Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening

Andersson, C. David; Karlberg, T.; Ekblad, T.; Lindgren, Åsa; Thorsell, A.G.; Spjut, Sara; Uciechowska, Urszula; Niemiec, Moritz S.; Wittung-Stafshede, Pernilla; Weigelt, J.; Elofsson, Mikael; Schüler, H.; Linusson, Anna

doi:10.1021/jm300746d

Cited by 36 publications

(37 citation statements)

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“…A recent study suggested that ARTD9 and ARTD1 physically and functionally interact and together mediate survival in response to genotoxic stress [80]. In order to test this hypothesis we treated ARTD8- or ARTD9-depleted PC3 cells in presence or absence of docetaxel with the ARTD1/2-specific inhibitors Olaparib and Veliparib [83-86] or with the more ARTD7/8-specific inhibitors DPQ and TIQ-A [83-85]. ARTD8- or ARTD9-depleted cells treated with Olaparib and Veliparib only showed a minor increase in cell death when compared to control cells.…”

Section: Resultsmentioning

confidence: 99%

DTX3L and ARTD9 inhibit IRF1 expression and mediate in cooperation with ARTD8 survival and proliferation of metastatic prostate cancer cells

et al. 2014

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BackgroundProstate cancer (PCa) is one of the leading causes of cancer-related mortality and morbidity in the aging male population and represents the most frequently diagnosed malignancy in men around the world. The Deltex (DTX)-3-like E3 ubiquitin ligase (DTX3L), also known as B-lymphoma and BAL-associated protein (BBAP), was originally identified as a binding partner of the diphtheria-toxin-like macrodomain containing ADP-ribosyltransferase-9 (ARTD9), also known as BAL1 and PARP9. We have previously demonstrated that ARTD9 acts as a novel oncogenic survival factor in high-risk, chemo-resistant, diffuse large B cell lymphoma (DLBCL). The mono-ADP-ribosyltransferase ARTD8, also known as PARP14 functions as a STAT6-specific co-regulator of IL4-mediated proliferation and survival in B cells.MethodsCo-expression of DTX3L, ARTD8, ARTD9 and STAT1 was analyzed in the metastatic PCa (mPCa) cell lines PC3, DU145, LNCaP and in the normal prostate luminal epithelial cell lines HPE and RWPE1. Effects on cell proliferation, survival and cell migration were determined in PC3, DU145 and/or LNCaP cells depleted of DTX3L, ARTD8, ARTD9, STAT1 and/or IRF1 compared to their proficient control cells, respectively. In further experiments, real-time RT-PCR, Western blot, immunofluorescence and co-immunoprecipitations were conducted to evaluate the physical and functional interactions between DTX3L, ARTD8 and ARTD9.ResultsHere we could identify DTX3L, ARTD9 and ARTD8 as novel oncogenic survival factors in mPCa cells. Our studies revealed that DTX3L forms a complex with ARTD8 and mediates together with ARTD8 and ARTD9 proliferation, chemo-resistance and survival of mPCa cells. In addition, DTX3L, ARTD8 and ARTD9 form complexes with each other. Our study provides first evidence that the enzymatic activity of ARTD8 is required for survival of mPCa cells. DTX3L and ARTD9 act together as repressors of the tumor suppressor IRF1 in mPCa cells. Furthermore, the present study shows that DTX3L together with STAT1 and STAT3 is implicated in cell migration of mPCa cells.ConclusionsOur data strongly indicate that a crosstalk between STAT1, DTX3L and ARTD-like mono-ADP-ribosyltransferases mediates proliferation and survival of mPCa cells. The present study further suggests that the combined targeted inhibition of STAT1, ARTD8, ARTD9 and/or DTX3L could increase the efficacy of chemotherapy or radiation treatment in prostate and other high-risk tumor types with an increased STAT1 signaling.

