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Tuesday, June 6
 

08:30

Coffee and registration
Tuesday June 6, 2017 08:30 - 09:00
Novo Nordisk Room

09:00

Welcome address
Speakers
avatar for Mads H Clausen

Mads H Clausen

Professor, Technical University of Denmark
avatar for Vicki Loise

Vicki Loise

CEO, SLAS


Tuesday June 6, 2017 09:00 - 09:15
Auditorium 4

09:15

Plenary Lecture - Bringing the full power of chemical synthesis to bear on the discovery of new antibiotics - Andy Myers
Many of the classes of antibiotics in current use were revealed by screening of fermentation broths in the era circa 1940–1960, considered to be a golden age in the discovery of antibiotics. Since then new antibiotics have been developed mainly by the process of semi-synthesis, where natural (fermentation) products are modified by chemical synthesis. Many important therapeutic agents have arisen by semi-synthesis and no doubt many more remain to be discovered in this way, but the process is inherently limited. This lecture will focus on the development of new platforms for the discovery of antibiotics by applying the power of convergent chemical synthesis, providing readily modifiable scaffolds that were previously inaccessible by any other means.

Speakers
avatar for Andy Myers

Andy Myers

Professor, Harvard University
Andrew G. Myers graduated from MIT in 1981 with a Bachelor of Science degree. He was introduced to chemical research as an undergraduate in the laboratory of Professor William R. Roush, and went on to study with Professor E.J. Corey from 1981-1986 at Harvard University, both as a graduate student and then briefly as a postdoctoral researcher. Myers began his independent academic career at Caltech (1986), where he was Assistant, Associate, and then Full Professor (1994). In 1998, he moved to the Department of Chemistry and Chemical Biology at Harvard University, served as Chair of the Department from 2007-2010, and is currently Amory Houghton Professor of... Read More →


Tuesday June 6, 2017 09:15 - 10:15
Auditorium 4

10:15

Keynote Lecture - Adam Nelson

Natural products continue to inspire both drug discovery and chemical biology.  Natural products are necessarily biologically-relevant because they arise through the evolution of biosynthetic pathways, driven by functional benefit to the host organism.  In this lecture, two complementary and unified approaches for the synthesis and elaboration of fragments will be described that have taken some inspiration from natural products and biosynthesis.

First, the design and synthesis of natural product-inspired scaffolds will be described.  The scaffolds were designed to have high natural product-likeness, and to be decorated to yield screening compounds with lead-like molecular properties.  To demonstrate their biological relevance, a set of fragments has been prepared from the scaffolds, and has been screened against a disparate range of protein targets using high-throughput protein crystallography.  It is demonstrated that the fragments can provide distinctive starting points for the discovery of modulators of epigenetic protein targets.

 

Second, a novel discovery approach – activity-directed synthesis (ADS) – will be described.  Unlike traditional medicinal chemistry workflows, ADS deliberately harnesses the promiscuity of reactions that can yield alternative products.  Although such reactions explore diverse chemical space, they are rarely exploited in current discovery approaches which generally require reactions that yield predictable products.  In each round of ADS, a reaction array is performed with outcomes that are critically dependent on the specific substrates/catalysts/conditions used.  Reactions that yield highly active product mixtures are scaled up to reveal, after purification, the responsible bioactive structures.  Thereby, ADS can exploit adventurous and powerful synthetic methods in the discovery of bioactive molecules in parallel with associated syntheses.  


Speakers
avatar for Adam Nelson

Adam Nelson

Professor, University of Leeds
Adam Nelson is Professor of Chemical Biology at the University of Leeds (since 2005). He was Director of the Astbury Centre for Structural Molecular Biology at Leeds (2009-11) and has been awarded the RSC Meldola medal (2001), the Pfizer academic aware (2002), an AstraZeneca award in Organic Chemistry (2005), the RSC Corday-Morgan medal... Read More →


Tuesday June 6, 2017 10:15 - 11:00
Auditorium 4

11:00

Coffee, Posters & Exhibition
Tuesday June 6, 2017 11:00 - 11:30
Auditorium

11:30

Session 1
Thomas Poulsen, Aarhus University:

Rakicidin A, a cyclic lipodepsipeptide (CLD) isolated from Micromonospora sp., exhibits selective cytotoxicity towards hypoxic cancer cells and induces apoptosis in quiescent imatinib-resistant stem-like CML cells. Hypoxic cancer cells display increased resistance to both chemo-and radiotherapy and hypoxia has been found to mediate cellular dedifferentiation in several cancer sub-types. BE-43547 is a structurally related natural product class that also displays potent anti-proliferative activity although its sub-selectivities towards hypoxic cancer cells had until recently not been elucidated. The macrocyclic systems of both rakicidin A and the BE-43547A-class constitute significant synthetic challenges due to the presence of congested structural elements and a labile 4-amido-2,4-pentadienoate (APD) functionality. The latter is unique to this family of natural products that we collectively refer to as APD-CLDs. In my presentation, I will present highlights form our recent efforts resulting in chemical syntheses of both rakicidin A[1] and the BE-43547A1-scaffold[2] and further provide a concise account of our studies aimed at elucidating the mode-of-action of these natural products.

