Treatment of polycystic diseases with an HDAC6 inhibitor
View Patent ↗An HDAC6-specific inhibitor (i.e., a compound of Formula I or II) is shown to reduce the pathogenesis associated with polycystic disease. Administration of an HDAC6-specific inhibitor attenuated many of the symptoms characteristic of polycystic liver disease including cyst formation, cyst growth and cholangiocyte proliferation. Treatment with a HDAC6-specific inhibitor also increased the amount of bile duct acetylated tubulin and β-catenin phosphorylation and/or acetylation while reducing bile duct β-catenin synthesis. These results demonstrate that HDAC6 is overexpressed in cystic cholangiocytes and that its pharmacological inhibition reduces cholangiocyte proliferation and cyst growth.
1. A method for treating a polycystic disease comprising: administering to a subject with a polycystic disease a therapeutically effective amount of a histone deacetylase 6 (HDAC6) specific inhibitor, wherein the HDAC6 specific inhibitor is:
or a pharmaceutically acceptable salt thereof; or
or a pharmaceutically acceptable salt thereof.
2. The method for treating polycystic disease according to claim 1 , wherein the amount of the histone deacetylase 6 (HDAC6) specific inhibitor compound is effective at reducing cyst growth in the subject.
3. The method for treating polycystic disease according to claim 1 , wherein the polycystic disease is renal cystic disease.
4. The method for treating polycystic disease according to claim 3 , wherein the renal cystic disease is polycystic kidney disease.
5. The method for treating polycystic disease according to claim 2 , wherein the cysts are located in the kidney.
6. The method for treating a polycystic disease according to claim 3 , wherein the renal cystic disease is an autosomal dominant polycystic kidney disease (ADPKD).
7. The method for treating a polycystic disease according to claim 3 , wherein the renal cystic disease is autosomal recessive polycystic kidney disease (ARPKD).
8. The method for treating a polycystic disease according to claim 1 , wherein the amount of the histone deacetylase 6 (HDAC6) specific inhibitor compound is effective at preventing the formation of cysts.
9. The method for treating a polycystic disease according to claim 1 , wherein the amount of the histone deacetylase 6 (HDAC6) specific inhibitor compound is effective at inhibiting cholangiocyte proliferation.
10. The method for treating a polycystic disease according to claim 1 , wherein the amount of the histone deacetylase 6 (HDAC6) specific inhibitor compound is effective at increasing the amount of bile duct acetylated tubulin.
11. The method for treating a polycystic disease according to claim 1 , wherein the amount of the histone deacetylase 6 (HDAC6) specific inhibitor compound is effective at reducing bile duct β-catenin synthesis.
12. The method for treating a polycystic disease according to claim 1 , wherein the amount of the histone deacetylase 6 (HDAC6) specific inhibitor compound is effective at increasing bile duct β-catenin phosphorylation and/or acetylation.
13. The method for treating a polycystic disease according to claim 1 , wherein the amount of the histone deacetylase 6 (HDAC6) specific inhibitor compound is effective at reducing cyst growth in the subject.
14. The method for treating a polycystic disease according to claim 1 , wherein the amount of the histone deacetylase 6 (HDAC6) specific inhibitor compound is effective at inhibiting cholangiocyte proliferation.