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Instruments / Technical Area	Publication Details	Published
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function Maurice Michel , Carlos Benítez-Buelga , Patricia A. Calvo , Bishoy M. F. Hanna , Oliver Mortusewicz , Geoffrey Masuyer , Jonathan Davies , Olov Wallner , Sanjiv Kumar , Julian J. Albers , Sergio Castañeda-Zegarra , Ann-Sofie Jemth , Torkild Visnes , Ana Sastre-Perona , Akhilesh N. Danda , Evert J. Homan , Karthick Marimuthu , Zhao Zhenjun , Celestine N. Chi , Antonio Sarno , Elisée Wiita , Catharina Von Nicolai , Anna J. Komor , Varshni Rajagopal , Sarah Müller , Emily C. Hank , Marek Varga , Emma R. Scaletti , Monica Pandey , Stella Karsten , Hanne Haslene-Hox , Simon Loevenich , Petra Marttila , Azita Rasti , Kirill Mamonov , Florian Ortis , Fritz Schömberg , Olga Loseva , Josephine Stewart , Nicholas D’arcy-Evans , Tobias Koolmeister , Martin Henriksson , Dana Michel , Ana De Ory , Lucia Acero , Oriol Calvete , Martin Scobie , Christian Hertweck , Ivan Vilotijevic , Christina Kalderén , Ana Osorio , Rosario Perona , Alexandra Stolz , Pal Stenmark , Ulrika Warpman Berglund , Miguel De Vega , Thomas Helleday Science 376, 1471 - 1476 DOI: 10.1126/science.abf8980 Diamond Proposal Number(s): [15806, 21625] Show Abstract ▼ Abstract: 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.	Jun 2022
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress Nadilly Bonagas , Nina M. S. Gustafsson , Martin Henriksson , Petra Marttila , Robert Gustafsson , Elisée Wiita , Sanjay Borhade , Alanna C. Green , Karl S. A. Vallin , Antonio Sarno , Richard Svensson , Camilla Göktürk , Therese Pham , Ann-Sofie Jemth , Olga Loseva , Victoria Cookson , Nicole Kiweler , Lars Sandberg , Azita Rasti , Judith E. Unterlass , Martin Haraldsson , Yasmin Andersson , Emma R. Scaletti , Christoffer Bengtsson , Cynthia B. J. Paulin , Kumar Sanjiv , Eldar Abdurakhmanov , Linda Pudelko , Ben Kunz , Matthieu Desroses , Petar Iliev , Katarina Färnegårdh , Andreas Krämer , Neeraj Garg , Maurice Michel , Sara Häggblad , Malin Jarvius , Christina Kalderén , Amanda Bögedahl Jensen , Ingrid Almlöf , Stella Karsten , Si Min Zhang , Maria Häggblad , Anders Eriksson , Jianping Liu , Björn Glinghammar , Natalia Nekhotiaeva , Fredrik Klingegård , Tobias Koolmeister , Ulf Martens , Sabin Llona-Minguez , Ruth Moulson , Helena Nordström , Vendela Parrow , Leif Dahllund , Birger Sjöberg , Irene L. Vargas , Duy Duc Vo , Johan Wannberg , Stefan Knapp , Hans E. Krokan , Per I. Arvidsson , Martin Scobie , Johannes Meiser , Pal Stenmark , Ulrika Warpman Berglund , Evert J. Homan , Thomas Helleday Nature Cancer 3, 156 - 172 DOI: 10.1038/s43018-022-00331-y Open Access Show Abstract ▼ Abstract: The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.	Feb 2022
I24-Microfocus Macromolecular Crystallography	Crystal structures of NUDT15 variants enabled by a potent inhibitor reveal the structural basis for thiopurine sensitivity Daniel Rehling , Si Min Zhang , Ann-Sofie Jemth , Tobias Koolmeister , Adam Throup , Olov Wallner , Emma Scaletti , Takaya Moriyama , Rina Nishii , Jonathan Davies , Matthieu Desroses , Sean G. Rudd , Martin Scobie , Evert Homan , Ulrika Warpman Berglund , Jun J. Yang , Thomas Helleday , Pal Stenmark Journal Of Biological Chemistry 271 DOI: 10.1016/j.jbc.2021.100568 Diamond Proposal Number(s): [21625] Open Access Show Abstract ▼ Abstract: The enzyme NUDT15 efficiently hydrolyses the active metabolites of thiopurine drugs, which are routinely used for treating cancer and inflammatory diseases. Loss-of-function variants in NUDT15 are strongly associated with thiopurine intolerance, such as leukopenia, and pre-emptive NUDT15 genotyping has been clinically implemented to personalize thiopurine dosing. However, understanding the molecular consequences of these variants has been difficult, as no structural information was available for NUDT15 proteins encoded by clinically actionable pharmacogenetic variants due to their inherent instability. Recently, the small molecule NUDT15 inhibitor TH1760 has been shown to sensitize cells to thiopurines, through enhanced accumulation of 6-thio-guanine in DNA. Building upon this, we herein report the development of the potent