Tankyrases (TNKS1 and TNKS2) 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 β-catenin degradation. 
Inhibition of tankyrases may offer a novel approach to the treatment of 
APC-mutant colorectal cancer. Hit compound 8 was identified as an inhibitor of 
tankyrases through a combination of substructure searching of the Amgen compound 
collection based on a minimal binding pharmacophore hypothesis and 
high-throughput screening. Herein we report the structure- and property-based 
optimization of compound 8 leading to the identification of more potent and 
selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic 
properties in rodents, which are well suited as tool compounds for further in 
vivo validation studies.