EUbOPEN: Enabling and Unlocking biology in the OPEN

Livrables

1,500 proteins purified at a rate of approximately 300 per year (reported at M12, M36, M60). Expression constructs and proteins will be produced by UOXF, GUF, KI, UNIVDUN, LUMC, with contributions from EFPIA and Associated Partners where applicable.

Applied to ≥2 new chemical series in year 3

First version of platform for automated compound synthesis applied to 2 new scaffoldsyear M36 M60

Additional ten PCAs established and/or optimised (20 in total)

Ten PCAs established and/or optimised (20 in total, 10 by month 24 and additional 10 by month 48).

Family wide screening platform for kinases using NanoBRET or ABPP technology

Family wide screening platform for kinases and one new family using NanoBRET or ABPP technology M24 M60

40 CRISPR knockout cell lines in year 1

40 CRISPR knockout cell lines per year (total 160) (M12, M36, M48).

First set of community engagement events or symposium held

Community engagement events and symposia held

Deposit intermediate set of data in sustainable resources
Evaluation of Raman assays and establishment of protocols in cell culture and patient-derived tissues

Evaluation of Raman assays and establishment of protocols in cell culture and patient-derived tissues.

Data for initial CG set released

Data for each Chemogenomic set release in EUbOPEN gateway Zenodo

50 targets enabled with in vitro assays and 30 targets with cellular assays

D5.1 250 targets enabled with assays for chemical probe discovery and optimisation at a rate of approximately 50 per year and 150 targets enabled with an in-cell target engagement assay at a rate of about 30 per year (M12, M36, M60).

EUbOPEN database gateway development

EUbOPEN database gateway specification and further development

Acquisition of > 500 compounds for CGL covering >250 targets

Acquisition of CG compounds (500 compounds/year) from commercial sources, academic partners and EFPIA.

EUbOPEN database gateway specification

EUbOPEN database gateway specification and further development.

Guiding principles for global network with similar organisations

Guiding principles for global network with similar organisations.

Five aggregated, anonymized and quality assured screening data sets released to the public

Five aggregated anonymized and quality assured screening data sets released to the public on annual basis through project website and other dissemination channels

20 recombinant antibodies or binders in year 2 and 3

50 recombinant antibodies or other binders at a rate of about 10 per year reported at M12 M36 M60 Binders will be generated by KI and ReSOLUTE with donations from Pharma partners

100 protein structures in year 1

100 protein structures in year 1.

Standardized chip design and processing established

Standardized chip design and processing established.

20 CP in year 1

20 EUbOPEN-generated CPs in year 1, including EFPIA contributions and jointly generated CPs as well as contributions from other scientists outside EUbOPEN.

First version of platform for automated compound synthesis

First version of platform for automated compound synthesis M24

Additional five aggregated, anonymized and quality assured screening data sets released to the public

Five aggregated anonymized and quality assured screening data sets released to the public on annual basis through project website and other dissemination channels

First EUbOPEN website review and development

EUbOPEN website development with regular reviews and updates

Update on web-based internal database system development

Webbased internal database system implementation and development

Intermediate release of curated CG compound profiling data

Release of curated CGL profiling data

First review of data ontology

Data ontology defined by working group and regularly reviewed

Acquisition of > 2,000 compounds for CGL covering >750 new targets

Acquisition of CG compounds (500 compounds/year) from commercial sources, academic partners and EFPIA.

Web-based internal database system initial implementation

Web-based internal database system implementation and development.

LiP-MS or BioID datasets of ≥10 probe-cell interactions

LiPMS datasets of 5 probecell interactionsyear M36 M60

Agreed quality control criteria approved by JMC

Agreed quality control criteria approved by JMC.

Ten PCAs established and/or optimised (20 in total)

Ten PCAs established andor optimised 20 in total 10 by month 24 and additional 10 by month 48

>1500 novel CG compounds sourced

At least 1500 CG compounds sourced or synthesised .

600 proteins purified in year 2 and 3

1500 proteins purified at a rate of approximately 300 per year reported at M12 M36 M60 Expression constructs and proteins will be produced by UOXF GUF KI UNIVDUN LUMC with contributions from EFPIA and Associated Partners where applicable

Data ontology defined by working group

Data ontology defined by working group.

A total of fifteen aggregated, anonymized and quality assured screening data sets released to the public

Five aggregated, anonymized and quality assured screening data sets released to the public on annual basis through project website and other dissemination channels.

40 CP in year 2 and 3

40 EUbOPENgenerated CPs in year 2 and 3 to a total of 60 CPs The CPs will include EFPIA contributions and jointly generated CPs as well as contributions from other scientists outside EUbOPEN

10 recombinant antibodies or binders in year 1

50 recombinant antibodies or other binders at a rate of about 10 per year (reported at M12, M36, M60). Binders will be generated by KI and ReSOLUTE with donations from Pharma partners.

Data deposition of genome/proteome wide analysis for >60 CG compounds

Genomeproteome wide analysis of subset of CG compounds 150 in total and deposition of data in sustainable resources M24 M60

100 targets enabled with in vitro assays and 60 targets with cellular assays in year 2 and 3

D51 250 targets enabled with assays for chemical probe discovery and optimisation at a rate of approximately 50 per year and 150 targets enabled with an incell target engagement assay at a rate of about 30 per year M12 M36 M60

Steady state sample access (1-2 per week) from IBD and CRC

Steady state sample access (1-2 per week) from IBD and CRC.

Establish data publication standard and database
200 protein structures in years 2 and 3

200 protein structures in year 2 and 3

Assembly of expanded reaction toolkit and fragment set for plate-based chemistry

Assembly of expanded reaction toolkit and fragment set for platebased chemistry

New protein family sentinel selectivity panel

New protein family sentinel selectivity panel for three families

Initial protocols made openly available through portal and public databases

Protocols made openly available through portal and public databases

Partnerships with >25 international partners

Partnerships with 25 international organisations with efforts in screening assay development patientderived cell assays chemical screening chemical probe generation and compound profiling established

80 CRISPR knockout cell lines in years 2 and 3

40 CRISPR knockout cell lines per year total 160 M12 M36 M48

Online compound ordering system for the public

Online compound ordering system for the public operational.