 

Aurora Martinez Discovery of pharmacological chaperones for the correction of loss of function genetic disorders

 Small molecular weight compounds that selectively bind and stabilize mutant misfolded proteins may totally or partially recover the function and localization of the mutant proteins in the cell. These stabilizing compounds are called pharmacological chaperones and are the focus of increasing interest due to their therapeutic potential for correction of loss-of-function misfolding diseases. Phenylketonuria (PKU) is the most common inborn error of metabolism, caused by mutations in the gene encoding the enzyme phenylalanine hydroxylase (PAH), resulting in increased phenylalanine levels in blood and toxic levels in brain. The two current treatments of PKU, namely a strict phenylalanine diet and the administration of Kuvan®, are unsatisfactory since they are associated with neurodevelopmental or psychosocial problems and low responsiveness, respectively, and new therapeutic strategies are needed. In PKU, the majority of the (>900) mutations in PAH lead to a decrease in protein stability, and PKU is considered a paradigm of loss-of-function misfolding diseases. We thus initiated the screening and validation of compounds searching for stabilizers of PAH that can be developed into pharmacological chaperones for PKU treatment. The screening consisted of a sequential workflow comprising an initial high-throughput screening (HTS) of a 10,000-compound diversity library by differential scanning fluorimetry, a validation of the binding through surface plasmon resonance and activity assays, and an efficacy assessment in cultured cells constitutively expressing PAH, both in terms of specific activity and amount of protein. Subsequently, a further characterization of the mode and thermodynamics of the binding was performed. From a total of 109 positive compounds in the HTS the validations lead to the selection of 2 compound hits that are at present being expanded and optimized in a hit-to-lead phase, where validations on cells expressing PKU mutants has also been included. The same screening and validation strategy has been successfully applied to the selection of hit compounds with potential to be developed into pharmacological chaperones for other genetic neurometabolic disorders, such as rare dopamine deficiencies. 

Johanna U. E. Sollid, Antibacterial marine natural product mimics for treatment of infections

Bacterial infections are still among the urgent global challenges. Antibiotic resistance is currently causing around 700 000 deaths annually, with an estimated rise to 10 million over the next 30 years. Continuous development of antimicrobial compounds with new modes of action is essential to reduce the threat posed by antimicrobial resistance. Compounds with novel structures and properties such as synthetic compounds, based on known natural antimicrobials are promising in this respect.

A library of Marine Natural Product Mimics (MNPMs) constructed using a bioactivity-guided synthesis approach, was assessed. The bioactivity test platform included a reference panel of laboratory bacterial strains and an expanded panel of clinical isolates of human pathogens. A set of in vitro assays was applied to define the mode of action for selected molecules.

The aim was to identify antibacterial compounds by multistep screening of a synthetic MNPMs library and determine the mode of action of selected MNPMs.

Our strategy yielded several molecules with promising antibacterial activity. One example, E23 was active against clinical isolates of human pathogenic bacteria, including drug-resistant bacteria, in vitro. The primary killing mechanism of E23 is cytoplasmic membrane disruption. No resistance development towards E23 was revealed by serial passage experiments.

 

 

 

 

 

 

 

 


Moderators
avatar for Jeanette Andersen

Jeanette Andersen

Research Manager, UiT-The Arctic University of Norway
Jeanette Hammer Andersen (PhD) is head of Marbio, an analytical platform for natural product drug discovery at UiT- The Arctic University of Norway. Marbio has experience in screening extract library of natural product origin, both terrestrial and marine organisms and has successfully identified several novel bioactive compounds in marine natural products libraries. Main research interests are: marine biodiscovery, natural products, bioassays and high throughput screening technology. Industry collaboration through MabCent-SFI a centre for research based innovation centre for marine bioactives and drug discovery since 2007. Partner and work package leader in the EU FP7 project PharmaSea- Increasing Value and Flow in the Marine Biodiscovery Pipeline (2012-2016). MABIT board member since 2009. The MABIT-programme is an industrial... Read More →

Speakers
avatar for Aurora Martinez

Aurora Martinez

Professor Department of Biomedicine, University of Bergen
avatar for Thomas Poulsen

