Development and structural analysis of adenosine site binding tankyrase inhibitors

Haikarainen, T.; Waaler, Jo; Ignatev, Alexander; Nkizinkiko, Yves; Venkannagari, Harikanth; Obaji, Ezeogo; Krauß, Stefan; Lehtiö, L.

doi:10.1016/j.bmcl.2015.12.018

Cited by 24 publications

(23 citation statements)

References 26 publications

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“…Since the ART is highly conserved, binding to an alternate site may elicit binding specificity (619). Haikaranen and coworkers identified an inhibitor, JW55, as well as several of its analogues which were shown to be potent and selective tankyrase inhibitors that bound to the adenine subsite (620). Continued development of inhibitors of the tankyrases target other binding sites, while some have been designed to target both the adenine subsite and the NAD ϩ -binding site, effectively tuning inhibitor specificity for the tankyrases (621).…”

Section: Inhibitor Classesmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

Brady

Goel

Johnson

2019

Microbiol Mol Biol Rev

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SUMMARYThe literature review presented here details recent research involving members of the poly(ADP-ribose) polymerase (PARP) family of proteins. Among the 17 recognized members of the family, the human enzyme PARP1 is the most extensively studied, resulting in a number of known biological and metabolic roles. This review is focused on the roles played by PARP enzymes in host-pathogen interactions and in diseases with an associated inflammatory response. In mammalian cells, several PARPs have specific roles in the antiviral response; this is perhaps best illustrated by PARP13, also termed the zinc finger antiviral protein (ZAP). Plant stress responses and immunity are also regulated by poly(ADP-ribosyl)ation. PARPs promote inflammatory responses by stimulating proinflammatory signal transduction pathways that lead to the expression of cytokines and cell adhesion molecules. Hence, PARP inhibitors show promise in the treatment of inflammatory disorders and conditions with an inflammatory component, such as diabetes, arthritis, and stroke. These functions are correlated with the biophysical characteristics of PARP family enzymes. This work is important in providing a comprehensive understanding of the molecular basis of pathogenesis and host responses, as well as in the identification of inhibitors. This is important because the identification of inhibitors has been shown to be effective in arresting the progression of disease.

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Section: Inhibitor Classesmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

Brady

Goel

Johnson

2019

Microbiol Mol Biol Rev

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“…TNKS inhibitors were kindly provided by Dr. Lari Lehtiö (Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland). The reported potencies and IC50 are summarized in Table 2 (Haikarainen et al, 2013;Haikarainen, Krauss & Lehtio, 2014;Riffell, Lord & Ashworth, 2012;Lehtiö, Chi & Krauss, 2013;Mariotti, Pollock & Guettler, 2017;Thorsell et al, 2017;Haikarainen et al, 2016). Vero cells were treated with TNKS inhibitors (TNKSi) at the moment of seeding.…”

Section: Sds-page and Western Blotmentioning

confidence: 99%

First body of evidence suggesting a role of a tankyrase-binding motif (TBM) of vinculin (VCL) in epithelial cells

Larrea

Valsecchi

Villamil

et al. 2021

PeerJ

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Background Adherens junctions (AJ) are involved in cancer, infections and neurodegeneration. Still, their composition has not been completely disclosed. Poly(ADP-ribose) polymerases (PARPs) catalyze the synthesis of poly(ADP-ribose) (PAR) as a posttranslational modification. Four PARPs synthesize PAR, namely PARP-1/2 and Tankyrase-1/2 (TNKS). In the epithelial belt, AJ are accompanied by a PAR belt and a subcortical F-actin ring. F-actin depolymerization alters the AJ and PAR belts while PARP inhibitors prevent the assembly of the AJ belt and cortical actin. We wondered which PARP synthesizes the belt and which is the PARylation target protein. Vinculin (VCL) participates in the anchorage of F-actin to the AJ, regulating its functions, and colocalized with the PAR belt. TNKS has been formerly involved in the assembly of epithelial cell junctions. Hypothesis TNKS poly(ADP-ribosylates) (PARylates) epithelial belt VCL, affecting its functions in AJ, including cell shape maintenance. Materials and Methods Tankyrase-binding motif (TBM) sequences in hVCL gene were identified and VCL sequences from various vertebrates, Drosophila melanogaster and Caenorhabditis elegans were aligned and compared. Plasma membrane-associated PAR was tested by immunocytofluorescence (ICF) and subcellular fractionation in Vero cells while TNKS role in this structure and cell junction assembly was evaluated using specific inhibitors. The identity of the PARylated proteins was tested by affinity precipitation with PAR-binding reagent followed by western blots. Finally, MCF-7 human breast cancer epithelial cells were subjected to transfection with Tol2-plasmids, carrying a dicistronic expression sequence including Gallus gallus wt VCL (Tol-2-GgVCL), or the same VCL gene with a point mutation in TBM-II (Tol2-GgVCL/*TBM) under the control of a β-actin promoter, plus green fluorescent protein following an internal ribosome entry site (IRES-GFP) to allow the identification of transfected cells without modifying the transfected protein of interest. Results and discussion In this work, some of the hypothesis predictions have been tested. We have demonstrated that: (1) VCL TBMs were conserved in vertebrate evolution while absent in C. elegans; (2) TNKS inhibitors disrupted the PAR belt synthesis, while PAR and an endogenous TNKS pool were associated to the plasma membrane; (3) a VCL pool was covalently PARylated; (4) transfection of MCF-7 cells leading to overexpression of Gg-VCL/*TBM induced mesenchymal-like cell shape changes. This last point deserves further investigation, bypassing the limits of our transient transfection and overexpression system. In fact, a 5th testable prediction would be that a single point mutation in VCL TBM-II under endogenous expression control would induce an epithelial to mesenchymal transition (EMT). To check this, a CRISPR/Cas9 substitution approach followed by migration, invasion, gene expression and chemo-resistance assays should be performed.

