Discovery of Novel Spiroindoline Derivatives as Selective Tankyrase Inhibitors

The canonical WNT pathway plays an
important role in cancer pathogenesis.
Inhibition of poly­(ADP-ribose) polymerase catalytic activity of the
tankyrases (TNKS/TNKS2) has been reported to reduce the Wnt/β-catenin
signal by preventing poly ADP-ribosylation-dependent degradation of
AXIN, a negative regulator of Wnt/β-catenin signaling. With
the goal of investigating the effects of tankyrase and Wnt pathway
inhibition on tumor growth, we set out to find small-molecule inhibitors
of TNKS/TNKS2 with suitable drug-like properties. Starting from 1a, a high-throughput screening hit, the spiroindoline derivative 40c (RK-287107) was discovered as a potent TNKS/TNKS2 inhibitor
with >7000-fold selectivity against the PARP1 enzyme, which inhibits
WNT-responsive TCF reporter activity and proliferation of human colorectal
cancer cell line COLO-320DM. RK-287107 also demonstrated dose-dependent
tumor growth inhibition in a mouse xenograft model. These observations
suggest that RK-287107 is a promising lead compound for the development
of novel tankyrase inhibitors as anticancer agents.