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

Amit Nathubhai; Teemu Haikarainen; Jarkko Koivunen; Sudarshan Murthy; Françoise Koumanov; Matthew D. Lloyd; Geoffrey D. Holman; Taina Pihlajaniemi; David Tosh; Lari Lehtiö; Michael D. 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 antiproliferative activity

Amit Nathubhai^*
, Teemu Haikarainen
, Jarkko Koivunen
, Sudarshan Murthy
, Françoise Koumanov
, Matthew D. Lloyd
, Geoffrey D. Holman
, Taina Pihlajaniemi
, David Tosh
, Lari Lehtiö
, Michael D. Threadgill

^*Corresponding author for this work

Not published at VTT

University of Bath
University of Oulu

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

55 Citations (Scopus)

Abstract

Compounds 13 and 14 were evaluated against 11 PARP isoforms to reveal that both 13 and 14 were more potent and isoform selective toward 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
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01574
Publication status	Published - 26 Jan 2017
MoE publication type	A1 Journal article-refereed

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Nathubhai, A., Haikarainen, T., Koivunen, J., Murthy, S., Koumanov, F., Lloyd, M. D., Holman, G. D., Pihlajaniemi, T., Tosh, D., Lehtiö, L., & Threadgill, M. D. (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. https://doi.org/10.1021/acs.jmedchem.6b01574

@article{74c19bcd8a9a44a5be44a0c72ab5f8ac,

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

abstract = "Compounds 13 and 14 were evaluated against 11 PARP isoforms to reveal that both 13 and 14 were more potent and isoform selective toward 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.",

author = "Amit Nathubhai and Teemu Haikarainen and Jarkko Koivunen and Sudarshan Murthy and Fran{\c c}oise Koumanov and Lloyd, \{Matthew D.\} and Holman, \{Geoffrey D.\} and Taina Pihlajaniemi and David Tosh and Lari Lehti{\"o} and Threadgill, \{Michael D.\}",

year = "2017",

month = jan,

day = "26",

doi = "10.1021/acs.jmedchem.6b01574",

language = "English",

volume = "60",

pages = "814--820",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

number = "2",

}

Nathubhai, A, Haikarainen, T, Koivunen, J, Murthy, S, Koumanov, F, Lloyd, MD, Holman, GD, Pihlajaniemi, T, Tosh, D, Lehtiö, L & Threadgill, MD 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, vol. 60, no. 2, pp. 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 antiproliferative 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 › Scientific › peer-review

TY - JOUR

T1 - Highly potent and isoform selective dual site binding tankyrase/Wnt signaling inhibitors that increase cellular glucose uptake and have antiproliferative activity

AU - Nathubhai, Amit

AU - Haikarainen, Teemu

AU - Koivunen, Jarkko

AU - Murthy, Sudarshan

AU - Koumanov, Françoise

AU - Lloyd, Matthew D.

AU - Holman, Geoffrey D.

AU - Pihlajaniemi, Taina

AU - Tosh, David

AU - Lehtiö, Lari

AU - Threadgill, Michael D.

PY - 2017/1/26

Y1 - 2017/1/26

N2 - Compounds 13 and 14 were evaluated against 11 PARP isoforms to reveal that both 13 and 14 were more potent and isoform selective toward 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.

AB - Compounds 13 and 14 were evaluated against 11 PARP isoforms to reveal that both 13 and 14 were more potent and isoform selective toward 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.

UR - https://www.scopus.com/pages/publications/85021860090

U2 - 10.1021/acs.jmedchem.6b01574

DO - 10.1021/acs.jmedchem.6b01574

M3 - Article

C2 - 27983846

AN - SCOPUS:85021860090

SN - 0022-2623

VL - 60

SP - 814

EP - 820

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 2

ER -

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

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