R18 are each independently selected from H and methyl, R16 and R17 are each H, and a = 0, b = 0, c = 1, and d = 1.
At least 80% stereochemical purity for Formula (IV)
The compound of Formula (IV) has a stereochemical purity of at least 80%.
NMD-associated splicing modulation without inhibiting NMD
Splicing is modulated by modulating NMD of an mRNA processed from an intron splice site sequence, without inhibiting NMD, to increase splicing and thereby decrease expression of a target protein encoded by the processed mRNA.
Overall, claim coverage is directed to splicing modulation at a bulged-nucleotide splice site using a Formula (IV) agent that binds pre-mRNA and meets a stereochemical purity threshold of at least 80%. The claims further include refinements to sequence context, bulged nucleotide identity, increased splicing, and NMD-linked modulation without NMD inhibition.
Stated Advantages
Increases splicing at a splice site sequence in the context of NMD modulation without inhibiting NMD.
Decreases expression of a target protein encoded by the processed mRNA when splicing is increased via NMD modulation without inhibiting NMD.
Modulates splicing of a pre-mRNA at a splice site sequence comprising a bulged nucleotide at a defined position.
The agent binds the pre-mRNA and modulates splicing.
Documented Applications
Modulating splicing of pre-mRNA at a splice site sequence comprising a bulged nucleotide by contacting the pre-mRNA or cells comprising the pre-mRNA with an agent that binds the pre-mRNA.
Modulating splicing through NMD of an mRNA processed from an intron splice site sequence, without inhibiting NMD, to increase splicing and decrease expression of a target protein encoded by the processed mRNA.
Modulating alternative splicing of numerous pre-mRNAs, including MAPT (tau) exon 10 alternative splicing to shift 3R/4R tau isoform ratios in tumor cells.
Treat diseases by modulating splicing of pre-mRNA/mRNA using small molecule splicing modulator compounds (SMSMs).
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