Inhibition of gamma-secretase by the CK1 inhibitor IC261 does not depend on CK1delta
Bioorg Med Chem Lett. 2010 Mar 4. [Epub ahead of print]
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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 CK1deltaon gamma-secretase, because any change in the substitution pattern of IC261 diminished CK1 inhibition, whereas gamma-secretase inhibition is still exerted by several analogues. Copyright © 2010 Elsevier Ltd. All rights reserved.