The evolutionarily conserved Wnt/b-catenin (canonical) signaling transduction pathway plays a critical role in embryonic development and maintenance of homeostasis in mature tissues. Tankyrases are proteins in the poly-ADP-ribose polymerase (PARP) family.  They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting b-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer.  Hit compound was identified as an inhibitor of tankyrase through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening.  Structure-based optimization of the hit compound led to the identification of more potent and selective tankyrase inhibitors with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.

Structure-based design of potent and selective tankyrase inhibitors to target the Wnt pathway

248th National Meeting (2014)

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