Inhibition of gamma-secretase by the CK1 inhibitor IC261 does not depend on CK1delta

Bioorg Med Chem Lett. 2010 May 1;20(9):2958-63. doi: 10.1016/j.bmcl.2010.02.110. Epub 2010 Mar 4.


CK1 and gamma-secretase are interesting targets for therapeutic intervention in the treatment of cancer and Alzheimer's disease. The CK1 inhibitor IC261 was reported to inhibit gamma-secretase activity. The question is: Does CK1 inhibition directly influence gamma-secretase activity? Therefore we analyzed the SAR of 15 analogues and their impact on gamma-secretase activity. The most active compounds were investigated on CK1delta activity. These findings exclude a direct influence of CK1delta on gamma-secretase, because any change in the substitution pattern of IC261 diminished CK1 inhibition, whereas gamma-secretase inhibition is still exerted by several analogues.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Binding Sites
  • Casein Kinase I / antagonists & inhibitors*
  • Casein Kinase I / metabolism
  • Casein Kinase Idelta / antagonists & inhibitors*
  • Casein Kinase Idelta / metabolism
  • Indoles / chemistry*
  • Indoles / pharmacology
  • Phloroglucinol / analogs & derivatives*
  • Phloroglucinol / chemistry
  • Phloroglucinol / pharmacology
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Structure-Activity Relationship


  • IC 261
  • Indoles
  • Protease Inhibitors
  • Phloroglucinol
  • Casein Kinase I
  • Casein Kinase Idelta
  • Amyloid Precursor Protein Secretases