Highly potent and isoform selective dual site binding tankyrase/Wnt signaling inhibitors that increase cellular glucose uptake and have antiproliferative activity

Highly potent and isoform selective dual site binding tankyrase/Wnt signaling inhibitors that increase cellular glucose uptake and have antiproliferative activity

http://urn.fi/urn:nbn:fi-fe201702201787

Teksti

Nathubhai, A. (Amit) ; Haikarainen, T. (Teemu) ; Koivunen, J. (Jarkko) ; Murthy, S. (Sudarshan) ; Koumanov, F. (Françoise) ; Lloyd, M. D. (Matthew D.) ; Holman, G. D. (Geoffrey D.) ; Pihlajaniemi, T. (Taina) ; Tosh, D. (David) ; Lehtiö, L. (Lari) ; Threadgill, M. D. (Michael D.)

American Chemical Society

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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Crystal structure