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

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.

Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting

“…One speculated reason has been the lack of convenient enzymatic targets in canonical WNT signaling relative to other developmental signaling pathways [148], as well as the challenge of targeting components of the pathway downstream of APC in colorectal cancers harboring APC mutations [149]. Another proposed obstacle has been the possibility that the synthetic TOPFLASH reporter system used for candidate discovery fails to recapitulate the endogenous complexity of WNT activation and inactivation sufficiently to facilitate identification of clinically relevant targets [150]. Finally, even an effective WNT inhibitor may be accompanied by significant safety concerns due to the critical role of canonical WNT signaling in normal processes such as somatic stem cell maintenance [148].…”

“…Disruptors of the β-catenin and CBP interaction include PRI-724 (also known as ICG-001), currently in clinical trials for newly-diagnosed metastatic colorectal cancer [150]. Small molecule antagonists of the β-catenin / TCF complex include PKF115-584 and CGP049090, which appear to function by binding directly β-catenin [165] but are not currently in clinical trials.…”

β-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models

“…Despite the central role of Wnt/β-catenin in CRC, pharmacological intervention of this critical pathway has proven to be challenging, and consequently there is a dearth of drug development programs that have proceeded to advanced clinical trials (29, 30). With few exceptions, the majority of prior efforts to inhibit Wnt signaling do not target β-catenin itself, but rather target specific Wnt ligands or ligand secretory pathways, Wnt receptors or transcriptional co-activators where pathway redundancies may limit efficacy (31).…”

Brain Beta-Catenin Signalling During Stress and Depression

“…Furthermore, as has been detailed in this review, even in the brain alone, the increase or decrease in beta-catenin levels during depression and stress are region-dependent. There is already a beta-catenin specific antagonist (PRI-724) undergoing clinical trials [83, 84]; although this agent shows promise, its trials focus primarily on intestinal and pancreatic cancer. In terms of depression, the question of delivering beta-catenin treatment to specific regions of the brain is yet to be addressed.…”