Wnt Drug Discovery: Weaving Through the Screens, Patents and Clinical Trials.

Benjamin Lu,Brooke Green,Jacqueline Farr,Terence Van Raay,Flávia Lopes

doi:10.3390/cancers8090082

Abstract

The Wnt signaling pathway is intricately involved in many aspects of development and is the root cause of an increasing number of diseases. For example, colorectal cancer is the second leading cause of death in the industrialized world and aberration of Wnt signaling within the colonic stem cell is the cause of more than 90% of these cancers. Despite our advances in successfully targeting other pathways, such as Human Epidermal Growth Factor Receptor 2 (HER2), there are no clinically relevant therapies available for Wnt-related diseases. Here, we investigated where research activities are focused with respect to Wnt signaling modulators by searching the United States Patent and Trade Office (USPTO) for patents and patent applications related to Wnt modulators and compared this to clinical trials focusing on Wnt modulation. We found that while the transition of intellectual property surrounding the Wnt ligand-receptor interface to clinical trials is robust, this is not true for specific inhibitors of β-catenin, which is constitutively active in many cancers. Considering the ubiquitous use of the synthetic T-cell Factor/Lymphoid Enhancer Factor (TCF/Lef) reporter system and its success in identifying novel modulators in vitro, we speculate that this model of drug discovery does not capture the complexity of in vivo Wnt signaling that may be required if we are to successfully target the Wnt pathway in the clinic. Notwithstanding, increasingly more complex models are being developed, which may not be high throughput, but more pragmatic in our pursuit to control Wnt signaling.

Highlights

The Wnt signaling pathway is one of the oldest signaling pathways in multicellular eukaryotes and is involved in many aspects of development and in the maintenance of stem cells [1–3]
We focused on the United States Patent and Trade Office (USPTO) Patents and Patent Application (P/PA) databases searching abstracts for “Wnt AND cancer” or “-catenin AND cancer” and combined these results with the general search term “Wnt inhibitor”
Inhibiting or enhancing Wnt signaling at the ligand-receptor level appears to have more traction

Summary

Introduction

The Wnt signaling pathway is one of the oldest signaling pathways in multicellular eukaryotes and is involved in many aspects of development and in the maintenance of stem cells [1–3]. 19 Wnt ligands, 10 Frizzled receptors and a host of other co-receptors and extracellular modifiers [7], one would think that there would be several opportunities to target a Wnt-related disease based on the combination of ligand and receptors. Towards this end, there are many high throughput screens that have identified some promising candidates [8–12], but there are currently no specific. The results of many of these screens are not published prior to securing intellectual property rights This makes it rather difficult to assess what potential therapies may be in the pipeline. We attempted to obtain a view of where researchers are focusing

Methods

Results

Discussion

Conclusion