Development of a 1,2,4-Triazole-Based Lead Tankyrase Inhibitor: Part II

Abstract

Tankyrase 1 and 2 (TNKS1/2) catalyze post-translational modification by poly-ADP-ribosylation of a plethora of target proteins. In this function, TNKS1/2 also impact the WNT/β-catenin and Hippo signaling pathways that are involved in numerous human disease conditions including cancer. Targeting TNKS1/2 with small-molecule inhibitors shows promising potential to modulate the involved pathways, thereby potentiating disease intervention. Based on our 1,2,4-triazole-based lead compound <b>1</b> (OM-1700), further structure-activity relationship analyses of East-, South- and West-single-point alterations and hybrids identified compound <b>24</b> (OM-153). Compound <b>24</b> showed picomolar IC₅₀ inhibition in a cellular (HEK293) WNT/β-catenin signaling reporter assay, no off-target liabilities, overall favorable absorption, distribution, metabolism, and excretion (ADME) properties, and an improved pharmacokinetic profile in mice. Moreover, treatment with compound <b>24</b> induced dose-dependent biomarker engagement and reduced cell growth in the colon cancer cell line COLO 320DM.