Highly potent and isoform selective dual site binding tankyrase/Wnt signaling inhibitors that increase cellular glucose uptake and have antiproliferative activity
Nathubhai, Amit; Haikarainen, Teemu; Koivunen, Jarkko; Murthy, Sudarshan; Koumanov, Françoise; Lloyd, Matthew D.; Holman, Geoffrey D.; Pihlajaniemi, Taina; Tosh, David; Lehtiö, Lari; Threadgill, Michael D. (2016-12-16)
Nathubhai, A., Haikarainen, T., Koivunen, J., Murthy, S., Koumanov, F., Lloyd, M., Holman, G., Pihlajaniemi, T., Tosh, D., Lehtiö, L., Threadgill, M. (2017) Highly Potent and Isoform Selective Dual Site Binding Tankyrase/Wnt Signaling Inhibitors That Increase Cellular Glucose Uptake and Have Antiproliferative Activity. Journal of Medicinal Chemistry 60(2): 814-820. doi:10.1021/acs.jmedchem.6b01574
© 2016 American Chemical Society. Published in this repository with the kind permission of the publisher.
https://rightsstatements.org/vocab/InC/1.0/
https://urn.fi/URN:NBN:fi-fe201702201787
Tiivistelmä
Abstract
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.
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