Chemical Disruption of Wnt-dependent Cell Fate Decision-making Mechanisms in Cancer and Regenerative Medicine

Abstract

Cell-to-cell signaling molecules such as the Wnt proteins that directly influence the expression of cell-type specific transcriptional programs are essential for tissue generation in metazoans. The mechanisms supporting cellular responses to these molecules represent potential points of intervention for directing cell fate outcomes in therapeutic contexts. Small molecules that modulate Wnt-mediated cellular responses have proven to be powerful probes for Wnt protein function in diverse biological settings including cancer, development, and regeneration. Whereas efforts to develop these chemicals as therapeutic agents have dominated conversation, the unprecedented modes-of-action associated with these molecules and their implications for drug development deserve greater examination. In this review, we will discuss how medicinal chemistry efforts focused on first in class small molecules targeting two Wnt pathway components – the polytopic Porcupine (Porcn) acyltransferase and the cytoplasmic Tankyrase (Tnks) poly-ADP-ribosylases – have contributed to our understanding of the druggable genome and expanded the armamentarium of chemicals that can be used to influence cell fate decision-making.

ERAD‐dependent control of the Wnt secretory factor Evi

“…A better understanding of the mechanisms underlying Wnt signaling therefore might lay the foundation for novel therapeutic approaches. Blocking Wnt secretion with the Porcn inhibitor LGK974 induced regression of multiple tumor models in vivo (Liu et al , 2013) and is currently being investigated in clinical studies (Lum & Chen, 2015; Zhan et al , 2017). Despite the high relevance of secreted Wnt ligands in different cancers and the reported additional Wnt‐independent functions of Porcn (Covey et al , 2012; Erlenhardt et al , 2016), inhibition of Porcn is to date the only pharmacological approach to inhibit Wnt secretion.…”

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

“…Despite the importance of Wnt signaling in cancer and the intense interest in Porcn inhibitors as anticancer agents, the contribution of Wnt proteins in cell-fate decision making and in transcriptional regulation in fibroblasts suggests that such agents could be useful in other therapeutic arenas, including regenerative medicine (9). Our in vivo chemical screen using WNT-974 has identified a tissue that is not detrimentally affected by suppression of Wnt signaling and that may benefit from diminished fibrotic responses induced by Porcn inhibition.…”

“…Despite the intense interest in Porcn inhibitors as anticancer agents, the importance of Wnt signaling in diverse cell types-including fibroblasts, which produce connective tissue-suggests that such agents could be useful in regenerative medicine (9). Here we have applied the clinical candidate Porcn inhibitor (WNT-974) to characterize the response of diverse tissues to transient chemical suppression of Wnt signaling.…”

Delivery of the Porcupine Inhibitor WNT974 in Mice

“…Although some cancer-associated mutations such as loss of the Wnt receptor ubiquitin ligase RNF43 are anticipated to promote Wnt ligand-mediated signaling in certain types of cancers [1-5], an incomplete inventory of Wnt pathway regulators suggests that genetic mutations yet to be unidentified may give rise to tumors that would be responsive to Porcn inhibitors. At the same time, regenerative medicine goals may see advances with the help of Wnt pathway modulators such as WNT974 by facilitating wound healing [6]. Thus, preclinical testing of compounds such as WNT974 in mouse models of disease is critical to a broader understanding of chemical utility.…”