Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex.
Key molecular lesions in colorectal and other cancers cause beta-catenin-dependent transactivation of T cell factor (Tcf)-dependent genes. Disruption of this signal represents an opportunity for rational cancer therapy. To identify compounds that inhibit association between Tcf4 and beta-catenin, we screened libraries of natural compounds in a high-throughput assay for immunoenzymatic detection of the protein-protein interaction. Selected compounds disrupt Tcf/beta-catenin complexes in several independent in vitro assays and potently antagonize cellular effects of beta-catenin-dependent activities, including reporter gene activation, c-myc or cyclin D1 expression, cell proliferation, and duplication of the Xenopus embryonic dorsal axis. These compounds thus meet predicted criteria for disrupting Tcf/beta-catenin complexes and define a general standard to establish mechanism-based activity of small molecule inhibitors of this pathogenic protein-protein interaction.
Lepourcelet
Maina
M
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Chen
Ying-Nan P
YN
France
Dennis S
DS
Wang
Huisheng
H
Crews
Phillip
P
Petersen
Frank
F
Bruseo
Charles
C
Wood
Alexander W
AW
Shivdasani
Ramesh A
RA
D000818:Animals; D019556:COS Cells; D002455:Cell Division / Q000502:physiology; D002522:Chlorocebus aethiops; D020650:Combinatorial Chemistry Techniques; D019938:Cyclin D1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction / Q000502:physiology*; D020349:Surface Plasmon Resonance; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014981:Xenopus / Q000378:metabolism; D029867:Xenopus Proteins; D051176:beta Catenin
C495266:CTNNB1 protein, Xenopus; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D029867:Xenopus Proteins; D051176:beta Catenin; D019938:Cyclin D1