Highly Potent and Isoform Selective Dual Site Binding Tankyrase/Wnt Signaling Inhibitors That Increase Cellular Glucose Uptake and Have Antiproliferative Activity



: Nathubhai A, Haikarainen T, Koivunen J, Murthy S, Koumanov F, Lloyd MD, Holman GD, Pihlajaniemi T, Tosh D, Lehtio L, Threadgill MD

Publisher: AMER CHEMICAL SOC

: 2017

: Journal of Medicinal Chemistry

: JOURNAL OF MEDICINAL CHEMISTRY

: J MED CHEM

: 60

: 814

: 820

: 7

: 0022-2623

DOI: https://doi.org/10.1021/acs.jmedchem.6b01574


Compounds 13 and 14 were evaluated against 11 PARP isoforms to reveal that both 13 and 14 were more potent and isoform selective toward inhibiting tankyrases (TNKSs) than the "standard" inhibitor 1 (XAV939)(5), i.e., IC50 = 100 pM vs TNKS2 and IC50 = 6.5 mu M vs 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.



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