Methods and compositions for modulating splicing
Inventors
Luzzio, Michael • McCarthy, Kathleen • Haney, William
Assignees
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Publication Number
US-11091475-B2
Publication Date
2021-08-17
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 provides a method of treating a condition or disease of brain or the central nervous system (CNS) associated with aberrant splicing in a human subject in need thereof. The method comprises administering an effective amount of a pharmaceutical composition comprising a therapeutic agent and a pharmaceutically acceptable carrier, where the therapeutic agent comprises a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof. The therapeutic agent modulates splicing at a splice site sequence of a pre-mRNA in a cell of the subject, thereby treating the condition or disease.
The therapeutic agent is defined by structural features within Formula (IV), including ring Q and ring P as substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, X as —NR3— with R3 being methyl, Z as CR7 with R7 being H or D, and W as substituted or unsubstituted C1-C4 alkylene. Additional structural parameters include R being H, R15 and R18 each independently selected from H and methyl, R16 and R17 each being H, and stereochemical purity of at least 80%.
A central aspect is that the therapeutic agent penetrates the blood brain barrier (BBB) when administered to the subject, and splicing of the pre-mRNA at the splice site sequence is modulated to treat the condition or disease. In embodiments where the condition or disease of brain or the CNS is cancer, tumor growth is inhibited by at least 10% or a tumor is reduced in size. The description also links splicing modulation to nonsense-mediated degradation (NMD) of processed messenger RNA (mRNA), which decreases expression of a protein encoded by the processed mRNA.
Claims Coverage
1 independent claim is identified. It covers a method of treating a brain/CNS condition associated with aberrant splicing in a human by administering a pharmaceutical composition containing a therapeutic agent of Formula (IV) that penetrates the BBB and modulates pre-mRNA splicing at a splice site sequence, thereby treating the condition, with cancer embodiments requiring tumor growth inhibition or tumor size reduction. Dependent claims add specific splice site sequence options, quantitative BBB exposure, cell viability IC50, a dosing range, and an NMD-related effect.
Treating a brain/CNS condition associated with aberrant splicing via BBB-penetrant Formula (IV) splicing modulation
A method of treating a condition or disease of brain or central nervous system (CNS) associated with aberrant splicing in a human subject by administering an effective amount of a pharmaceutical composition comprising an effective dose of a therapeutic agent comprising a compound of Formula (IV) (or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable carrier; wherein the therapeutic agent modulates splicing at a splice site sequence of a pre-mRNA in a cell of the subject, and an effective amount of the therapeutic agent penetrates the blood brain barrier (BBB) when administered; wherein splicing of the pre-mRNA at the splice site sequence is modulated thereby treating the condition or disease; wherein the condition or disease of brain or the CNS is cancer and tumor growth is inhibited by at least 10% or a tumor is reduced in size.
Formula (IV) stereochemical purity and structural definition
The compound of Formula (IV) has a stereochemical purity of at least 80%, with structural definitions including ring Q and ring P being substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, X as —NR3— with R3 being methyl, Z as CR7 with R7 being H or D, W as substituted or unsubstituted C1-C4 alkylene, R as H, R15 and R18 each independently selected from H and methyl, and R16 and R17 each being H.
Specific splice site sequence pattern selection
The splice site sequence is selected from NGAgunvm, NHAdddddn, NNBnnnnnn, or NHAddmhvk, using defined letter-to-nucleotide mappings.
Quantified BBB exposure using unbound brain to unbound plasma AUC ratio
The therapeutic agent has an (unbound brain AUC)/(unbound plasma AUC) of at least about 0.3 after the effective dose is given.
Cell viability IC50 threshold for the Formula (IV) compound
The compound of Formula (IV) has a cell viability IC50 of at least 50 nM.
Therapeutic agent dosing range in the pharmaceutical composition
A pharmaceutical composition containing 1 to 1000 mg of the therapeutic agent.
NMD modulation causing decreased protein expression
The method modulates nonsense-mediated degradation (NMD) of processed messenger RNA (mRNA), thereby decreasing expression of a protein encoded by the processed mRNA.
Overall, the claim coverage centers on administering a BBB-penetrant Formula (IV) therapeutic agent with at least 80% stereochemical purity that modulates pre-mRNA splicing at a defined splice site sequence to treat a brain/CNS condition associated with aberrant splicing, including cancer with specified tumor-growth outcomes. Dependent claims further restrict the splice site sequence, specify BBB exposure, cell viability, dosing, and an NMD-linked decrease in protein expression.
Stated Advantages
Treats a condition or disease of brain or the CNS associated with aberrant splicing.
Penetrates the blood brain barrier (BBB) when administered.
Modulates splicing at a splice site sequence of a pre-mRNA, thereby treating the condition or disease.
For cancer, inhibits tumor growth by at least 10% or reduces tumor size.
The compound of Formula (IV) has stereochemical purity of at least 80%.
Modulates nonsense-mediated degradation (NMD) of processed messenger RNA (mRNA) to decrease expression of a protein encoded by that processed mRNA.
Documented Applications
Treating a condition or disease of brain or the central nervous system (CNS) associated with aberrant splicing in a human subject, including cancer with tumor growth inhibition by at least 10% or tumor size reduction.
Modulating splicing of pre-mRNA at a splice site sequence in cells of the subject to achieve treatment of the brain/CNS condition or disease.
Treating cancer in the brain or CNS, where tumor growth is inhibited by at least 10% or a tumor is reduced in size.
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