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

作者：Amit Nathubhai, T. Haikarainen, Jarkko T. Koivunen, Sudarshan Murthy, Françoise Koumanov, Matthew D. Lloyd, Geoffrey David Holman, Taina A. Pihlajaniemi, David Tosh, L. Lehtiö, Michael D. Threadgill · 发表于：Journal of Medicinal Chemistry · 年份：2016 · DOI：10.1021/acs.jmedchem.6b01574 · 被引用次数：57 · 研究领域：Wnt/β-catenin signaling in development and cancer、Cancer-related gene regulation、Coagulation, Bradykinin, Polyphosphates, and Angioedema

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., IC 50 = 100 pM vs TNKS2 and IC 50 = 6.5 μM 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 .