ICG-001, a novel small molecule regulator of TCF/beta-catenin transcription.
Inherited and somatic mutations in the APC gene, a human tumor-suppressor, occur in a large percentage of colon cancers, leading to elevated levels of nuclear beta-Catenin, and to activation of TCF/beta-Catenin-responsive genes including cyclin D1 and c-myc. To identify small molecule antagonists of this pathway, we screened transformed colorectal cells with a secondary structure-templated chemical library, in search of compounds that attenuated a TCF/beta-Catenin-responsive reporter gene. From this library we selected ICG-001 (IC50=3 microM) as a lead compound. Design and synthesis of the chemical library and some preliminary biological evaluation is described.
Eguchi
Masakatsu
M
Institute for Chemical Genomics, 600 Broadway, Suite 580, Seattle, WA 98122, USA.
Nguyen
Cu
C
Lee
Sung Chan
SC
Kahn
Michael
M
D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051820:TCF Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D019086:Bridged Bicyclo Compounds, Heterocyclic; C492448:ICG 001; D011744:Pyrimidinones; D051820:TCF Transcription Factors; D051176:beta Catenin