Several cellular signaling pathways are regulated by ADP-ribosylation, a posttranslational modification catalyzed by members
of the ARTD superfamily. Tankyrases are distinguishable from the rest of this family by their unique domain organization, notably the
sterile alpha motif responsible for oligomerization and ankyrin repeats mediating protein-protein interactions. Tankyrases are involved in
various cellular functions, such as telomere homeostasis, Wnt/β-catenin signaling, glucose metabolism, and cell cycle progression. In
these processes, Tankyrases regulate the interactions and stability of target proteins by poly (ADP-ribosyl)ation. Modified proteins are
subsequently recognized by the E3 ubiquitin ligase RNF146, poly-ubiquitinated and predominantly guided to 26S proteasomal degradation.
Several small molecule inhibitors have been described for Tankyrases; they compete with the co-substrate NAD+ for binding to the
ARTD catalytic domain. The recent, highly potent and selective inhibitors possess several properties of lead compounds and can be used
for proof-of-concept studies in cancer and other Tankyrase linked diseases.
Keywords: Cancer, drug design, enzyme, inhibitor, tankyrase, telomere, Wnt/β-catenin signaling.
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