Highly Potent and Isoform Selective Dual Site Binding Tankyrase/Wnt Signaling Inhibitors That Increase Cellular Glucose Uptake and Have Antiproliferative Activity
详细信息 查看全文
- 作者：Amit NathubhaiTeemu Haikarainen ; Jarkko Koivunen ; Sudarshan Murthy ; Françoise Koumanov ; Matthew D. Lloyd ; Geoffrey D. Holman ; Taina Pihlajaniemi ; David Tosh ; Lari Lehtiö ; Michael D. Threadgill
- 刊名：Journal of Medicinal Chemistry
- 出版年：2017
- 出版时间：January 26, 2017
- 年：2017
- 卷：60
- 期：2
- 页码：814-820
- 全文大小：431K
- ISSN：1520-4804
文摘
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)<sup>5sup>, i.e., IC<sub>50sub> = 100 pM vs TNKS2 and IC<sub>50sub> = 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.