The Wnt-dependent signaling pathways as target in oncology drug discovery

Abstract

Our current understanding of the Wnt-dependent signaling pathways is mainly based on studies performed in a number of model organisms including, Xenopus, Drosophila melanogaster, Caenorhabditis elegans and mammals. These studies clearly indicate that the Wnt-dependent signaling pathways are conserved through evolution and control many events during embryonic development. Wnt pathways have been shown to regulate cell proliferation, morphology, motility as well as cell fate. The increasing interest of the scientific community, over the last decade, in the Wnt-dependent signaling pathways is supported by the documented importance of these pathways in a broad range of physiological conditions and disease states. For instance, it has been shown that inappropriate regulation and activation of these pathways is associated with several pathological disorders including cancer, retinopathy, tetra-amelia and bone and cartilage disease such as arthritis. In addition, several components of the Wnt-dependent signaling pathways appear to play important roles in diseases such as Alzheimer's disease, schizophrenia, bipolar disorder and in the emerging field of stem cell research. In this review, we wish to present a focused overview of the function of the Wnt-dependent signaling pathways and their role in oncogenesis and cancer development. We also want to provide information on a selection of potential drug targets within these pathways for oncology drug discovery, and summarize current data on approaches, including the development of small-molecule inhibitors, that have shown relevant effects on the Wnt-dependent signaling pathways.

Figure 1

Schematic overview of the Wnt signaling pathways. In the absence of active Wnt (left) β-catenin is degraded and Tcf/Lef transcription factors act as repressor. When a Wnt signal is present (right) β-catenin accumulates in the cytoplasm, localizes then to the nucleus, and activates transcription together with Tcf/Lef transcription factors.

Figure 2

Interaction sites for binding partners of β-catenin (from http://www.stanford.edu/~rnusse/wntwindow.html).

Figure 3

Lead structures for Wnt signaling pathway inhibitors.

Figure 4

Chemical structure of ICG-001.