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Section: Resultsmentioning

confidence: 99%

DTX3L and ARTD9 inhibit IRF1 expression and mediate in cooperation with ARTD8 survival and proliferation of metastatic prostate cancer cells

et al. 2014

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“…In addition to the structures highlighted in this review, we have recently seen the first structures of poly(ADP-ribose) glycohydrolase (PARG) enzymes that reverse the modification [53-55], protein modules that recognize the modification (WWE [56,57] and PBZ [58-61]), catalytic domains from additional PARP family enzymes [30,32,34], and the regulatory ankyrin domains of PARP-5, or Tankyrase, in complex with target protein peptides [62,63]. Collectively, these structural insights have moved forward our understanding of the biology and regulation of this interesting posttranslational modification, and pave the way for exciting new discoveries.…”

Section: Resultsmentioning

confidence: 99%

PARP-1 mechanism for coupling DNA damage detection to poly(ADP-ribose) synthesis

Langelier

Pascal

2013

Current Opinion in Structural Biology

185

150

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Poly(ADP-ribose) polymerase 1 (PARP-1) regulates gene transcription, cell death signaling, and DNA repair through production of the posttranslational modification poly(ADP-ribose). During the cellular response to genotoxic stress PARP-1 rapidly associates with DNA damage, which robustly stimulates poly(ADP-ribose) production over a low basal level of PARP-1 activity. DNA damage-dependent PARP-1 activity is central to understanding PARP-1 biological function, but structural insights into the mechanisms underlying this mode of regulation have remained elusive, in part due to the highly modular six-domain architecture of PARP-1. Recent structural studies have illustrated how PARP-1 uses specialized zinc fingers to detect DNA breaks through sequence-independent interaction with exposed nucleotide bases, a common feature of damaged and abnormal DNA structures. The mechanism of coupling DNA damage detection to elevated poly(ADP-ribose) production has been elucidated based on a crystal structure of the essential domains of PARP-1 in complex with a DNA strand break. The multiple domains of PARP-1 collapse onto damaged DNA, forming a network of interdomain contacts that introduce destabilizing alterations in the catalytic domain leading to an enhanced rate of poly(ADP-ribose) production.

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“…The less studied members of the superfamily, mARTDs, have recently attracted attention as potential new drug targets (Andersson et al, 2012;Ekblad et al, 2015;Morgan et al, 2015;Wahlberg et al, 2012). It is clear that the existing ARTD inhibitors are not selective and, although they inhibit certain mARTDs, they can not be used to evaluate the cellular effects of inhibiting these enzymes (Wahlberg et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage

Venkannagari

Verheugd

Koivunen

et al. 2016

Cell Chemical Biology

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SUMMARYMembers of the human diphtheria toxin-likeADP-ribosyltransferase (ARTD or PARP) family play important roles in regulating biological activities by mediating either a mono-ADP-ribosylation MARylation) of a substrate or a poly-ADP-ribosylation (PARylation). ARTD10/PARP10 belongs to the MARylating ARTDs (mARTDs) subfamily, and plays important roles in biological processes that range from cellular signaling, DNA repair, and cell proliferation to immune response. Despite their biological and disease relevance, no selective inhibitors for mARTDs are available. Here we describe a small-molecule ARTD10 inhibitor, OUL35, a selective and potent inhibitor for this enzyme. We characterize its selectivity profile, model its binding, and demonstrate activity in HeLa cells where OUL35 rescued cells from ARTD10 induced cell death. Using OUL35 as a cell biology tool we show that ARTD10 inhibition sensitizes the cells to the hydroxyurea-induced genotoxic stress. Our study supports the proposed role of ARTD10 in DNA-damage repair and provides a tool compound for selective inhibition of ARTD10-mediated MARylation.3

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Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening

Cited by 36 publications

References 60 publications

DTX3L and ARTD9 inhibit IRF1 expression and mediate in cooperation with ARTD8 survival and proliferation of metastatic prostate cancer cells

DTX3L and ARTD9 inhibit IRF1 expression and mediate in cooperation with ARTD8 survival and proliferation of metastatic prostate cancer cells

PARP-1 mechanism for coupling DNA damage detection to poly(ADP-ribose) synthesis

Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage

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