A5037166494- Wnt/β-catenin signaling in development and cancer
- Cancer-related gene regulation
- Microbial metabolism and enzyme function
- Mechanisms of cancer metastasis
- Ubiquitin and proteasome pathways
- Enzyme function and inhibition
- Microtubule and mitosis dynamics
- Cancer, Hypoxia, and Metabolism
- Nutrition, Genetics, and Disease
- PI3K/AKT/mTOR signaling in cancer
- Cancer-related Molecular Pathways
- Protein Kinase Regulation and GTPase Signaling
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Enzyme Structure and Function
- Kruppel-like factors research
- Cancer, Lipids, and Metabolism
- Hippo pathway signaling and YAP/TAZ
- 14-3-3 protein interactions
- Liver physiology and pathology
- Aldose Reductase and Taurine
- Polyamine Metabolism and Applications
- Cancer Mechanisms and Therapy
- Cancer Cells and Metastasis
- Fibroblast Growth Factor Research
- Signaling Pathways in Disease
Oslo University Hospital
2015-2025
University of Oslo
2011-2025
Institute of Physiology and Basic Medicine
2020
Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences
2020
Toxicologie, Pharmacologie et Signalisation Cellulaire
2019
Czech Academy of Sciences, Institute of Molecular Genetics
2011-2013
Czech Academy of Sciences
2011-2013
Norwegian Institute of Public Health
2011
Max Delbrück Center
2011
Increased nuclear accumulation of β-catenin, a mediator canonical Wnt signaling, is found in numerous tumors and frequently associated with tumor progression metastasis. Inhibition Wnt/β-catenin signaling therefore an attractive strategy for anticancer drugs. In this study, we have identified novel small molecule inhibitor the β-catenin pathway, JW55, that functions via inhibition PARP domain tankyrase 1 2 (TNKS1/2), regulators destruction complex. TNKS1/2 poly(ADP-ribosyl)ation activity by...
Abstract Most colorectal cancers (CRC) are initiated by mutations of APC, leading to increased β-catenin–mediated signaling. However, continued requirement Wnt/β-catenin signaling for tumor progression in the context acquired KRAS and other is less well-established. To attenuate tumors, we have developed potent specific small-molecule tankyrase inhibitors, G007-LK G244-LM, that reduce preventing poly(ADP-ribosyl)ation-dependent AXIN degradation, thereby promoting β-catenin destabilization....
Abstract Canonical Wnt signaling is deregulated in several types of human cancer where it plays a central role tumor cell growth and progression. Here we report the identification 2 new small molecules that specifically inhibit canonical pathway at level destruction complex. Specificity was verified various cellular reporter systems, Xenopus double-axis formation assay gene expression profile analysis. In colorectal (CRC) cells, compounds JW67 JW74 rapidly reduced active β-catenin with...
Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological biotargets with possible applications for the development of novel anticancer therapeutics. A focused structure–activity relationship study was conducted based on tankyrase inhibitor JW74 (1). Chemical analoging improved 1,2,4-triazole core led to 4-{5-[(E)-2-{4-(2-chlorophenyl)-5-[5-(methylsulfonyl)pyridin-2-yl]-4H-1,2,4-triazol-3-yl}ethenyl]-1,3,4-oxadiazol-2-yl}benzonitrile (G007-LK), a potent, "rule 5" compliant metabolically...
Designing inhibitors is a complex task that requires deep understanding of protein–ligand interactions and their dynamics. Ligands often interact with multiple binding subsites, noncovalent affecting affinity. Conformational changes plasticity both, the ligand protein influence energetics. We investigated tankyrase ADP-ribosyltransferase as promising drug target regulating many cellular pathways. Despite existence diverse inhibitors, energetics contributions flexible cryptic subpockets to...
In the past, development of tankyrases inhibitors has focused on ADP-ribosyltransferase domain. Targeting tankyrases' ability to interact with protein substrates through their ARC domains represents an alternative strategy be explored as therapeutic approach against specific protein-protein interactions. this paper, we employed a FRET-based assay identify ARC4-binding compounds by screening EU-OPENSCREEN Pilot and Commercials Diversity libraries. We discovered effective series same scaffold...
Wnt/β-catenin is a major regulator of stem cell self-renewal and differentiation this signaling pathway aberrantly activated in several cancers, including osteosarcoma (OS). Attenuation activity by tankyrase inhibitors an appealing strategy treatment OS. The efficacy the inhibitor JW74 was evaluated three OS lines (KPD, U2OS, SaOS-2) both at molecular functional level. At level, induces stabilization AXIN2, key component β-catenin destruction complex, resulting reduced levels nuclear...
Abstract Overactivation of the WNT/β-CATENIN signaling axis is a common denominator in colorectal cancer. Currently, there no available WNT inhibitor clinical practice. Although TANKYRASE (TNKS) inhibitors have been proposed as promising candidates, are many cancer models that do not respond positively to TNKS inhibition vitro and vivo. Therefore, combinatorial therapeutic approach combining (G007-LK) with PI3K (BKM120) EGFR (erlotinib) was investigated. The data demonstrate enhances effect...
Abstract Tankyrase (TNKS) enzymes, due to their poly(ADP-ribose) polymerase activity, have emerged as potential targets in experimental cancer therapy. However, the functional consequences of TNKS inhibition remain incompletely resolved because binding promiscuity TNKS. One hallmarks small-molecule inhibitors (TNKSi) is stabilization AXIN, which plays a pivotal role WNT/β-catenin signaling pathway. The present study focused on known ability TNKSi induce cytoplasmic puncta (degradasomes)...
