A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected].
Inherited and somatic mutations in the adenomatous polyposis coli occur in most colon cancers, leading to activation of beta-catenin-responsive genes. To identify small molecule antagonists of this pathway, we challenged transformed colorectal cells with a secondary structure-templated chemical library, looking for compounds that inhibit a beta-catenin-responsive reporter. We identified ICG-001, a small molecule that down-regulates beta-catenin/T cell factor signaling by specifically binding to cyclic AMP response element-binding protein. ICG-001 selectively induces apoptosis in transformed cells but not in normal colon cells, reduces in vitro growth of colon carcinoma cells, and is efficacious in the Min mouse and nude mouse xenograft models of colon cancer.
Institute for Chemical Genomics, 600 Broadway, Seattle, WA 98122, USA.
Katayoon H
KH
Emami
Cu
C
Nguyen
Hong
H
Ma
Dae Hoon
DH
Kim
Kwang Won
KW
Jeong
Masakatsu
M
Eguchi
Randall T
RT
Moon
Jia-Ling
JL
Teo
Se Woong
SW
Oh
Hak Yeop
HY
Kim
Sung Hwan
SH
Moon
Jong Ryul
JR
Ha
Michael
M
Kahn
D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D002460:Cell Line; D003106:Colon / Q000033:anatomy & histology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D051034:Inhibitor of Apoptosis Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D009363:Neoplasm Proteins; D011744:Pyrimidinones / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology; D000077022:Survivin; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D051176:beta Catenin
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D019086:Bridged Bicyclo Compounds, Heterocyclic; C495267:CTNNB1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C492448:ICG 001; D051034:Inhibitor of Apoptosis Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011744:Pyrimidinones; D000077022:Survivin; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D019938:Cyclin D1