Development of Novel Dual Binders as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors
文摘
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 尾-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound <b>8b> 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 <b>8b> leading to the identification of more potent and selective tankyrase inhibitors <b>22b> and <b>49b> with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.