Olov Wallner | Karolinska Institutet (original) (raw)

Papers by Olov Wallner

Research paper thumbnail of Pharmacological OGG1 inhibition decreases murine allergic airway inflammation

Frontiers in Pharmacology

Background and aim: Allergic asthma is a complex inflammatory disease involving type 2 innate lym... more Background and aim: Allergic asthma is a complex inflammatory disease involving type 2 innate lymphoid cells, type 2 T helper cells, macrophages, and eosinophils. The disease is characterized by wheezing, dyspnea, coughing, chest tightness and variable airflow limitation for which there is no cure and is symptomatically treated with inhaled corticosteroids and β2-agonists. Molecular mechanisms underlying its complex pathogenesis are not fully understood. However, 8-oxoguanine DNA glycosylase-1 (OGG1), a DNA repair protein may play a central role, as OGG1 deficiency decreases both innate and allergic inflammation.Methods: Using a murine ovalbumin (OVA) model of allergic airway inflammation we assessed the utility of an inhibitor of OGG1 (TH5487) in this disease context. Cytokines and chemokines, promoting immune cell recruitment were measured using a 23-multiplex assay and Western blotting. Additionally, immune cell recruitment to bronchi was measured using flow cytometry. Histologic...

Research paper thumbnail of γ-Selective Pd-Catalyzed Cross-Coupling of Allylboronic Acids with Iodobenzenes

Research paper thumbnail of MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

Research paper thumbnail of Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function

Science

Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excis... more Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed β,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.

Research paper thumbnail of Optimization of N-piperidinyl-benzimidazolone derivatives as potent and selective inhibitors of 8-Oxo Guanine DNA Glycosylase 1

8-oxo Guanine DNA Glycosylase 1 is the initiating enzyme within base excision repair and removes ... more 8-oxo Guanine DNA Glycosylase 1 is the initiating enzyme within base excision repair and removes oxidized guanines from damaged DNA. Since unrepaired 8-oxoG could lead to G:C→T:A transversion, base removal is of the utmost importance for cells to ensure genomic integrity. For cells with elevat-ed levels of reactive oxygen species this dependency is further increased. In the past we and others have validated OGG1 as a target for inhibitors to treat cancer and inflammation. Here, we present the optimization campaign that led to the broadly used tool compound TH5487. Based on a high-throughput screen, we performed hit to lead expansion and arrived at potent and selective substituted N-piperidinyl-benzimidazolones. Using X-ray crystallography data, we describe the surprising bind-ing mode of the most potent member of the class, TH8535. Here, the N-Piperidinyl-linker adopts a chair instead of a boat conformation which was found for weaker analogues. We further demonstrate cellular target...

Research paper thumbnail of Palladium-Catalyzed Synthesis and Transformations of Organometallic Compounds

Four new chiral pincer-complexes were prepared based on coupling of BINOL and TADDOL moieties wit... more Four new chiral pincer-complexes were prepared based on coupling of BINOL and TADDOL moieties with iodoresorcinol followed by oxidative addition of palladium(0). The X-ray analysis of complex 5a revealed that the BINOL rings form a well-defined chiral pocket around the palladium atom. This chiral environment can be further modified by γ-substitution of the BINOL rings. Preliminary studies for electrophilic allylation of sulfonimine 2 with allylstannane revealed that the presented chiral complexes are promising asymmetric catalysts for preparation of chiral homoallyl amines. The best result was achieved employing catalytic amounts of γ-Me BINOL complex 6 affording homoallyl amine 4 with 59% ee and 74% isolated yield.

Research paper thumbnail of Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects

Scientific Reports

The most common oxidative DNA lesion is 8-oxoguanine which is mainly recognized and excised by th... more The most common oxidative DNA lesion is 8-oxoguanine which is mainly recognized and excised by the 8-oxoG DNA glycosylase 1 (OGG1), initiating the base excision repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress (OS) which disrupts telomere homeostasis triggering genome instability. In the present study, we have investigated the effects of inactivating BER in OS conditions, by using a specific inhibitor of OGG1 (TH5487). We have found that in OS conditions, TH5487 blocks BER initiation at telomeres causing an accumulation of oxidized bases, that is correlated with telomere losses, micronuclei formation and mild proliferation defects. Moreover, the antimetabolite methotrexate synergizes with TH5487 through induction of intracellular reactive oxygen species (ROS) formation, which potentiates TH5487-mediated telomere and genome instability. Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to in...

