title: Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Maina
authors.initials: M
authors.lastname: Lepourcelet
authors.forename: Ying-Nan P
authors.initials: YN
authors.lastname: Chen
authors.forename: Dennis S
authors.initials: DS
authors.lastname: France
authors.forename: Huisheng
authors.initials: H
authors.lastname: Wang
authors.forename: Phillip
authors.initials: P
authors.lastname: Crews
authors.forename: Frank
authors.initials: F
authors.lastname: Petersen
authors.forename: Charles
authors.initials: C
authors.lastname: Bruseo
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wood
authors.forename: Ramesh A
authors.initials: RA
authors.lastname: Shivdasani
mesh_terms: 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
chemical_list: 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