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“…The first potent toolbox TNKSi, XAV939 (Huang et al, ), IWR‐1 and IWR‐2 (Chen et al, ; Gunaydin et al, ), were discovered in phenotypic screens designed to identify antagonists of the Wnt/β‐catenin pathway, as were the inhibitors JW74 (Waaler et al, ), JW55 (Waaler et al, ), WIKI4 (James et al, ) and K‐756 (Okada‐Iwasaki et al, ). Numerous additional inhibitors were established through diverse approaches (see Zhan et al, ), including screening for compounds that rescue tankyrase‐induced lethality of yeast cells (Yashiroda et al, ) or induce a mitotic spindle defect (Johannes et al, ), fragment screening (Larsson et al, ; de Vicente et al, ), proteomics (Thomson et al, ), in silico screening or substructure searching, followed by compound optimization (Bregman et al, ; Elliott et al, ), screening of a DNA‐encoded library (Samain et al, ) and extensive structure–activity relationship studies, assisted by the structural analysis of tankyrase/PARP:inhibitor complexes (Hua et al, ; Shultz et al, ; Voronkov et al, ; Narwal et al, ; Liscio et al, ; Qiu et al, ; Haikarainen et al, ; Kumpan et al, ; Nkizinkiko et al, ; Paine et al, ; Haikarainen et al, ; Thomson et al, ). Numerous more drug‐like molecules, with optimized pharmacological properties, are now available, for example, G007‐LK (Lau et al, ; Voronkov et al, ) and NVP‐TNKS656 (Shultz et al, ).…”

Section: Tankyrase Inhibitorsmentioning

confidence: 99%

Regulation of Wnt/β‐catenin signalling by tankyrase‐dependent poly(ADP‐ribosyl)ation and scaffolding

Mariotti

Pollock

Guettler

2017

British J Pharmacology

112

120

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The Wnt/β‐catenin signalling pathway is pivotal for stem cell function and the control of cellular differentiation, both during embryonic development and tissue homeostasis in adults. Its activity is carefully controlled through the concerted interactions of concentration‐limited pathway components and a wide range of post‐translational modifications, including phosphorylation, ubiquitylation, sumoylation, poly(ADP‐ribosyl)ation (PARylation) and acetylation. Regulation of Wnt/β‐catenin signalling by PARylation was discovered relatively recently. The PARP tankyrase PARylates AXIN1/2, an essential central scaffolding protein in the β‐catenin destruction complex, and targets it for degradation, thereby fine‐tuning the responsiveness of cells to the Wnt signal. The past few years have not only seen much progress in our understanding of the molecular mechanisms by which PARylation controls the pathway but also witnessed the successful development of tankyrase inhibitors as tool compounds and promising agents for the therapy of Wnt‐dependent dysfunctions, including colorectal cancer. Recent work has hinted at more complex roles of tankyrase in Wnt/β‐catenin signalling as well as challenges and opportunities in the development of tankyrase inhibitors. Here we review some of the latest advances in our understanding of tankyrase function in the pathway and efforts to modulate tankyrase activity to re‐tune Wnt/β‐catenin signalling in colorectal cancer cells.Linked ArticlesThis article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc

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Development and structural analysis of adenosine site binding tankyrase inhibitors

Cited by 24 publications

References 26 publications

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

First body of evidence suggesting a role of a tankyrase-binding motif (TBM) of vinculin (VCL) in epithelial cells

Regulation of Wnt/β‐catenin signalling by tankyrase‐dependent poly(ADP‐ribosyl)ation and scaffolding

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