Methods and compounds for stimulating read-through of premature termination codons

Patent metadata

Field	Value
Publication number	US-10960018-B2
Application number	US-201716093516-A
Country	US
Kind code	B2
Filing date	Apr 17, 2017
Priority date	Apr 15, 2016
Publication date	Mar 30, 2021
Grant date	Mar 30, 2021

Abstract

The present disclosure provides compositions and methods for treating and/preventing diseases and conditions associated with premature termination mutations. The methods disclosed herein comprise the step of administering to the subject a therapeutically effective dose of a compound described herein that induces read-through of the premature termination codon. The methods of the present disclosure may further comprise treating the subject with enzyme replacement therapy wherein the enzyme replacement therapy is selected for the disease or condition to be treated. Furthermore, the present disclosure provides method of pharmacologically suppressing premature termination codons in a subject in need of such suppression.

First claim

What is claimed:

1. A method for treating Hurler syndrome mediated by the presence of a premature termination codon, the method comprising the step of stimulating read-through of the premature termination codon by administering to the subject a therapeutically effective amount of a compound that stimulates the read-through of the premature termination codon in the subject, the compound selected from the group consisting of: escin, a compound of the formula IIa, or a pharmaceutically acceptable salt, hydrate or solvate of any of the foregoing:

wherein
R 1 , R 2 and R 3 are each independently selected from the group consisting of: —H, alkyl, alkenyl, alkanoyl and alkenoyl; and
R 4 is selected from the group consisting of: a linear saccharide chain of 1-11 saccharide units, a branched saccharide chain of 1-11 saccharide units and —H.

2. The method of claim 1 , wherein the compound is the compound of formula IIa, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

3. The method of claim 2 , wherein
R 1 is selected from the group consisting of: —H, alkyl, alkenyl, acetyl, hexanoyl, benzoyl, ethylbutyryl, ethanoyl, propionyl, isobutyryl, butyryl, angeloyl, tigoyl, senecioyl, crotonoyl, 3,3-Dimethylartyloyl, cinnamoyl, pentenoyl, 2-propenoyl, (2E)-2-pentenoyl and 4-pentenoyl;
R 2 is acetyl or —H; and
R 3 is —H or acetyl.

4. The method of claim 2 , wherein
R 1 is selected from the group consisting of: angeloyl and tigoyl;
R 2 is acetyl; and
R 3 is —H.

5. The method of claim 2 , wherein
R 1 is selected from the group consisting of: angeloyl, and tigoyl;
R 2 is —H; and
R 3 is acetyl.

6. The method of claim 2 , wherein R 4 is:

7. The method of claim 2 , wherein the compound has the formula Ia:

wherein:
R 1 is selected from the group consisting of: angeloyl and tigoyl;
R 2 is selected from the group consisting of: acetyl and —H; and
R 3 is selected from the group consisting of: acetyl and —H.

8. The method of claim 7 , wherein R 1 is tigoyl, R 2 is acetyl and R 3 is —H, R 1 is angeloyl, R 2 is acetyl and R 3 is —H, R 1 is tigoyl, R 2 is —H and R 3 is acetyl, R 1 is angeloyl, R 2 is —H and R 3 is acetyl or a combination of the foregoing.

9. The method of claim 1 , wherein the administering increases the stability of a mRNA containing the premature termination codon.

10. The method of claim 1 , wherein the premature termination codon is selected from the group consisting of: W402X, Q70X, R628X, Q148X, E404X, Y343X and Q548X.

11. The method of claim 1 further comprising administering a secondary agent to the subject.

12. The method of claim 11 , wherein the secondary agent is an NMD inhibitor, a histone deacetylase inhibitor combination of the foregoing.

13. A method for pharmacologically suppressing a premature termination codon associated with Hurler syndrome in a subject, the method comprising the step of stimulating read-through of the premature termination codon by administering to the subject a therapeutically effective amount of a compound that stimulates the read-through of the premature termination codon associated with Hurler syndrome in the subject, the compound selected from the group consisting of: escin, a compound of the formula IIa, or a pharmaceutically acceptable salt, hydrate or solvate of any of the foregoing:

wherein
R 1 , R 2 and R 3 are each independently selected from the group consisting of: —H, alkyl, alkenyl, alkanoyl and alkenoyl; and
R 4 is selected from the group consisting of: a linear saccharide chain of 1-11 saccharide units, a branched saccharide chain of 1-11 saccharide units and —H.

14. The method of claim 13 , wherein the compound is the compound of formula IIa, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

15. The method of claim 14 , wherein
R 1 is selected from the group consisting of: —H, alkyl, alkenyl, acetyl, hexanoyl, benzoyl, ethylbutyryl, ethanoyl, propionyl, isobutyryl, butyryl, angeloyl, tigoyl, senecioyl, crotonoyl, 3,3-Dimethylartyloyl, cinnamoyl, pentenoyl, 2-propenoyl, (2E)-2-pentenoyl and 4-pentenoyl;
R 2 is acetyl or —H; and
R 3 is —H or acetyl.

16. The method of claim 14 , wherein
R 1 is selected from the group consisting of: angeloyl and tigoyl;
R 2 is acetyl; and
R 3 is —H.

17. The method of claim 14 , wherein
R 1 is selected from the group consisting of: angeloyl, and tigoyl;
R 2 is —H; and
R 3 is acetyl.

18. The method of claim 14 , wherein R 4 is:

19. The method of claim 14 , wherein the compound has the formula:

wherein:
R 1 is selected from the group consisting of: angeloyl and tigoyl;
R 2 is selected from the group consisting of: acetyl and —H; and
R 3 is selected from the group consisting of: acetyl and —H.

20. The method of claim 19 , wherein R 1 is tigoyl, R 2 is acetyl and R 3 is —H, R 1 is angeloyl, R 2 is acetyl and R 3 is —H, R 1 is tigoyl, R 2 is —H and R 3 is acetyl, R 1 is angeloyl, R 2 is —H and R 3 is acetyl or a combination of the foregoing.

21. The method of claim 13 , wherein the administering increases the stability of a mRNA containing the premature termination codon.

22. The method of claim 13 , wherein the premature termination codon is selected from the group consisting of: W402X, Q70X, R628X, Q148X, E404X, Y343X and Q548X.

23. The method of claim 13 further comprising administering a secondary agent to the subject.

24. The method of claim 23 , wherein the secondary agent is an NMD inhibitor, a histone deacetylase inhibitor combination of the foregoing.

Assignees

• Uab Res Found

Inventors

• Rowe Steven
• Bedwell David M
• Mutyam Venkateshwar
• Du Ming
• Keeling Kim M

Classifications

• A61K31/165

  having aromatic rings, e.g. colchicine, atenolol, progabide · CPC title

• A61K31/45

  having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide · CPC title

• C12Q1/68

  involving nucleic acids · CPC title

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A61K31/498

  Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine · CPC title