EUbOPEN website implementation

EUbOPEN website development with regular reviews and updates (M3, M36, M60).

Define criteria for compounds of CGL

The criteria underlying the list of targets to be covered by the CGL will be defined by the JMC and TPN (M3), and surveyed in regular meetings to govern the activities of Pillar 1.

Define target list of 1,000 targets

Defined target list of 1,000 proteins covered by the CGL.

Revised target list

The target list will be revised during the project.

Distribution of additionally approved CG sets and CP

Additionally approved CGs and CPs will be assembled and released with appropriate instructions to the public.

Extended FRAGALYSIS cloud infrastructure for in silico compound design

Extended FRAGALYSIS cloud infrastructure for in silico compound design Comprehensive compound prioritisation based on commercially available compounds

Extended FRAGALYSIS cloud infrastructure for de novo compound design

FRAGALYSIS de novo compound design interface compatible with platforms for automated compound synthesis.

Distribution of approved CG sets and CP

Newly approved CGs and CPs will be assembled and released with appropriate instructions to the public.

Publications

Comparative structural analyses of the NHL domains from the human E3 ligase TRIM-NHL family

Auteurs: Chaikuad A, Zhubi R, Tredup C, Knapp S.
Publié dans: IUCr, 2022, ISSN 2052-2525
Éditeur: IUCr Journals
DOI: 10.1107/s2052252522008582

Technologies for Direct Detection of Covalent Protein–Drug Adducts

Auteurs: Elma Mons, Robbert Q. Kim, Monique P. C. Mulder
Publié dans: Pharmaceuticals, 2023, ISSN 1424-8247
Éditeur: Multidisciplinary Digital Publishing Institute (MDPI)
DOI: 10.3390/ph16040547

Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile-Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence.

Auteurs: Zhou J, Horton JR, Menna M, Fiorentino F, Ren R, Yu D, Hajian T, Vedadi M, Mazzoccanti G, Ciogli A, Weinhold E, HÃ¼ben M, Blumenthal RM, Zhang X, Mai A, Rotili D, Cheng X
Publié dans: J Med Chem, 2022, ISSN 0022-2623
Éditeur: American Chemical Society
DOI: 10.1021/acs.jmedchem.2c01789

Building ubiquitination machineries: E3 ligase multi-subunit assembly and substrate targeting by PROTACs and molecular glues

Auteurs: Sarath Ramachandran, Alessio Ciulli
Publié dans: Current Opinion in Structural Biology, Numéro 67, 2021, Page(s) 110-119, ISSN 0959-440X
Éditeur: Elsevier BV
DOI: 10.1016/j.sbi.2020.10.009

Development of a Selective Dual Discoidin Domain Receptor (DDR)/p38 Kinase Chemical Probe.

Auteurs: Rohm, S., Berger, B. T., Schroder, M., Chatterjee, D., Mathea, S., Joerger, A. C., Pinkas, D. M., Bufton, J. C., Tjaden, A., Kovooru, L., Kudolo, M., Pohl, C., Bullock, A. N., Muller, S., Laufer, S. and Knapp, S
Publié dans: J Med Chem., 2021, ISSN 0022-2623
Éditeur: American Chemical Society
DOI: 10.1021/acs.jmedchem.1c00868

Development and Characterization of Type I, Type II, and Type III LIM-Kinase Chemical Probes

Auteurs: Hanke T, Mathea S, Woortman J, Salah E, Berger BT, Tumber A, Kashima R, Hata A, Kuster B, Müller S, Knapp S. J Med Chem 2022.
Publié dans: Journal of Medicinal Chemistry, 2022, ISSN 0022-2623
Éditeur: American Chemical Society
DOI: 10.1021/acs.jmedchem.2c01106

Breaking free from the crystal lattice: Structural biology in solution to study protein degraders

Auteurs: Kevin Haubrich; Valentina A. Spiteri; William Farnaby; Frank Sobott; Alessio Ciulli
Publié dans: Crossref, Numéro 2, 2023, ISSN 0346-251X
Éditeur: Pergamon Press Ltd.
DOI: 10.1016/j.sbi.2023.102534

Ubiquitin ligases: guardians of mammalian development

Auteurs: Cruz Walma, D. A., Chen, Z., Bullock, A. N. and Yamada, K. M
Publié dans: Nat Rev Mol Cell Biol, 2022, ISSN 1471-0072
Éditeur: Nature Publishing Group
DOI: 10.1038/s41580-021-00448-5

Hepatic miR-144 Drives Fumarase Activity Preventing NRF2 Activation During Obesity

Auteurs: Azzimato, V., Chen, P., Barreby, E., Morgantini, C., Levi, L., Vankova, A., ... & Aouadi, M.
Publié dans: Gastroenterology, 2021, ISSN 0016-5085
Éditeur: W. B. Saunders Co., Ltd.
DOI: 10.1053/j.gastro.2021.08.030

Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation.

