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Publication Number
US-11129829-B2
Publication Date
2021-09-28
Expiration Date
Abstract
Described herein are methods of use of small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded by genes, and methods of treating diseases and conditions associated with gene expression or activity of proteins encoded by genes.
Core Innovation
The invention relates to decreasing expression of a target protein by contacting a small molecule splicing modulator (SMSM) with a pre-mRNA encoding the target protein or a cell comprising the pre-mRNA. The pre-mRNA comprises a splice site with the sequence GAguaag, and the SMSM binds to the pre-mRNA and modulates splicing at that splice site to generate a spliced product that comprises a poison exon. The spliced product undergoes nonsense-mediated mRNA decay (NMD), resulting in decreased expression of the target protein compared to the pre-mRNA or cell not contacted with the SMSM.
The SMSM is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, with stereochemical purity of at least 80%. The disclosed Formula (IV) includes defined structural variables and ring features, including ring Q as 2-hydroxy-phenyl substituted with heteroaryl having 5 or 6 ring atoms and optionally substituted, together with additional substituent constraints and linkage options.
The broader description situates these small molecule splicing modulators within spliceosome and alternative splicing biology, including cis-acting splice-site elements and poison exon inclusion linked to nonsense-mediated mRNA decay. The document also refers to broader treatment concepts tied to effective amount and restoring normal transcript, isoform, or protein levels.
Claims Coverage
The provided material includes one independent claim that defines a method for decreasing target protein expression by SMSM-mediated splicing at a GAguaag splice site to generate a poison exon-containing spliced product that undergoes NMD, with the SMSM restricted to Formula (IV) compounds (or pharmaceutically acceptable salts or solvates) having stereochemical purity of at least 80%.
SMSM-mediated splicing at GAguaag to generate a poison exon
Contacting a small molecule splicing modulator (SMSM) with a pre-mRNA encoding the target protein or a cell comprising the pre-mRNA, wherein the pre-mRNA comprises a splice site with the sequence GAguaag, and the SMSM binds to the pre-mRNA and modulates splicing at the splice site to generate a spliced product comprising a poison exon.
Poison-exon spliced product undergoes nonsense-mediated mRNA decay
The spliced product that comprises a poison exon undergoes nonsense-mediated mRNA decay (NMD), and expression of the target protein encoded by the spliced product is decreased compared to the pre-mRNA or cell not contacted with the SMSM.
Formula (IV) SMSM with stereochemical purity at least 80%
The SMSM is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, with defined substituent and ring-variable constraints and stereochemical purity of at least 80%.
Overall, the claim coverage centers on SMSM binding to a GAguaag splice site to produce a poison exon-containing spliced product that undergoes NMD and decreases target protein expression, using an SMSM limited to Formula (IV) compounds (or salts/solvates) with at least 80% stereochemical purity.
Stated Advantages
Decreases expression of the target protein compared to the pre-mRNA or cell not contacted with the SMSM.
Decreases expression of the target protein by producing a poison exon-containing spliced product that undergoes nonsense-mediated mRNA decay (NMD).
Documented Applications
Modulating splicing at a GAguaag splice site to generate a poison exon that undergoes NMD.
Restoring normal transcript, isoform, or protein levels.
Target genes/diseases listed in the document, including EXOC3, ARID1B, POLQ, WRN, PDE7A, GCFC2, ZMYM6, FHOD3, and CTNS.
Tumor-related contexts, including tumor killing/viability and tumor size/growth inhibition.
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