Research paper thumbnail of Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses

Viruses

Recent RNA virus outbreaks such as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a... more Recent RNA virus outbreaks such as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus (EBOV) have caused worldwide health emergencies highlighting the urgent need for new antiviral strategies. Targeting host cell pathways supporting viral replication is an attractive approach for development of antiviral compounds, especially with new, unexplored viruses where knowledge of virus biology is limited. Here, we present a strategy to identify host-targeted small molecule inhibitors using an image-based phenotypic antiviral screening assay followed by extensive target identification efforts revealing altered cellular pathways upon antiviral compound treatment. The newly discovered antiviral compounds showed broad-range antiviral activity against pathogenic RNA viruses such as SARS-CoV-2, EBOV and Crimean-Congo hemorrhagic fever virus (CCHFV). Target identification of the antiviral compounds by thermal protein profiling revealed major effects on proteostasis pathw...

Research paper thumbnail of Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis

Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent m... more Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. Despite substantial advancement in our understanding of IPF progression, numerous questions remain concerning disease pathology. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is upregulated following TGF-β1 exposure in several fibrosis-associated cell types. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study, administration of Ogg1-targetting siRNA, mitigated bleomycin-induced pulmonary fibrosis in mice, thereby highlighting OGG1 as a tractable target in lung fibrosis. The novel small molecule OGG1 inhibitor, TH5487, decreased myofibroblast transition and asso...

Research paper thumbnail of Assembly and Application of a Low Budget Photo Reactor

Photochemistry is a fast growing research field and many transformations previously not accessibl... more Photochemistry is a fast growing research field and many transformations previously not accessible to chemists now have become part of an ever growing standard repertoire. The limiting factors for a photo reactor system however is the possibility to perform stirring, removal of excess heat and the irradiation with UV or visible light – all that within a secure surrounding. Systems for starters may be as expensive as several thousand Euro. Here we design and assemble a LED photo reactor using scrap and standard materials, only spending less than 30 € for a LED. The system may be adjusted to any required wave length and its assembly is shown for the use of a 400 nm wave length lamp. To demonstrate its application, we then exemplarily use the reactor in the removal of a photo labile protection group during the synthesis of a SARS-CoV-2 spike protein glyco peptide.

Research paper thumbnail of Crystal structures of NUDT15 variants enabled by a potent inhibitor reveal the structural basis for thiopurine sensitivity

Journal of Biological Chemistry

Research paper thumbnail of MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia

Research paper thumbnail of Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids

Viruses

RNA viruses have gained plenty of attention during recent outbreaks of Severe acute respiratory s... more RNA viruses have gained plenty of attention during recent outbreaks of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Zika virus (ZIKV), and Ebola virus. ZIKV is a vector borne Flavivirus that is spread by mosquitoes and it mainly infects neuronal progenitor cells. One hallmark of congenital ZIKV disease is a reduced brain size in fetuses, leading to severe neurological defects. The World Health Organization (WHO) is urging the development of new antiviral treatments against ZIKV, as there are no efficient countermeasures against ZIKV disease. Previously, we presented a new class of host-targeting antivirals active against a number of pathogenic RNA viruses, such as SARS-CoV-2. Here, we show the transfer of the image-based phenotypic antiviral assay to ZIKV-infected brain cells, followed by mechanism-of-action studies and a proof-of-concept study in a three-dimensional (3D) organoid model. The novel antiviral compounds showed a therapeutic window against ZIKV in sever...

Research paper thumbnail of Targeting OGG1 arrests cancer cell proliferation by inducing replication stress

Nucleic Acids Research

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidati... more Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic appro...

Research paper thumbnail of Abstract 4799: OGG1 depleted cancer cells are sensitive to anti-malarial drug proguanil: Repurposing for cancer treatment

Molecular and Cellular Biology / Genetics

Research paper thumbnail of Development of a chemical probe against NUDT15

Research paper thumbnail of Author Correction: Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

Nature Communications

An amendment to this paper has been published and can be accessed via a link at the top of the pa... more An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Research paper thumbnail of Computational and Experimental Druggability Assessment of Human DNA Glycosylases

Research paper thumbnail of Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation

Science

The onset of inflammation is associated with reactive oxygen species and oxidative damage to macr... more The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor–α–induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.

Research paper thumbnail of Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

Nature communications, Jan 17, 2018

With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide... more With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a prom...