Auteurs: Fraser BJ, Beldar S, Seitova A, Hutchinson A, Mannar D, Li Y, Kwon D, Tan R, Wilson RP, Leopold K, Subramaniam S, Halabelian L, Arrowsmith CH, BÃ©nard F
Publié dans: Nat Chem Biol, 2022, ISSN 1552-4450
Éditeur: Nature Publishing Group
DOI: 10.1038/s41589-022-01059-7

The ethnogeographic variability of genetic factors underlying G6PD deficiency

Auteurs: Koromina, M., Pandi, M. T., van der Spek, P. J., Patrinos, G. P., & Lauschke, V. M.
Publié dans: Pharmacological Research, 2021, ISSN 1043-6618
Éditeur: Academic Press
DOI: 10.1016/j.phrs.2021.105904

Population-scale predictions of DPD and TPMT phenotypes using a quantitative pharmacogene-specific ensemble classifier

Auteurs: Yitian Zhou, Carolina Dagli Hernandez, Volker M. Lauschke
Publié dans: British Journal of Cancer, Numéro 123/12, 2020, Page(s) 1782-1789, ISSN 0007-0920
Éditeur: Nature Publishing Group
DOI: 10.1038/s41416-020-01084-0

Histone lysine methacrylation is a dynamic post-translational modification regulated by HAT1 and SIRT2

Auteurs: Delaney K, Tan M, Zhu Z, Gao J, Dai L, Kim S, Ding J, He M, Halabelian L, Yang L, Nagarajan P, Parthun MR, Lee S, Khochbin S, Zheng YG, Zhao Y
Publié dans: Cell Discov, 2022, ISSN 2056-5968
Éditeur: Nature Publishing Group
DOI: 10.1038/s41421-021-00344-4

PRMT inhibition induces a viral mimicry response in triple-negative breast cancer.

Auteurs: Wu Q, Nie DY, Ba-Alawi W, Ji Y, Zhang Z, Cruickshank J, Haight J, Ciamponi FE, Chen J, Duan S, Shen Y, Liu J, Marhon SA, Mehdipour P, Szewczyk MM, Dogan-Artun N, Chen W, Zhang LX, Deblois G, Prinos P, Massirer KB, Barsyte-Lovejoy D, Jin J, De Carvalho DD, Haibe-Kains B, Wang X, Cescon DW, Lupien M, Arrowsmith CH
Publié dans: Nature Chemical Biology, 2022, ISSN 1552-4450
Éditeur: Nature Publishing Group
DOI: 10.1038/s41589-022-01024-4

High-content live-cell multiplex screen for chemogenomic compound annotation based on nuclear morphology

Auteurs: Tjaden A, Giessmann RT, Knapp S, Schröder M, Müller S.
Publié dans: STAR Protoc., 2022, ISSN 2666-1667
Éditeur: Cell Press
DOI: 10.1016/j.xpro.2022.101791

No shortcuts to SARS-CoV-2 antivirals.

Auteurs: Edwards A, Hartung IV
Publié dans: Science, 2021, ISSN 0036-8075
Éditeur: American Association for the Advancement of Science
DOI: 10.1126/science.abj9488

Crystal Structure-Guided Design of Bisubstrate Inhibitors and Photoluminescent Probes for Protein Kinases of the PIM Family

Auteurs: Olivier E. Nonga, Darja Lavogina, Erki Enkvist, Katrin Kestav, Apirat Chaikuad, Sarah E. Dixon-Clarke, Alex N. Bullock, Sergei Kopanchuk, Taavi Ivan, Ramesh Ekambaram, Kaido Viht, Stefan Knapp, Asko Uri
Publié dans: Molecules, Numéro 26/14, 2021, Page(s) 4353, ISSN 1420-3049
Éditeur: Multidisciplinary Digital Publishing Institute (MDPI)
DOI: 10.3390/molecules26144353

Mutation in Abl kinase with altered drug-binding kinetics indicates a novel mechanism of imatinib resistance

Auteurs: Lyczek A, Berger BT, Rangwala AM, Paung Y, Tom J, Philipose H, Guo J, Albanese SK, Robers MB, Knapp S, Chodera JD, Seeliger MA.
Publié dans: Proc Natl Acad Sci U S A, 2021, ISSN 0027-8424
Éditeur: National Academy of Sciences
DOI: 10.1073/pnas.2111451118

The Kinase Chemogenomic Set (KCGS): An Open Science Resource for Kinase Vulnerability Identification

Auteurs: Carrow I. Wells, Hassan Al-Ali, David M. Andrews, Christopher R. M. Asquith, Alison D. Axtman, Ivan Dikic, Daniel Ebner, Peter Ettmayer, Christian Fischer, Mathias Frederiksen, Robert E. Futrell, Nathanael S. Gray, Stephanie B. Hatch, Stefan Knapp, Ulrich Lücking, Michael Michaelides, Caitlin E. Mills, Susanne Müller, Dafydd Owen, Alfredo Picado, Kumar S. Saikatendu, Martin Schröder, Alexandra
Publié dans: International Journal of Molecular Sciences, Numéro 22/2, 2021, Page(s) 566, ISSN 1422-0067
Éditeur: Multidisciplinary Digital Publishing Institute (MDPI)
DOI: 10.3390/ijms22020566

Post-transcriptional and Post-translational Modifications of Primary Cilia: How to Fine Tune Your Neuronal Antenna.

Auteurs: Rocha C, Prinos P
Publié dans: Front Cell Neurosci, 2022, ISSN 1662-5102
Éditeur: Frontiers Research Foundation
DOI: 10.3389/fncel.2022.809917

DFG-1 Residue Controls Inhibitor Binding Mode and Affinity, Providing a Basis for Rational Design of Kinase Inhibitor Selectivity

Auteurs: Martin Schröder, Alex N. Bullock, Oleg Fedorov, Franz Bracher, Apirat Chaikuad, Stefan Knapp
Publié dans: Journal of Medicinal Chemistry, Numéro 63/18, 2020, Page(s) 10224-10234, ISSN 0022-2623
Éditeur: American Chemical Society
DOI: 10.1021/acs.jmedchem.0c00898

Genotoxicity and Epigenotoxicity of Carbazole-Derived Molecules on MCF-7 Breast Cancer Cells

Auteurs: Claudio Luparello, Ilenia Cruciata, Andreas C. Joerger, Cory A. Ocasio, Rhiannon Jones, Raysa Khan Tareque, Mark C. Bagley, John Spencer, Martin Walker, Carol Austin, Tiziana Ferrara, Pietro D′Oca, Rossella Bellina, Rossella Branni, Fabio Caradonna
Publié dans: International Journal of Molecular Sciences, Numéro 22/7, 2021, Page(s) 3410, ISSN 1422-0067
Éditeur: Multidisciplinary Digital Publishing Institute (MDPI)
DOI: 10.3390/ijms22073410

Autoantibodies against Four-and-a-Half-LIM Domain 1 (FHL1) in Inflammatory Myopathies: Results from an Australian Single-Center Cohort.

