Highly potent and isoform selective dual site binding tankyrase/Wnt signaling inhibitors that increase cellular glucose uptake and have antiproliferative activity

Abstract

<div lang="en" class="abs"><p class="abs_header">Abstract</p><p>Compounds 𝟏𝟑 and 𝟏𝟒 were evaluated against eleven PARP isoforms to reveal that both 𝟏𝟑 and 𝟏𝟒 were more potent and isoform-selective towards inhibiting tankyrases (TNKSs) than the “standard” inhibitor 𝟏 (XAV939)⁵, <em>i.e.</em> IC₅₀ = 100 pM <em>vs.</em> TNKS2 and IC₅₀ = 6.5 μM <em>vs.</em> PARP1 for 𝟏𝟒. In cellular assays, 𝟏𝟑 and 𝟏𝟒 inhibited Wnt-signaling, enhanced insulin-stimulated glucose uptake and inhibited the proliferation of DLD-1 colorectal adenocarcinoma cells to a greater extent than 𝟏.</p></div>