Research paper thumbnail of Pharmacological OGG1 inhibition decreases murine allergic airway inflammation

Frontiers in Pharmacology

Background and aim: Allergic asthma is a complex inflammatory disease involving type 2 innate lym... more Background and aim: Allergic asthma is a complex inflammatory disease involving type 2 innate lymphoid cells, type 2 T helper cells, macrophages, and eosinophils. The disease is characterized by wheezing, dyspnea, coughing, chest tightness and variable airflow limitation for which there is no cure and is symptomatically treated with inhaled corticosteroids and β2-agonists. Molecular mechanisms underlying its complex pathogenesis are not fully understood. However, 8-oxoguanine DNA glycosylase-1 (OGG1), a DNA repair protein may play a central role, as OGG1 deficiency decreases both innate and allergic inflammation.Methods: Using a murine ovalbumin (OVA) model of allergic airway inflammation we assessed the utility of an inhibitor of OGG1 (TH5487) in this disease context. Cytokines and chemokines, promoting immune cell recruitment were measured using a 23-multiplex assay and Western blotting. Additionally, immune cell recruitment to bronchi was measured using flow cytometry. Histologic...

Research paper thumbnail of γ-Selective Pd-Catalyzed Cross-Coupling of Allylboronic Acids with Iodobenzenes

Research paper thumbnail of MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

Research paper thumbnail of Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function

Science

Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excis... more Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed β,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.

Research paper thumbnail of Optimization of N-piperidinyl-benzimidazolone derivatives as potent and selective inhibitors of 8-Oxo Guanine DNA Glycosylase 1

8-oxo Guanine DNA Glycosylase 1 is the initiating enzyme within base excision repair and removes ... more 8-oxo Guanine DNA Glycosylase 1 is the initiating enzyme within base excision repair and removes oxidized guanines from damaged DNA. Since unrepaired 8-oxoG could lead to G:C→T:A transversion, base removal is of the utmost importance for cells to ensure genomic integrity. For cells with elevat-ed levels of reactive oxygen species this dependency is further increased. In the past we and others have validated OGG1 as a target for inhibitors to treat cancer and inflammation. Here, we present the optimization campaign that led to the broadly used tool compound TH5487. Based on a high-throughput screen, we performed hit to lead expansion and arrived at potent and selective substituted N-piperidinyl-benzimidazolones. Using X-ray crystallography data, we describe the surprising bind-ing mode of the most potent member of the class, TH8535. Here, the N-Piperidinyl-linker adopts a chair instead of a boat conformation which was found for weaker analogues. We further demonstrate cellular target...

Research paper thumbnail of Palladium-Catalyzed Synthesis and Transformations of Organometallic Compounds

Four new chiral pincer-complexes were prepared based on coupling of BINOL and TADDOL moieties wit... more Four new chiral pincer-complexes were prepared based on coupling of BINOL and TADDOL moieties with iodoresorcinol followed by oxidative addition of palladium(0). The X-ray analysis of complex 5a revealed that the BINOL rings form a well-defined chiral pocket around the palladium atom. This chiral environment can be further modified by γ-substitution of the BINOL rings. Preliminary studies for electrophilic allylation of sulfonimine 2 with allylstannane revealed that the presented chiral complexes are promising asymmetric catalysts for preparation of chiral homoallyl amines. The best result was achieved employing catalytic amounts of γ-Me BINOL complex 6 affording homoallyl amine 4 with 59% ee and 74% isolated yield.

Research paper thumbnail of Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects

Scientific Reports

The most common oxidative DNA lesion is 8-oxoguanine which is mainly recognized and excised by th... more The most common oxidative DNA lesion is 8-oxoguanine which is mainly recognized and excised by the 8-oxoG DNA glycosylase 1 (OGG1), initiating the base excision repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress (OS) which disrupts telomere homeostasis triggering genome instability. In the present study, we have investigated the effects of inactivating BER in OS conditions, by using a specific inhibitor of OGG1 (TH5487). We have found that in OS conditions, TH5487 blocks BER initiation at telomeres causing an accumulation of oxidized bases, that is correlated with telomere losses, micronuclei formation and mild proliferation defects. Moreover, the antimetabolite methotrexate synergizes with TH5487 through induction of intracellular reactive oxygen species (ROS) formation, which potentiates TH5487-mediated telomere and genome instability. Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to in...

