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

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 1 (OM-1700), further structure–activity relationship
analyses of East-, South- and West-single-point alterations and hybrids
identified compound 24 (OM-153). Compound 24 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 24 induced dose-dependent
biomarker engagement and reduced cell growth in the colon cancer cell
line COLO 320DM.