EU-OPENSCREEN: A Novel Collaborative Approach to Facilitate Chemical Biology

Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN’s compound collection, equipment, and generated data. To demonstrate the power of this collaborative approach, this perspective article highlights recent projects from EU-OPENSCREEN partner institutions. These studies yielded (1) 2-aminoquinazolin-4(3H)-ones as potential lead structures for new antimalarial drugs, (2) a novel lipodepsipeptide specifically inducing apoptosis in cells deficient for the pVHL tumor suppressor, (3) small-molecule-based ROCK inhibitors that induce definitive endoderm formation and can potentially be used for regenerative medicine, (4) potential pharmacological chaperones for inborn errors of metabolism and a familiar form of acute myeloid leukemia (AML), and (5) novel tankyrase inhibitors that entered a lead-to-candidate program. Collectively, these findings highlight the benefits of small-molecule screening, the plethora of assay designs, and the close connection between screening and medicinal chemistry within EU-OPENSCREEN.

[1]  Aurora Martínez,et al.  Early Stage Discovery and Validation of Pharmacological Chaperones for the Correction of Protein Misfolding Diseases. , 2018, Methods in molecular biology.

[2]  B. Merinero,et al.  New perspectives for pharmacological chaperoning treatment in methylmalonic aciduria cblB type. , 2018, Biochimica et biophysica acta. Molecular basis of disease.

[3]  Stefan Krauss,et al.  Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach. , 2017, Journal of medicinal chemistry.

[4]  Aurora Martínez,et al.  Conformational stabilization as a strategy to prevent nucleophosmin mislocalization in leukemia , 2017, Scientific Reports.

[5]  Kenji Schorpp,et al.  A high-content small molecule screen identifies novel inducers of definitive endoderm , 2017, Molecular metabolism.

[6]  Aurora Martínez,et al.  Pharmacological Chaperoning: A Potential Treatment for PMM2‐CDG , 2017, Human mutation.

[7]  D. Leonoudakis,et al.  A high throughput drug screening assay to identify compounds that promote oligodendrocyte differentiation using acutely dissociated and purified oligodendrocyte precursor cells , 2016, BMC Research Notes.

[8]  Adrian J. Verster,et al.  High-Content Screening for Quantitative Cell Biology. , 2016, Trends in cell biology.

[9]  J. Luke,et al.  Correlation of WNT/β-catenin pathway activation with immune exclusion across most human cancers. , 2016 .

[10]  L. Federici,et al.  Molecules that target nucleophosmin for cancer treatment: an update , 2016, Oncotarget.

[11]  K. O'Byrne,et al.  Drug Discovery Approaches Utilizing Three-Dimensional Cell Culture. , 2016, Assay and drug development technologies.

[12]  E. Parmee,et al.  The Impact of Chemical Probes in Drug Discovery: A Pharmaceutical Industry Perspective. , 2016, Cell chemical biology.

[13]  A. Jirgensons,et al.  Fragment-Based Discovery of 2-Aminoquinazolin-4(3H)-ones As Novel Class Nonpeptidomimetic Inhibitors of the Plasmepsins I, II, and IV. , 2016, Journal of medicinal chemistry.

[14]  Aurora Martínez,et al.  Discovery of a Specific Inhibitor of Pyomelanin Synthesis in Legionella pneumophila. , 2015, Journal of medicinal chemistry.

[15]  Junjie Chen,et al.  Tankyrase Inhibitors Target YAP by Stabilizing Angiomotin Family Proteins. , 2015, Cell reports.

[16]  N. Fernàndez-Castillo,et al.  Discovery of compounds that protect tyrosine hydroxylase activity through different mechanisms. , 2015, Biochimica et biophysica acta.

[17]  John P. Overington,et al.  The promise and peril of chemical probes. , 2015, Nature chemical biology.

[18]  M. Mondal,et al.  Fighting malaria: structure-guided discovery of nonpeptidomimetic plasmepsin inhibitors. , 2015, Journal of medicinal chemistry.

[19]  Leonor Puchades-Carrasco,et al.  Fragment-based Drug Design Using NMR Methods , 2015 .

[20]  Jonathan Hall,et al.  Tankyrase 1 Inhibitors with Drug-like Properties Identified by Screening a DNA-Encoded Chemical Library. , 2015, Journal of medicinal chemistry.

[21]  Jesús Martín,et al.  Identification of the Lipodepsipeptide MDN-0066, a Novel Inhibitor of VHL/HIF Pathway Produced by a New Pseudomonas Species , 2015, PloS one.

[22]  T. Gajewski,et al.  Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity , 2015, Nature.

[23]  Jordi Mestres,et al.  Distant polypharmacology among MLP chemical probes. , 2015, ACS chemical biology.

[24]  O. Genilloud,et al.  Pseudomonas granadensis sp. nov., a new bacterial species isolated from the Tejeda, Almijara and Alhama Natural Park, Granada, Spain. , 2015, International journal of systematic and evolutionary microbiology.

[25]  D. Melton,et al.  Generation of Functional Human Pancreatic β Cells In Vitro , 2014, Cell.

[26]  Dragos Horvath,et al.  Design of a General‐Purpose European Compound Screening Library for EU‐OPENSCREEN , 2014, ChemMedChem.

[27]  James D. Johnson,et al.  Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells , 2014, Nature Biotechnology.

[28]  J. Schiesser,et al.  Generation of β cells from human pluripotent stem cells: Are we there yet? , 2014, Annals of the New York Academy of Sciences.

[29]  R. Banerjee,et al.  Pharmacological chaperones as a potential therapeutic option in methylmalonic aciduria cblB type. , 2013, Human molecular genetics.