Auteurs: Galindo-Feria AS, Horuluoglu B, Day J, Fernandes-Cerqueira C, Wigren E, Gräslund S, Proudman S, Lundberg IE, Limaye V
Publié dans: Rheumatology, 2022, ISSN 1462-0324
Éditeur: Oxford University Press
DOI: 10.1093/rheumatology/keac003

SS148 and WZ16 inhibit the activities of nsp10-nsp16 complexes from all seven human pathogenic coronaviruses.

Auteurs: Li F, Ghiabi P, Hajian T, Klima M, Li ASM, Yazdi AK, Chau I, Loppnau P, Kutera M, Seitova A, Bolotokova A, Hutchinson A, Perveen S, Boura E, Vedadi M
Publié dans: Biochim Biophys Acta, 2023, ISSN 0304-4165
Éditeur: Elsevier BV
DOI: 10.1016/j.bbagen.2023.130319

Prediction and Validation of a Protein's Free Energy Surface Using Hydrogen Exchange and (Importantly) Its Denaturant Dependence.

Auteurs: Peng X, Baxa M, Faruk N, Sachleben JR, Pintscher S, Gagnon IA, Houliston S, Arrowsmith CH, Freed KF, Rocklin GJ, Sosnick TR
Publié dans: J Chem Theory Comput, 2021, ISSN 1549-9618
Éditeur: American Chemical Society
DOI: 10.1021/acs.jctc.1c00960

Discovery and Characterization of BAY-805, a Potent and Selective Inhibitor of Ubiquitin-Specific Protease USP21

Auteurs: Fabian Göricke; Victoria Vu; Leanna Smith; Ulrike Scheib; Raphael Böhm; Namik Akkilic; Gerd Wohlfahrt; Jörg Weiske; Ulf Bömer; Krzysztof Brzezinka; Niels Lindner; Philip Lienau; Stefan Gradl; Hartmut Beck; Peter J. Brown; Vijayaratnam Santhakumar; Masoud Vedadi; Dalia Barsyte-Lovejoy; Cheryl H. Arrowsmith; Norbert Schmees; Kirstin Petersen
Publié dans: Crossref, Numéro 3, 2023, ISSN 0022-2623
Éditeur: American Chemical Society
DOI: 10.1021/acs.jmedchem.2c01933

7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a “Cut and Glue” Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors

Auteurs: Mehmet Karatas, Apirat Chaikuad, Bianca Berger, Michael H. G. Kubbutat, Frank Totzke, Stefan Knapp, Conrad Kunick
Publié dans: Molecules, Numéro 26/6, 2021, Page(s) 1611, ISSN 1420-3049
Éditeur: Multidisciplinary Digital Publishing Institute (MDPI)
DOI: 10.3390/molecules26061611

Pharmacogenomics in the era of next generation sequencing – from byte to bedside

Auteurs: Laura E. Russell, Yitian Zhou, Ahmed A. Almousa, Jasleen K. Sodhi, Chukwunonso K. Nwabufo, Volker M. Lauschke
Publié dans: Drug Metabolism Reviews, 2021, Page(s) 1-26, ISSN 0360-2532
Éditeur: Marcel Dekker Inc.
DOI: 10.1080/03602532.2021.1909613

Structure and Function of Protein Arginine Methyltransferase PRMT7.

Auteurs: Halabelian L, Barsyte-Lovejoy D
Publié dans: Life (Basel), 2021, ISSN 2075-1729
Éditeur: MDPI
DOI: 10.3390/life11080768

Scaffold hopping from amodiaquine to novel Nurr1 agonist chemotypes via microscale analogue libraries.

Auteurs: Willems, S.; Müller, M.; Ohrndorf, J.; Heering, J.; Proschak, E.; Merk, D.
Publié dans: ChemMedChem, 2022, ISSN 1860-7179
Éditeur: Wiley - V C H Verlag GmbbH & Co.
DOI: 10.1002/cmdc.202200026

Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2

Auteurs: Sven H. Schmidt, Jui-Hung Weng, Phillip C. Aoto, Daniela Boassa, Sebastian Mathea, Steve Silletti, Junru Hu, Maximilian Wallbott, Elizabeth A. Komives, Stefan Knapp, Friedrich W. Herberg, Susan S. Taylor
Publié dans: Proceedings of the National Academy of Sciences, Numéro 118/23, 2021, Page(s) e2100844118, ISSN 0027-8424
Éditeur: National Academy of Sciences
DOI: 10.1073/pnas.2100844118

Integrated analysis of Shank1 PDZ interactions with C-terminal and internal binding motifs

Auteurs: Muhammad Ali, Mishal Mariam McAuley, Susanne Lüchow, Stefan Knapp, Andreas C. Joerger, Ylva Ivarsson
Publié dans: Current Research in Structural Biology, Numéro 3, 2021, Page(s) 41-50, ISSN 2665-928X
Éditeur: Elsevier
DOI: 10.1016/j.crstbi.2021.01.001

Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation

Auteurs: Chen, Z., Ioris, R. M., Richardson, S., Van Ess, A. N., Vendrell, I., Kessler, B.M., Buffa, F.M., Busino, L., Clifford, S. C., Bullock, A. N. D'Angiolella, V.
Publié dans: Cell Death Differ., 2022, ISSN 1350-9047
Éditeur: Nature Publishing Group
DOI: 10.1038/s41418-022-00983-4

Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1.

