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

Amit Nathubhai, Teemu Haikarainen, Jarkko Koivunen, Sudarshan Murthy, Francoise Koumanov, Matthew Lloyd, Geoffrey Holman, Taina Pihlajaniemi, David Tosh, Lari Lehtio, Michael Threadgill

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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.
Original languageEnglish
Pages (from-to)814-820
Number of pages7
JournalJournal of Medicinal Chemistry
Volume60
Issue number2
Early online date16 Dec 2016
DOIs
Publication statusPublished - 26 Jan 2017

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Tankyrases
Inhibitory Concentration 50
Protein Isoforms
Binding Sites
Glucose
Adenocarcinoma
Insulin

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Highly potent and isoform-selective dual-site-binding tankyrase/Wnt signaling inhibitors that increase cellular glucose uptake and have anti-proliferative activity. / Nathubhai, Amit; Haikarainen, Teemu; Koivunen, Jarkko; Murthy, Sudarshan; Koumanov, Francoise; Lloyd, Matthew; Holman, Geoffrey; Pihlajaniemi, Taina; Tosh, David; Lehtio, Lari; Threadgill, Michael.

In: Journal of Medicinal Chemistry, Vol. 60, No. 2, 26.01.2017, p. 814-820.

Research output: Contribution to journalArticle

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AU - Nathubhai, Amit

AU - Haikarainen, Teemu

AU - Koivunen, Jarkko

AU - Murthy, Sudarshan

AU - Koumanov, Francoise

AU - Lloyd, Matthew

AU - Holman, Geoffrey

AU - Pihlajaniemi, Taina

AU - Tosh, David

AU - Lehtio, Lari

AU - Threadgill, Michael

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