Abstract The development of immune checkpoint inhibitors represents a major breakthrough in cancer therapy. Nevertheless, substantial number patients fail to respond pathway blockade. Evidence for WNT/β-catenin signaling-mediated evasion is found subset cancers including melanoma. Currently, there are no therapeutic strategies available targeting signaling. Here we show that specific small-molecule tankyrase inhibitor, G007-LK, decreases and YAP signaling the syngeneic murine B16-F10 Clone...
Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling Hippo pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety binding predominantly to adenosine site of catalytic domain. Here we describe systematic structure-guided lead optimization approach these inhibitors. The template trans-cyclobutyl linker compound were left unchanged, while side-group East, West, South moieties altered by introducing different building blocks defined as...
Abstract We have designed a versatile and sensitive liquid chromatographic (LC) system, featuring monolithic trap column very narrow (10 μm ID) fused silica open tubular chromatography (OTLC) separation functionalized with C 18 -groups, for separating wide range of molecules (from small metabolites to intact proteins). Compared today’s capillary/nanoLC approaches, our system provides significantly enhanced sensitivity (up several orders) matching or improved efficiency, highly repeatable...
A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor 16 displays high target affinity on 1 and 2 with biochemical cellular IC50 values 29 nM, 6.3 nM 19 respectively, selectivity toward other poly (ADP-ribose) polymerase enzymes. shows favorable in vitro ADME profile as well good oral bioavailability mice, rats, dogs. Critical for the was utilization an appropriate linker between...
Abstract Objective Human TNKS, encoding tankyrase 1 (TNKS1), localizes to a susceptibility locus for obesity and type 2 diabetes mellitus (T2DM). Here, we addressed the therapeutic potential of G007-LK, TNKS-specific inhibitor, T2DM. Methods We administered G007-LK diabetic db/db mice measured impact on body weight, abdominal adiposity, serum metabolites. Muscle, liver, white adipose tissues were analyzed by quantitative RT-PCR western blotting determine TNKS inhibition, lipolysis, beiging,...
Tankyrase 1 and 2 (TNKS1/2) catalyze post-translational modification by poly-ADP-ribosylation of a plethora target proteins. In this function, TNKS1/2 also impact the WNT/β-catenin Hippo signaling pathways that are involved in numerous human disease conditions including cancer. Targeting with small-molecule inhibitors shows promising potential to modulate pathways, thereby potentiating intervention. Based on our 1,2,4-triazole-based lead compound (OM-1700), further structure–activity...
The catalytic enzymes tankyrase 1 and 2 (TNKS1/2) alter protein turnover by poly-ADP-ribosylating target proteins, which earmark them for degradation the ubiquitin–proteasomal system. Prominent targets of activity TNKS1/2 include AXIN resulting in being attractive biotargets addressing oncogenic WNT/β-catenin signaling. Although several potent small molecules have been developed to inhibit TNKS1/2, there are currently no inhibitors available clinical practice. development has mainly...
Tankyrases 1 and 2, the specialized members of ARTD protein family, are druggable biotargets whose inhibition may have therapeutic potential against cancer, metabolic disease, fibrotic wound healing HSV viral infections. We previously identified a novel tankyrase inhibitor scaffold, JW55, showed that it reduces mouse colon adenoma formation in vivo. Here we expanded scaffold profiled selectivity compounds panel human ARTDs. The also enables fine modulation towards either or 2. In order to...
The WNT pathway regulates intestinal stem cells and is frequently disrupted in adenomas. contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes tankyrase1 2. LGR5 a known target gene marker of cells. LGR5+ are located crypt base capable regenerating all epithelial cell lineages.We treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice with tankyrase inhibitor G007-LK up to 3 weeks assess effect on duodenal homeostasis integrity epithelium. At...
Evidence suggests that the growth and therapeutic resistance of glioblastoma (GBM) may be enabled by a population glioma stem cells (GSCs) are regulated typical cell pathways, including WNT/β-catenin signaling pathway. We wanted to explore effect treating GSCs with small-molecule inhibitor tankyrase, G007-LK, which has been shown potent modulator Hippo pathways in colon cancer. Four primary GSC cultures two adult neural were treated G007-LK subsequently evaluated through measurement...
Small-molecule tankyrase 1 and 2 (TNKS1/2) inhibitors are effective antitumor agents in selected tumor cell lines mouse models. Here, we characterized the response signatures in-depth mechanisms for antiproliferative effect of inhibition (TNKSi). The TNKS1/2-specific inhibitor G007-LK was used to screen 537 human a panel particularly TNKSi-sensitive identified. Transcriptome, proteome, bioinformatic analyses revealed overall TNKSi-induced panel. TNKSi-mediated wingless-type mammary virus...
The development of immune checkpoint inhibitors represents a major breakthrough in cancer therapy. Nevertheless, substantial number patients fail to respond pathway blockade. β-catenin is the key transcriptional regulator WNT/β-catenin signaling. Evidence for β-catenin-mediated evasion found 13% all cancers, 42% primary cutaneous melanoma and mouse model. Currently, there are no therapeutic strategies available targeting signaling counteract inhibitor resistance melanoma. Here we report that...
Dual inhibitors of MET and WNT signaling may have synergistic effects, the design, synthesis evaluation such first-in-class small-molecules are reported.
Abstract Human diphtheria toxin-like ADP-ribosyltransferases, PARPs and tankyrases, transfer ADP-ribosyl groups to other macromolecules, thereby controlling various signaling events in cells. They are considered promising drug targets, especially oncology, some small molecule inhibitors have already been developed. These typically interact with the nicotinamide binding site extend along NAD + groove of catalytic domain. Quinazolin-4-ones explored as scaffolds for such we identified a new...