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

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

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
Early online date	9 Jan 2017
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01574
Publication status	Published - 26 Jan 2017

Keywords

Aminoquinolines/chemical synthesis
Antineoplastic Agents/chemical synthesis
Cell Line, Tumor
Crystallography, X-Ray
Drug Screening Assays, Antitumor
Glucose/metabolism
HEK293 Cells
Heterocyclic Compounds, 3-Ring/pharmacology
Humans
Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesis
Protein Isoforms/antagonists & inhibitors
Quinazolinones/chemical synthesis
Tankyrases/antagonists & inhibitors
Wnt Signaling Pathway/drug effects

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10.1021/acs.jmedchem.6b01574

https://pubs.acs.org/doi/10.1021/acs.jmedchem.6b01574

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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

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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.",

keywords = "Aminoquinolines/chemical synthesis, Antineoplastic Agents/chemical synthesis, Cell Line, Tumor, Crystallography, X-Ray, Drug Screening Assays, Antitumor, Glucose/metabolism, HEK293 Cells, Heterocyclic Compounds, 3-Ring/pharmacology, Humans, Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesis, Protein Isoforms/antagonists \& inhibitors, Quinazolinones/chemical synthesis, Tankyrases/antagonists \& inhibitors, Wnt Signaling Pathway/drug effects",

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",

publisher = "American Chemical Society",

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 › 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.

KW - Aminoquinolines/chemical synthesis

KW - Antineoplastic Agents/chemical synthesis

KW - Cell Line, Tumor

KW - Crystallography, X-Ray

KW - Drug Screening Assays, Antitumor

KW - Glucose/metabolism

KW - HEK293 Cells

KW - Heterocyclic Compounds, 3-Ring/pharmacology

KW - Humans

KW - Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesis

KW - Protein Isoforms/antagonists & inhibitors

KW - Quinazolinones/chemical synthesis

KW - Tankyrases/antagonists & inhibitors

KW - Wnt Signaling Pathway/drug effects

UR - https://purehost.bath.ac.uk/ws/portalfiles/portal/185714873/Nathubhai_Just_accepted_proof_revisions.pdf

U2 - 10.1021/acs.jmedchem.6b01574

DO - 10.1021/acs.jmedchem.6b01574

M3 - Article

C2 - 27983846

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

Abstract

Keywords

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