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, i.e. IC50 = 100 pM vs. TNKS2 and IC50 = 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.
Nathubhai, A., Haikarainen, T., Koivunen, J., Murthy, S., Koumanov, F., Lloyd, M., ... Threadgill, M. (2017). Highly potent and isoform-selective dual-site-binding tankyrase/Wnt signaling inhibitors that increase cellular glucose uptake and have anti-proliferative activity. Journal of Medicinal Chemistry, 60(2), 814-820. https://doi.org/10.1021/acs.jmedchem.6b01574