Design and Discoveryof an Orally Efficacious Spiroindolinone-BasedTankyrase Inhibitor for the Treatment of Colon Cancer
2020
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.
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