Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer

Tankyrases
(TNKS/TNKS2) belong to the poly­(ADP-ribose) polymerase
family. Inhibition of their enzymatic activities attenuates the Wnt/β-catenin
signaling, which plays an important role in cancer pathogenesis. We
previously reported the discovery of RK-287107, a spiroindoline-based,
highly selective, potent tankyrase inhibitor. Herein we describe the
optimization process of RK-287107 leading to RK-582, which exhibits
a markedly improved robust tumor growth inhibition in a COLO-320DM
mouse xenograft model when orally administered. In addition to the
dose-dependent elevation and attenuation of the levels of biomarkers
AXIN2 and β-catenin, respectively, results of the TCF reporter
and cell proliferation studies on COLO-320DM are discussed.