Indole-2-amide based biochemical antagonist of Dishevelled PDZ domain interaction down-regulates Dishevelled-driven Tcf transcriptional activity.
We designed and synthesized a series of indole-2-amide-based compounds that antagonize interaction between the Dishevelled (Dvl) PDZ domain and a peptide derived from the natural PDZ ligand Frizzled-7 (Fz7). These compounds inhibit Tcf-mediated transcription activated by exogenous Dvl via the biochemical antagonism. We confirmed tumor cell-selective activation of caspases by these compounds.
Mahindroo
Neeraj
N
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Punchihewa
Chandanamali
C
Bail
Allison M
AM
Fujii
Naoaki
N
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D000072261:Dishevelled Proteins; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D054731:PDZ Domains / Q000187:drug effects; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D051820:TCF Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D051153:Wnt Proteins / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D000577:Amides; D000072261:Dishevelled Proteins; D007211:Indoles; D010750:Phosphoproteins; D051820:TCF Transcription Factors; D051153:Wnt Proteins