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

doi:10.1021/acs.jmedchem.6b01574

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

Research output: Contribution to journal › Article › peer-review

42 Citations (SciVal)

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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 language	English
Pages (from-to)	814-820
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	2
Early online date	16 Dec 2016
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01574
Publication status	Published - 26 Jan 2017

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10.1021/acs.jmedchem.6b01574

Nathubhai_Just_accepted_proof_revisions.pdf
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see 10.1021/acs.jmedchem.6b01574.
Accepted author manuscript, 920 KB

Role of Rab3 in Peripheral Tissue Insulin Resistance
Koumanov, F., Betts, J., Gonzalez, J., Thompson, D. & Whitley, P.
Medical Research Council
1/12/16 → 31/07/20
Project: Research council
Elucidation of Final Stages in Coupling of Insulin Signalling to CLUT4 Translocation
Holman, G. & Koumanov, F.
Medical Research Council
1/07/12 → 30/06/15
Project: Research council
FUNCTIONAL ANALYSIS AND PATHOPHYSIOLOGY OF GLUCOSE TRANSPORT ERS
Holman, G.
Medical Research Council
1/10/03 → 28/02/09
Project: Research council

David Tosh
- D.Toshbath.acuk
- Department of Life Sciences - Professor
- Centre for Therapeutic Innovation
Person: Research & Teaching

MC2- Nuclear Magnetic Resonance (NMR)
Material and Chemical Characterisation (MC2)
Facility/equipment: Technology type
MC2- X-ray diffraction (XRD)
Material and Chemical Characterisation (MC2)
Facility/equipment: Technology type

Cite this

Nathubhai, A., Haikarainen, T., Koivunen, J., Murthy, S., Koumanov, F., Lloyd, M., Holman, G., Pihlajaniemi, T., Tosh, D., Lehtio, L., & 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

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

Research output: Contribution to journal › Article › peer-review

Nathubhai, A, Haikarainen, T, Koivunen, J, Murthy, S, Koumanov, F , Lloyd, M , Holman, G, Pihlajaniemi, T, Tosh, D, Lehtio, L & 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, vol. 60, no. 2, pp. 814-820. https://doi.org/10.1021/acs.jmedchem.6b01574

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

Abstract

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Projects

Role of Rab3 in Peripheral Tissue Insulin Resistance

Elucidation of Final Stages in Coupling of Insulin Signalling to CLUT4 Translocation

FUNCTIONAL ANALYSIS AND PATHOPHYSIOLOGY OF GLUCOSE TRANSPORT ERS

Profiles

David Tosh

Equipment

MC2- Nuclear Magnetic Resonance (NMR)

MC2- X-ray diffraction (XRD)

Cite this