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Highly Potent and Isoform Selective Dual Site Binding Tankyrase/Wnt Signaling Inhibitors That Increase Cellular Glucose Uptake and Have Antiproliferative Activity
Tekijät: Nathubhai A, Haikarainen T, Koivunen J, Murthy S, Koumanov F, Lloyd MD, Holman GD, Pihlajaniemi T, Tosh D, Lehtio L, Threadgill MD
Kustantaja: AMER CHEMICAL SOC
Julkaisuvuosi: 2017
Journal: Journal of Medicinal Chemistry
Tietokannassa oleva lehden nimi: JOURNAL OF MEDICINAL CHEMISTRY
Lehden akronyymi: J MED CHEM
Vuosikerta: 60
Aloitussivu: 814
Lopetussivu: 820
Sivujen määrä: 7
ISSN: 0022-2623
DOI: https://doi.org/10.1021/acs.jmedchem.6b01574
Tiivistelmä
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.
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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