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.
Keywords: Cancer, membrane bound O-acyl transferases, poly ADP-ribosylation, porcupine, regenerative medicine,
tankyrase, tissue homeostasis, Wnt signaling.
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