Inhibition of gamma-secretase by the CK1 inhibitor IC261 does not depend on CK1delta.
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.
Höttecke
Nicole
N
Clemens Schöpf-Institute of Chemistry and Biochemistry, Technische Universität Darmstadt, Petersenstr. 22, D-64287 Darmstadt, Germany.
Liebeck
Miriam
M
Baumann
Karlheinz
K
Schubenel
Robert
R
Winkler
Edith
E
Steiner
Harald
H
Schmidt
Boris
B
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D047389:Casein Kinase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
C411652:IC 261; D007211:Indoles; D011480:Protease Inhibitors; D010696:Phloroglucinol; D047389:Casein Kinase I; D048148:Casein Kinase Idelta; D053829:Amyloid Precursor Protein Secretases