Auteurs: Harding RJ, Deme JC, Hevler JF, Tamara S, Lemak A, Cantle JP, Szewczyk MM, Begeja N, Goss S, Zuo X, Loppnau P, Seitova A, Hutchinson A, Fan L, Truant R, Schapira M, Carroll JB, Heck AJR, Lea SM, Arrowsmith CH
Publié dans: Commun Biol, 2021, ISSN 2399-3642
Éditeur: Springer Nature
DOI: 10.1038/s42003-021-02895-4

Discovery of Nanomolar DCAF1 Small Molecule Ligands.

Auteurs: Li ASM, Kimani S, Wilson B, Noureldin M, GonzÃ¡lez-Ãlvarez H, Mamai A, Hoffer L, Guilinger JP, Zhang Y, von Rechenberg M, Disch JS, Mulhern CJ, Slakman BL, Cuozzo JW, Dong A, Poda G, Mohammed M, Saraon P, Mittal M, Modh P, Rathod V, Patel B, Ackloo S, Santhakumar V, Szewczyk MM, Barsyte-Lovejoy D, Arrowsmith CH, Marcellus R, GuiÃ© MA, Keefe AD, Brown PJ, Halabelian L, Al-Awar R, Vedadi M
Publié dans: Journal of Medicinal Chemistry, 2023, ISSN 0022-2623
Éditeur: American Chemical Society
DOI: 10.1021/acs.jmedchem.2c02132

Toxicogenomics of drug induced liver injury – from mechanistic understanding to early prediction.

Auteurs: Volker M. Lauschke
Publié dans: Drug Metabolism Reviews, 2021, Page(s) 1-8, ISSN 0360-2532
Éditeur: Marcel Dekker Inc.
DOI: 10.1080/03602532.2021.1894571

De novo design of immunoglobulin-like domains.

Auteurs: Chidyausiku TM, Mendes SR, Klima JC, Nadal M, Eckhard U, Roel-Touris J, Houliston S, Guevara T, Haddox HK, Moyer A, Arrowsmith CH, Gomis-RÃ¼th FX, Baker D, Marcos E
Publié dans: Nat Commun, 2022, ISSN 2041-1723
Éditeur: Nature Publishing Group
DOI: 10.1038/s41467-022-33004-6

Covalent Proximity Scanning of a Distal Cysteine to Target PI3Kα

Auteurs: Chiara Borsari, Erhan Keles, Jacob A. McPhail, Alexander Schaefer, Rohitha Sriramaratnam, Wojciech Goch, Thorsten Schaefer, Martina De Pascale, Wojciech Bal, Matthias Gstaiger, John E. Burke, and Matthias P. Wymann
Publié dans: Journal of the American Chemical Society, 2022, ISSN 0002-7863
Éditeur: American Chemical Society
DOI: 10.1021/jacs.1c13568

ProxyBind: A compendium of binding sites for proximity-induced pharmacology.

Auteurs: Rovers E, Liu L, Schapira M
Publié dans: Computational and Structural Biotechnology Journal, 2022, ISSN 2001-0370
Éditeur: Elsevier
DOI: 10.1016/j.csbj.2022.11.010

Nurr1 Modulation Mediates Neuroprotective Effects of Statins

Auteurs: Sabine Willems, Julian A. Marschner, Whitney Kilu, Giuseppe Faudone, Romy Busch, Silke Duensing-Kropp, Jan Heering, Daniel Merk
Publié dans: Adv. Sci, 2022, ISSN 2198-3844
Éditeur: Willey-VCH
DOI: 10.1002/advs.202104640

E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones

Auteurs: Tasuku Ishida, Alessio Ciulli
Publié dans: SLAS DISCOVERY: Advancing the Science of Drug Discovery, Numéro 26/4, 2021, Page(s) 484-502, ISSN 2472-5552
Éditeur: SAGE Journals
DOI: 10.1177/2472555220965528

Role of FAM134 paralogues in endoplasmic reticulum remodeling, ER‐phagy, and Collagen quality control

Auteurs: Alessio Reggio, Viviana Buonomo, Rayene Berkane, Ramachandra M Bhaskara, Mariana Tellechea, Ivana Peluso, Elena Polishchuk, Giorgia Di Lorenzo, Carmine Cirillo, Marianna Esposito, Adeela Hussain, Antje K Huebner, Christian A Hübner, Carmine Settembre, Gerhard Hummer, Paolo Grumati, Alexandra Stolz
Publié dans: EMBO reports, 2021, ISSN 1469-221X
Éditeur: Nature Publishing Group
DOI: 10.15252/embr.202052289

Target 2035 - update on the quest for a probe for every protein.

Auteurs: Muller, S., Ackloo, S., Al Chawaf, A., Al-Lazikani, B., Antolin, A., Baell, J. B., Beck, H., Beedie, S., Betz, U. A. K., Bezerra, G. A., Brennan, P. E., Brown, D., Brown, P. J., Bullock, A. N., Carter, A. J., Chaikuad, A., Chaineau, M., Ciulli, A., Collins, I., Dreher, J., Drewry, D., Edfeldt, K., Edwards, A. M., Egner, U., Frye, S. V., Fuchs, S. M., Hall, M. D., Hartung, I. V., Hillisch, A., Hitc
Publié dans: RSC Medicinal Chemistry, 2022, ISSN 2046-2069
Éditeur: Royal Society of Chemistry
DOI: 10.1039/d1md00228g

Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations

Auteurs: Lukas Grätz, Maria Kowalski-Jahn, Magdalena M. Scharf, Pawel Kozielewicz, Michael Jahn, Julien Bous, Nevin A. Lambert, David E. Gloriam & Gunnar Schulte
Publié dans: Nature Communications, 2023, ISSN 2041-1723
Éditeur: Nature Publishing Group
DOI: 10.1038/s41467-023-40213-0

A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II.