and specific NUDT15 inhibitor, TH7755. TH7755 demonstrates a greatly improved cellular target engagement and 6-thioguanine potentiation compared to TH1760, while showing no cytotoxicity on its own. This potent inhibitor also stabilized NUDT15, enabling analysis by X-ray crystallography. We have determined high-resolution structures of the clinically relevant NUDT15 variants Arg139Cys, Arg139His, Val18Ile and V18_V19insGlyVal. These structures provide clear insights into the structural basis for the thiopurine intolerance phenotype observed in patients carrying these pharmacogenetic variants. These findings will aid in predicting the effects of new NUDT15 sequence variations yet to be discovered in the clinic.	Mar 2021
I04-Macromolecular Crystallography	Targeting OGG1 arrests cancer cell proliferation by inducing replication stress Torkild Visnes , Carlos Benítez-Buelga , Armando Cázares-Körner , Kumar Sanjiv , Bishoy M. F. Hanna , Oliver Mortusewicz , Varshni Rajagopal , Julian J. Albers , Daniel W Hagey , Tove Bekkhus , Saeed Eshtad , Juan Miguel Baquero , Geoffrey Masuyer , Olov Wallner , Sarah Müller , Therese Pham , Camilla Göktürk , Azita Rasti , Sharda Suman , Raúl Torres-Ruiz , Antonio Sarno , Elisée Wiita , Evert J. Homan , Stella Karsten , Karthick Marimuthu , Maurice Michel , Tobias Koolmeister , Martin Scobie , Olga Loseva , Ingrid Almlöf , Judith Edda Unterlass , Aleksandra Pettke , Johan Boström , Monica Pandey , Helge Gad , Patrick Herr , Ann-Sofie Jemth , Samir El andaloussi , Christina Kalderén , Sandra Rodriguez-Perales , Javier Benítez , Hans E Krokan , Mikael Altun , Pal Stenmark , Ulrika Warpman Berglund , Thomas Helleday Nucleic Acids Research 434 DOI: 10.1093/nar/gkaa1048 Diamond Proposal Number(s): [15806] Open Access Show Abstract ▼ Abstract: 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 approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.	Nov 2020
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation Torkild Visnes , Armando Cázares-Körner , Wenjing Hao , Olov Wallner , Geoffrey Masuyer , Olga Loseva , Oliver Mortusewicz , Elisée Wiita , Antonio Sarno , Aleksandr Manoilov , Juan Astorga-Wells , Ann-Sofie Jemth , Lang Pan , Kumar Sanjiv , Stella Karsten , Camilla Gokturk , Maurice Grube , Evert J. Homan , Bishoy M. F. Hanna , Cynthia B. J. Paulin , Therese Pham , Azita Rasti , Ulrika Warpman Berglund , Catharina Von Nicolai , Carlos Benitez-Buelga , Tobias Koolmeister , Dag Ivanic , Petar Iliev , Martin Scobie , Hans E. Krokan , Pawel Baranczewski , Per Artursson , Mikael Altun , Annika Jenmalm Jensen , Christina Kalderén , Xueqing Ba , Roman A. Zubarev , Pal Stenmark , Istvan Boldogh , Thomas Helleday Science 362, 834 - 839 DOI: 10.1126/science.aar8048 Diamond Proposal Number(s): [15806] Show Abstract ▼ Abstract: 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.	Nov 2018
I04-1-Macromolecular Crystallography (fixed wavelength)	Fragment-based discovery and optimization of enzyme inhibitors by docking of commercial chemical space Axel Rudling , Robert Gustafsson , Ingrid Almlöf , Evert J. Homan , Martin Scobie , Ulrika Warpman Berglund , Thomas Helleday , Pal Stenmark , Jens Carlsson Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.7b01006 Diamond Proposal Number(s): [11265] Show Abstract ▼ Abstract: Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Despite that fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0.3 million fragments to a crystal structure of cancer target MTH1 was performed. Twenty-two predicted fragment ligands, for which analogs could be acquired commercially, were experimentally evaluated. Five fragments inhibited MTH1 with IC50 values ranging from 6 to 79 μM. Structure-based optimization guided by predicted binding modes and analogs from commercial chemical libraries yielded nanomolar inhibitors. Subsequently solved crystal structures confirmed binding modes predicted by docking for three scaffolds. Structure-guided exploration of commercial chemical space using molecular docking gives access to fragment libraries that are several orders of magnitude larger than those screened experimentally and can enable efficient optimization of hits to potent leads.	Sep 2017

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