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)
 
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URL:
https://doi.org/10.1021/acs.jmedchem.6b01574

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.
American Chemical Society
16.12.2016

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

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© 2016 American Chemical Society. Published in this repository with the kind permission of the publisher.
https://rightsstatements.org/vocab/InC/1.0/
doi:https://doi.org/10.1021/acs.jmedchem.6b01574
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https://urn.fi/URN:NBN:fi-fe201702201787
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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.

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