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Enzymatic nucleosome acetylation selectively affects activity of histone methyltransferases in vitro

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ChemBioPort: an online portal to navigate the structure, function and chemical inhibition of the human proteome

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A Consensus Compound/Bioactivity Dataset for Data-Driven Drug Design and Chemogenomics

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The Past, Present and Future of Intestinal In Vitro Cell Systems for Drug Absorption Studies

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Longitudinal assessment of reactivity and affinity profile of anti-Jo1 autoantibodies to distinct HisRS domains and a splice variant in a cohort of patients with myositis and anti-synthetase syndrome

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Target 2035 – an update on private sector contributions

Auteurs: Suzanne Ackloo, * a Albert A. Antolin, b Jose Manuel Bartolome, c Hartmut Beck, d Alex Bullock, e Ulrich A. K. Betz, f Jark Böttcher, g Peter J. Brown, h Menorca Chaturvedi, i Alisa Crisp,j Danette Daniels, k Jan Dreher, d Kristina Edfeldt, l Aled M. Edwards, a Ursula Egner, m Jon Elkins, e Christian Fischer, n Tine Glendorf, o Steven Goldberg, p Ingo V. Hartung, q Alexander Hillisch, d Evert Hom
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Recent developments in in vitro and in vivo models for improved translation of preclinical pharmacokinetics and pharmacodynamics data

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Assessing reversible and irreversible binding effects of kinase covalent inhibitors through ADP-Glo assays.

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The human pseudouridine synthase PUS7 recognizes RNA with an extended multi-domain binding surface.

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Human resident liver myeloid cells protect against metabolic stress in obesity

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Assembly and Application of a Low Budget Photoreactor**

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A Screening of Epigenetic Therapeutic Targets for Non-Small Cell Lung Cancer Reveals PADI4 and KDM6B as Promising Candidates

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Calcium/calmodulin-dependent protein kinase kinase 2 regulates hepatic fuel metabolism

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Chemical Toolkit for PARK7: Potent, Selective, and High-Throughput

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Insulin‐dependent glucose consumption dynamics in 3D primary human liver cultures measured by a sensitive and specific glucose sensor with nanoliter input volume

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Selective BH3 mimetics synergize with BET inhibition to induce mitochondrial apoptosis in rhabdomyosarcoma cells

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Detection of antibodies against the huntingtin protein in human plasma.

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Rare genetic variability in human drug target genes modulates drug response and can guide precision medicine

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A Chemical Toolbox for Labeling and Degrading Engineered Cas Proteins

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Cdyl Deficiency Brakes Neuronal Excitability and Nociception through Promoting Kcnb1 Transcription in Peripheral Sensory Neurons.

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Amide-to-ester substitution as a strategy for optimizing PROTAC permeability and cellular activity

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A Concerted Action of UBA5 C-Terminal Unstructured Regions Is Important for Transfer of Activated UFM1 to UFC1

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The MYC oncoprotein directly interacts with its chromatin cofactor PNUTS to recruit PP1 phosphatase.

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The Structure-Based Design of SARS-CoV-2 nsp14 Methyltransferase Ligands Yields Nanomolar Inhibitors.

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Discovery of a Chemical Probe to Study Implications of BPTF Bromodomain Inhibition in Cellular and in vivo Experiments

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In vitro and ex vivo modeling of enteric bacterial infections

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Single tracer-based protocol for broad-spectrum kinase profiling in live cells with NanoBRET

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Structure and Inhibitor Binding Characterization of Oncogenic MLLT1 Mutants

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Exploiting vulnerabilities of SWI/SNF chromatin remodelling complexes for cancer therapy

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Arginine ADP-Ribosylation: Chemical Synthesis of Post-Translationally Modified Ubiquitin Proteins

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Sequence and structural variations determining the recruitment of WNK kinases to the KLHL3 E3 ligase.

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A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization.

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Cellular shape reinforces niche to stem cell signaling in the small intestine

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Current Advances in CETSA

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PRMT5 regulates ATF4 transcript splicing and oxidative stress response.

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Structural and functional characterization of ubiquitin variant inhibitors for the JAMM-family deubiquitinases STAMBP and STAMBPL1.

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Chemical Starting Matter for HNF4α Ligand Discovery and Chemogenomics

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Human MettL3-MettL14 RNA adenine methyltransferase complex is active on double-stranded DNA containing lesions.

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Stopping pandemics before they start: Lessons learned from SARS-CoV-2

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A pro-Fluorescent Ubiquitin-based Probe to Monitor Cysteine-based E3 Ligase Activity

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Computational tools to assess the functional consequences of rare and noncoding pharmacogenetic variability

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Binding Adaptation of GS-441524Diversifies Macro Domains and Down-regulates SARS-CoV-2 de-MARylationCapacity

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Pharmacogene Sequencing of a Gabonese Population with Severe Plasmodium falciparum Malaria Reveals Multiple Novel Variants with Putative Relevance for Antimalarial Treatment

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Open resources for chemical probes and their implications for future drug discovery

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Automated Determination of Nuclear Magnetic Resonance Chemical Shift Perturbations in Ligand Screening Experiments: The PICASSO Web Server

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Discovery of Conformationally Constrained ALK2 Inhibitors

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Image-Based Annotation of Chemogenomic Libraries for Phenotypic Screening

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LRRK2 dynamics analysis identifies allosteric control of the crosstalk between its catalytic domains

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Bioengineered Pancreas–Liver Crosstalk in a Microfluidic Coculture Chip Identifies Human Metabolic Response Signatures in Prediabetic Hyperglycemia

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The Small-Molecule Inhibitor MRIA9 Reveals Novel Insights into the Cell Cycle Roles of SIK2 in Ovarian Cancer Cells

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Nudix hydrolase 18 catalyzes the hydrolysis of active triphosphate metabolites of the antivirals remdesivir, ribavirin, and molnupiravir

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PRMT7 ablation stimulates anti-tumor immunity and sensitizes melanoma to immune checkpoint blockade.

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The ChEMBL Database in 2023: a drug discovery platform spanning multiple bioactivity data types and time periods

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Phosphorylation-linked complex profiling identifies assemblies required for Hippo signal integration

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Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK

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Reprogramming Transcription Factors Oct4 and Sox2 Induce a BRD-Dependent Immunosuppressive Transcriptome in GBM-Propagating Cells.

