Author/Authors :
Han-Cheng Zhang، نويسنده , , Kimberly B. White، نويسنده , , Hong Ye، نويسنده , , David F. McComsey، نويسنده , , Claudia K. Derian، نويسنده , , Michael F. Addo، نويسنده , , Patricia Andrade-Gordon، نويسنده , , Annette J. Eckardt، نويسنده , , Bruce R. Conway، نويسنده , , Lori Westover، نويسنده , , Jun Z. Xu، نويسنده , , Richard Look، نويسنده , , Keith T. Demarest، نويسنده , , Stuart Emanuel، نويسنده , , Bruce E. Maryanoff، نويسنده ,
Abstract :
Efficient methods were developed to synthesize a novel series of macrocyclic bisindolylmaleimides containing linkers with multiple heteroatoms. Potent inhibitors (single digit nanomolar IC50) for PKC-β and GSK-3β were identified, and compounds showed good selectivity over PKC-α, -γ, -δ, - , and -ζ. Representative compound 5a also had high selectivity in a screening panel of 10 other protein kinases. In cell-based functional assays, several compounds effectively blocked interleukin-8 release induced by PKC-βII and increased glycogen synthase activity by inhibiting GSK-3β.