Research paper thumbnail of Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses

Viruses

Recent RNA virus outbreaks such as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a... more Recent RNA virus outbreaks such as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus (EBOV) have caused worldwide health emergencies highlighting the urgent need for new antiviral strategies. Targeting host cell pathways supporting viral replication is an attractive approach for development of antiviral compounds, especially with new, unexplored viruses where knowledge of virus biology is limited. Here, we present a strategy to identify host-targeted small molecule inhibitors using an image-based phenotypic antiviral screening assay followed by extensive target identification efforts revealing altered cellular pathways upon antiviral compound treatment. The newly discovered antiviral compounds showed broad-range antiviral activity against pathogenic RNA viruses such as SARS-CoV-2, EBOV and Crimean-Congo hemorrhagic fever virus (CCHFV). Target identification of the antiviral compounds by thermal protein profiling revealed major effects on proteostasis pathw...

Research paper thumbnail of Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis

Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent m... more Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. Despite substantial advancement in our understanding of IPF progression, numerous questions remain concerning disease pathology. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is upregulated following TGF-β1 exposure in several fibrosis-associated cell types. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study, administration of Ogg1-targetting siRNA, mitigated bleomycin-induced pulmonary fibrosis in mice, thereby highlighting OGG1 as a tractable target in lung fibrosis. The novel small molecule OGG1 inhibitor, TH5487, decreased myofibroblast transition and asso...

Research paper thumbnail of Assembly and Application of a Low Budget Photo Reactor

Photochemistry is a fast growing research field and many transformations previously not accessibl... more Photochemistry is a fast growing research field and many transformations previously not accessible to chemists now have become part of an ever growing standard repertoire. The limiting factors for a photo reactor system however is the possibility to perform stirring, removal of excess heat and the irradiation with UV or visible light – all that within a secure surrounding. Systems for starters may be as expensive as several thousand Euro. Here we design and assemble a LED photo reactor using scrap and standard materials, only spending less than 30 € for a LED. The system may be adjusted to any required wave length and its assembly is shown for the use of a 400 nm wave length lamp. To demonstrate its application, we then exemplarily use the reactor in the removal of a photo labile protection group during the synthesis of a SARS-CoV-2 spike protein glyco peptide.

Research paper thumbnail of Crystal structures of NUDT15 variants enabled by a potent inhibitor reveal the structural basis for thiopurine sensitivity

Journal of Biological Chemistry

Research paper thumbnail of MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia

Research paper thumbnail of Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids

Viruses

RNA viruses have gained plenty of attention during recent outbreaks of Severe acute respiratory s... more RNA viruses have gained plenty of attention during recent outbreaks of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Zika virus (ZIKV), and Ebola virus. ZIKV is a vector borne Flavivirus that is spread by mosquitoes and it mainly infects neuronal progenitor cells. One hallmark of congenital ZIKV disease is a reduced brain size in fetuses, leading to severe neurological defects. The World Health Organization (WHO) is urging the development of new antiviral treatments against ZIKV, as there are no efficient countermeasures against ZIKV disease. Previously, we presented a new class of host-targeting antivirals active against a number of pathogenic RNA viruses, such as SARS-CoV-2. Here, we show the transfer of the image-based phenotypic antiviral assay to ZIKV-infected brain cells, followed by mechanism-of-action studies and a proof-of-concept study in a three-dimensional (3D) organoid model. The novel antiviral compounds showed a therapeutic window against ZIKV in sever...

Research paper thumbnail of Targeting OGG1 arrests cancer cell proliferation by inducing replication stress

Nucleic Acids Research

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidati... more Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic appro...

Research paper thumbnail of Abstract 4799: OGG1 depleted cancer cells are sensitive to anti-malarial drug proguanil: Repurposing for cancer treatment

Molecular and Cellular Biology / Genetics

Research paper thumbnail of Development of a chemical probe against NUDT15

Research paper thumbnail of Author Correction: Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

Nature Communications

An amendment to this paper has been published and can be accessed via a link at the top of the pa... more An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Research paper thumbnail of Computational and Experimental Druggability Assessment of Human DNA Glycosylases

Research paper thumbnail of Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation

Science

The onset of inflammation is associated with reactive oxygen species and oxidative damage to macr... more The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor–α–induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.

Research paper thumbnail of Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

Nature communications, Jan 17, 2018

With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide... more With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a prom...