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A Toolbox for the Generation of Chemical Probes for Baculovirus IAP Repeat Containing Proteins

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RAS and PP2A activities converge on epigenetic gene regulation.

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Trends in kinase drug discovery: targets, indications and inhibitor design.

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3D Adipose Tissue Culture Links the Organotypic Microenvironment to Improved Adipogenesis

Auteurs: Joanne X. Shen, Morgane Couchet, Jérémy Dufau, Thais de Castro Barbosa, Maximilian H. Ulbrich, Martin Helmstädter, Aurino M. Kemas, Reza Zandi Shafagh, Marie‐Adeline Marques, Jacob B. Hansen, Niklas Mejhert, Dominique Langin, Mikael Rydén, Volker M. Lauschke
Publié dans: Advanced Science, 2021, Page(s) 2100106, ISSN 2198-3844
Éditeur: Advanced Science
DOI: 10.1002/advs.202100106

The Chemical Probes Portal: an expert review-based public resource to empower chemical probe assessment, selection and use

Auteurs: Antolin AA, Sanfelice D, Crisp A, Villasclaras Fernandez E, Mica IL, Chen Y, Collins I, Edwards A, Müller S, Al-Lazikani B, Workman P.
Publié dans: Nucleic Acids Research, 2022, ISSN 0305-1048
Éditeur: Oxford University Press
DOI: 10.1093/nar/gkac909

PharmVar GeneFocus: CYP2B6

Auteurs: Zeruesenay Desta, Ahmed El‐Boraie, Li Gong, Andrew A Somogyi, Volker M. Lauschke, Collet Dandara, Kathrin Klein, Neil A. Miller, Teri E. Klein, Rachel F. Tyndale, Michelle Whirl‐Carrillo, Andrea Gaedigk
Publié dans: Clinical Pharmacology & Therapeutics, 2021, ISSN 0009-9236
Éditeur: Nature Publishing Group
DOI: 10.1002/cpt.2166

Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Oral bioavailable and Blood Brain Barrier Penetrant PROTAC Degrader of Leucine Rich Repeat Kinase 2 (LRRK2)

Auteurs: Xingui Liu; Alexia Kalogeropulou; Sofia Domingos; Nikolai Makukhin; Raja Nirujogi; Francois Singh; Natalia Shpiro; Anton Saalfrank; Esther Sammler; Ian Ganley; Rui Moreira; Dario Alessi; Alessio Ciulli
Publié dans: Crossref, Numéro 4, 2022, ISSN 0002-7863
Éditeur: American Chemical Society
DOI: 10.26434/chemrxiv-2022-4gzm0

Organotypic human ex vivo models for coronavirus disease 2019 research and drug development

Auteurs: Sonia Youhanna, Shane C. Wright, Volker M. Lauschke
Publié dans: Current Opinion in Pharmacology, Numéro 59, 2021, Page(s) 11-18, ISSN 1471-4892
Éditeur: Elsevier BV
DOI: 10.1016/j.coph.2021.04.006

Dissecting the stability determinants of a challenging de novo protein fold using massively parallel design and experimentation.

Auteurs: Kim TE, Tsuboyama K, Houliston S, Martell CM, Phoumyvong CM, Lemak A, Haddox HK, Arrowsmith CH, Rocklin GJ
Publié dans: Proc Natl Acad Sci U S A, 2022, ISSN 0027-8424
Éditeur: National Academy of Sciences
DOI: 10.1073/pnas.2122676119

Antecedent chromatin organization determines cGAS recruitment to ruptured micronuclei.

Auteurs: MacDonald KM, Nicholson-Puthenveedu S, Tageldein MM, Khasnis S, Arrowsmith CH, Harding SM
Publié dans: Nat Commun, 2023, ISSN 2041-1723
Éditeur: Nature Publishing Group
DOI: 10.1038/s41467-023-36195-8

Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders

Auteurs: Anja Dölle, Bikash Adhikari, Andreas Krämer, Janik Weckesser, Nicola Berner, Lena-Marie Berger, Mathias Diebold, Magdalena M. Szewczyk, Dalia Barsyte-Lovejoy, Cheryl H. Arrowsmith, Jakob Gebel, Frank Löhr, Volker Dötsch, Martin Eilers, Stephanie Heinzlmeir, Bernhard Kuster, Christoph Sotriffer, Elmar Wolf, Stefan Knapp
Publié dans: Journal of Medicinal Chemistry, 2021, ISSN 0022-2623
Éditeur: American Chemical Society
DOI: 10.1021/acs.jmedchem.1c00146

The genetic landscape of major drug metabolizing cytochrome P450 genes—an updated analysis of population-scale sequencing data

Auteurs: Zhou, Y., Lauschke, V.M.
Publié dans: The Pharmacogenomics Journal, 2022, ISSN 1470-269X
Éditeur: Nature Publishing Group
DOI: 10.1038/s41397-022-00288-2

3D human liver spheroids for translational pharmacology and toxicology

Auteurs: Magnus Ingelman‐Sundberg, Volker M. Lauschke
Publié dans: Basic & Clinical Pharmacology & Toxicology, 2021, ISSN 1742-7835
Éditeur: Nordic Pharmacological Society
DOI: 10.1111/bcpt.13587

Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity

Auteurs: Imaide, S., Riching, K.M., Makukhin, N., Vetma, V., Whitworth, C., Hughes, S.J., Trainor, N., Mahan, S.D., Murphy, N., Cowan, A.D., Chan, K.-H., Craigon, C., Testa, A., Maniaci, C., Urh, M., Daniels, D.L.; Ciulli, A.
Publié dans: Nature Chemical Biology, 2021, ISSN 1552-4450
Éditeur: Nature Publishing Group
DOI: 10.1038/s41589-021-00878-4