[30]  A. Muga,et al.  Screening and evaluation of small organic molecules as ClpB inhibitors and potential antimicrobials. , 2013, Journal of medicinal chemistry.

[31]  Steve Schneider,et al.  Discovery of novel, induced-pocket binding oxazolidinones as potent, selective, and orally bioavailable tankyrase inhibitors. , 2013, Journal of medicinal chemistry.

[32]  Stephen W. Fesik,et al.  Fragment-based drug discovery using NMR spectroscopy , 2013, Journal of biomolecular NMR.

[33]  S. Krauss,et al.  A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. , 2013, Cancer research.

[34]  A. Fallarero,et al.  Screening and structural analysis of flavones inhibiting tankyrases. , 2013, Journal of medicinal chemistry.

[35]  G. Drewes,et al.  Structural basis and SAR for G007-LK, a lead stage 1,2,4-triazole based specific tankyrase 1/2 inhibitor. , 2013, Journal of medicinal chemistry.

[36]  B. Cautain,et al.  HCS strategy targeting dysregulation of the VHL/HIF pathway for drug discovery * , 2013 .

[37]  Aurora Martínez,et al.  Send Orders of Reprints at Reprints@benthamscience.net Phenylalanine Hydroxylase Misfolding and Pharmacological Chaperones † , 2022 .

[38]  Jordi Mestres,et al.  Identification of pim kinases as novel targets for PJ34 with confounding effects in PARP biology. , 2012, ACS chemical biology.

[39]  G. Keller,et al.  Generation of beta cells from human pluripotent stem cells: Potential for regenerative medicine. , 2012, Seminars in cell & developmental biology.

[40]  H. Dinh,et al.  A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. , 2012, Cancer research.

[41]  D. Goldberg,et al.  Recent advances in plasmepsin medicinal chemistry and implications for future antimalarial drug discovery efforts. , 2012, Current topics in medicinal chemistry.

[42]  A. Fallarero,et al.  Homogeneous Screening Assay for Human Tankyrase , 2012, Journal of biomolecular screening.

[43]  David J Newman,et al.  Natural products as sources of new drugs over the 30 years from 1981 to 2010. , 2012, Journal of natural products.

[44]  D. Chin,et al.  [1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazoles: antagonists of the Wnt pathway that inhibit tankyrases 1 and 2 via novel adenosine pocket binding. , 2012, Journal of medicinal chemistry.

[45]  L. Lehtiö,et al.  Structural basis of selective inhibition of human tankyrases. , 2012, Journal of medicinal chemistry.

[46]  Natalia Markova,et al.  Structural basis for the interaction between tankyrase-2 and a potent Wnt-signaling inhibitor. , 2010, Journal of medicinal chemistry.

[47]  L. Gossage,et al.  Alterations in VHL as potential biomarkers in renal-cell carcinoma , 2010, Nature Reviews Clinical Oncology.

[48]  J. Baell,et al.  New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. , 2010, Journal of medicinal chemistry.

[49]  P. Alonso,et al.  New medicines to improve control and contribute to the eradication of malaria. , 2009, Nature reviews. Drug discovery.

[50]  I. Burtscher,et al.  Foxa2 regulates polarity and epithelialization in the endoderm germ layer of the mouse embryo , 2009, Development.

[51]  P. Sutphin,et al.  Targeted therapy for the loss of von Hippel-Lindau in renal cell carcinoma: A novel molecule that induces autophagic cell death , 2008, Autophagy.

[52]  F. Diederich,et al.  Structure-based drug design: exploring the proper filling of apolar pockets at enzyme active sites. , 2008, The Journal of organic chemistry.

[53]  A. Velázquez‐Campoy,et al.  Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria. , 2008, The Journal of clinical investigation.

[54]  P. Sutphin,et al.  A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. , 2008, Cancer cell.

[55]  L. Serrano,et al.  Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases. , 2007, American journal of human genetics.

[56]  P. Sutphin,et al.  Targeting the loss of the von Hippel-Lindau tumor suppressor gene in renal cell carcinoma cells. , 2007, Cancer research.

[57]  L. Prade,et al.  Achiral, Cheap, and Potent Inhibitors of Plasmepsins I, II, and IV , 2006, ChemMedChem.

[58]  Anders Hallberg,et al.  Plasmepsins as potential targets for new antimalarial therapy , 2006, Medicinal research reviews.

[59]  F. Diederich,et al.  Starving the malaria parasite: inhibitors active against the aspartic proteases plasmepsins I, II, and IV. , 2006, Angewandte Chemie.

[60]  J. D. Sharer.  An Overview of Biochemical Genetics , 2005, Current protocols in human genetics.

[61]  R. Rickert,et al.  Hypoxia-Inducible Factor 1α Is Essential for Cell Cycle Arrest during Hypoxia , 2003, Molecular and Cellular Biology.

[62]  Jun Liu,et al.  Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[63]  A. Kibel,et al.  Tumour suppression by the human von Hippel-Lindau gene product , 1995, Nature Medicine.

[64]  W. Linehan,et al.  Genetics of renal-cell carcinoma and evidence for a critical role for von Hippel-Lindau in renal tumorigenesis. , 1995, Seminars in oncology.

[65]  M. Vicent,et al.  Combined polymer-curcumin conjugate and ependymal progenitor/stem cell treatment enhances spinal cord injury functional recovery. , 2017, Biomaterials.

[66]  Anders Hallberg,et al.  Potent inhibitors of the Plasmodium falciparum enzymes plasmepsin I and II devoid of cathepsin D inhibitory activity. , 2004, Journal of medicinal chemistry.

[67]  R. Rickert,et al.  Hypoxia-inducible factor 1alpha is essential for cell cycle arrest during hypoxia. , 2003, Molecular and cellular biology.