Population pharmacogenomics: an update on ethnogeographic differences and opportunities for precision public health

Auteurs: Zhou, Y. & Lauschke, V. M.
Publié dans: Human Genetics, 2021, ISSN 0340-6717
Éditeur: Springer Verlag
DOI: 10.1007/s00439-021-02385-x

Aurora Kinase A Is Involved in Controlling the Localization of Aquaporin-2 in Renal Principal Cells

Auteurs: Baltzer S, Bulatov T, Schmied C, Krämer A, Berger BT, Oder A, Walker-Gray R, Kuschke C, Zühlke K, Eichhorst J, Lehmann M, Knapp S, Weston J, von Kries JP, Süssmuth RD, Klussmann E.
Publié dans: Int J Mol Sci, 2022, ISSN 1422-0067
Éditeur: Multidisciplinary Digital Publishing Institute (MDPI)
DOI: 10.3390/ijms23020763

Nucelotide Binding, Evolutionary Insights and Interaction Partners of the Pseudokinase Unc-51-like Kinase 4

Auteurs: Preuss, F.; Knapp,S.; Chatterjee,D.; Mathea,S.; Shrestha,S.; St-Germain,J.; Saha, S.; Kannan, N.; Raught,B.; Rottapel, R.
Publié dans: Structure, 2020, ISSN 0969-2126
Éditeur: Cell Press
DOI: 10.1016/j.str.2020.07.016

ALK2 Receptor Kinase Association with FKBP12.6 Is Structurally Conserved with the ALK2-FKBP12 Complex

Auteurs: Eleanor Williams, Elise Riesebos, Georgina Kerr, Alex N. Bullock
Publié dans: Biomedicines, Numéro 9/2, 2021, Page(s) 129, ISSN 2227-9059
Éditeur: MDPI
DOI: 10.3390/biomedicines9020129

Targeting TRIM Proteins: A Quest towards Drugging an Emerging Protein Class

Auteurs: Francesca D'Amico, Rishov Mukhopadhyay, Huib Ovaa, Monique P. C. Mulder
Publié dans: ChemBioChem, 2021, ISSN 1439-4227
Éditeur: John Wiley & Sons Ltd.
DOI: 10.1002/cbic.202000787

Phosphorylation of the DNA repair scaffold SLX4drives folding of the SAP domain and activation of theMUS81-EME1 endonucleas

Auteurs: Payliss BJ, Tse YWE, Reichheld SE, Lemak A, Yun HY, Houliston S, Patel A, Arrowsmith CH, Sharpe S, Wyatt HDM
Publié dans: Cell Reports, 2022, ISSN 2211-1247
Éditeur: Cell Press
DOI: 10.1016/j.celrep.2022.111537

JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality

Auteurs: Justin Stebbing, Ginés Sánchez Nievas, Marco Falcone, Sonia Youhanna, Peter Richardson, Silvia Ottaviani, Joanne X. Shen, Christian Sommerauer, Giusy Tiseo, Lorenzo Ghiadoni, Agostino Virdis, Fabio Monzani, Luis Romero Rizos, Francesco Forfori, Almudena Avendaño Céspedes, Salvatore De Marco, Laura Carrozzi, Fabio Lena, Pedro Manuel Sánchez-Jurado, Leonardo Gianluca Lacerenza, Nencioni Cesira,
Publié dans: Science Advances, Numéro 7/1, 2021, Page(s) eabe4724, ISSN 2375-2548
Éditeur: Science
DOI: 10.1126/sciadv.abe4724

CACHE (Critical Assessment of Computational Hit-finding Experiments): A public–private partnership benchmarking initiative to enable the development of computational methods for hit-finding

Auteurs: Ackloo S, Al-awar R, Amaro RE, Arrowsmith CH, Azevedo H, Batey RA, et al.
Publié dans: Nat Rev Chem, 2022, ISSN 1755-4330
Éditeur: Nature Publishing Group
DOI: 10.1038/s41570-022-00363-z

Structural basis of the TAM domain of BAZ2A in binding toDNA or RNA independent of methylation status

Auteurs: Chen S, Zhou M, Dong A, Loppnau P, Wang M, Min J, Liu K
Publié dans: J Biol Chem, 2021, ISSN 0021-9258
Éditeur: American Society for Biochemistry and Molecular Biology Inc.
DOI: 10.1016/j.jbc.2021.101351

JAK Inhibitors — More Than Just Glucocorticoids

Auteurs: Justin Stebbing, Volker M. Lauschke
Publié dans: New England Journal of Medicine, Numéro 385/5, 2021, Page(s) 463-465, ISSN 0028-4793
Éditeur: Massachusetts Medical Society
DOI: 10.1056/nejme2108667

DNA double-strand break-derived RNA drives TIRR/53BP1 complex dissociation

Auteurs: Ketley RF., Battistini F., Alagia A., Mondielli C., Iehl F., Balikçi E., Huber KVM., Orozco M., Gullerova M.
Publié dans: Cell Reports, 2022, ISSN 2211-1247
Éditeur: Cell Press
DOI: 10.1016/j.celrep.2022.111526

Development of potent dual BET/HDAC inhibitors<i>via</i>pharmacophore merging and structure-guided optimization

Auteurs: Nicolas Bauer; Dimitrios-Ilias Balourdas; Joel R. Schneider; Xin Zhang; Lena M. Berger; Benedict-Tilman Berger; Nick A. Klopp; Jens T. Siveke; Stefan Knapp; Andreas C. Joerger
Publié dans: Crossref, Numéro 5, 2023, ISSN 2692-8205
Éditeur: Cold Spring Harbor Laboratory
DOI: 10.1101/2023.07.18.547334

Rewiring of catecholamine-induced calcium signalling is an early event in non-alcoholic fatty liver disease

Auteurs: Shane C. Wright, Volker M. Lauschke
Publié dans: The Journal of Physiology, 2023
Éditeur: Wiley-Blackwell
DOI: 10.1113/jp284526

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