Thomas Poulsen

Assistant Professor, Aarhus University, Department of Chemistry
Thomas B. Poulsen is an assistant professor at the Dept. of Chemistry, Aarhus University in Denmark. Thomas completed his PhD with Prof. Karl Anker Jørgensen in 2008 working on the development of a series of new asymmetric organocatalytic transformations. He then moved to Harvard University as a post-doctoral fellow with Prof. Matthew D. Shair at the Department of Chemistry and Chemical Biology, where he worked on target-identification studies of complex anti-cancer natural products. From 2011, Thomas was an independent researcher at the Dept. of Chemistry, Aarhus University supported by an elite junior scientist programme (Sapere Aude) from the Danish Research Council and since 2012 he has been an assistant professor at the same institution... Read More →
avatar for Johanna Sollid

Johanna Sollid

Professor in Microbiology, UiT The Arctic University of Norway
I am Johanna Sollid, born in 1962. I have a PhD in microbiology (1990) from the University of Umeå, Sweden. I was a post doc at UiT the Arctic University of Norway in Tromsø until appointed Associate professor in 1992. Since 2005, I am Professor in microbiology at the same University. My main research interests are determinants for bacterial colonisation and new antimicrobial strategies. I have 45 peer-reviewed scientific publications, 31 the last ten years, and my H-index is 24. I have supervised numerous postdocs, PhDs and MSc candidates. Presently I am the co-director of the national PhD school... Read More →


Tuesday June 6, 2017 11:30 - 12:50
Auditorium 4

12:50

Networking Lunch
Tuesday June 6, 2017 12:50 - 14:00
Auditorium

14:00

Plenary Lecture - From Biologicals to Pharmaceuticals: A Medicinal Chemistry Approach to Carbohydrate-Conjugate Vaccines Against Streptococcus pneumoniae and Other Bacteria - Peter Seeberger
Speakers
avatar for Peter Seeberger

Peter Seeberger

Director, Max-Planck-Institute of Colloids and Interfaces
Peter H. Seeberger studied chemistry in Erlangen (Germany) and completed a PhD in biochemistry in Boulder (USA). After performing research at the Sloan-Kettering Cancer Center Research in New York he built an independent research program at MIT where he was promoted to Firmenich Associate Professor of Chemistry with tenure. After six years as Professor at the Swiss Federal Institute of Technology (ETH) Zurich he assumed positions as Director at the Max-Planck Institute for Colloids and Surfaces in Potsdam and Professor at the Free University of Berlin in 2009. In addition he serves as honorary Professor at the University of Potsdam. From 2003-2014 he was Affiliate Professor at the Sanford-Burnham Institute for Medical Research (La Jolla, USA). Professor... Read More →


Tuesday June 6, 2017 14:00 - 15:00
Auditorium 4

15:00

Keynote Lecture - Anders E. Hansen - Teaching the immune system to fight cancer
Speakers
AE

Anders E. Hansen

Post-doc research fellow, DTU Nanotech


Tuesday June 6, 2017 15:00 - 15:45
Auditorium 4

15:45

16:30

Session 2

Mikael Elofsson - Exploring the chemistry and biology of benzofuran based natural products: Identification of novel antibacterial agents

Antibiotics are viewed as one the most important factors contributing to human health and prosperity. However, the indiscriminate use of antibiotics has led to the emergence of multi-resistant “superbugs” e.g. the gram-negative pathogen Pseudomonas aeruginosa that resist many antibiotic treatments including combination therapies. Our ability to prevent and treat infectious diseases is today severely threatened and the need for new antibacterial therapies is evident. Many clinically relevant gram-negative pathogens e.g. Salmonella spp., Chlamydia spp., Shigella spp., Pseudomonas spp. and Yersinia spp. use a conserved syringe-like machinery called the type III secretion (T3S) system to inject toxins into the cytosol of host cells. The toxins block host cell functions and thereby create a niche that allows bacterial growth. The T3S system is essential for pathogens to evade the host immune defense and agents that inhibit the system will attenuate virulence without directly affecting growth of the pathogen. This chemical attenuation could enable the host to clear the infection and we hypothesize that the selective pressure for resistance will be significantly lower than for conventional antibiotics.
Recently, we have employed phenotypic screening to discover (-)-hopeaphenol, a resveratrol tetramer, as an irreversible and selective inhibitor of T3S in Y. pseudotuberculosis and P. aeruginosa [1, 2]. The chemistry of resveratrol oligomers is however challenging and their syntheses generally require multistep procedures [3]. To further explore the chemistry and biology of resveratrol based natural products we have ongoing projects covering total synthesis or resveratrol dimers and development of synthetic methodology [4, 5], diversity-oriented synthesis as well as design, synthesis and applications of fluorescent probes and affinity reagents for target identification. 

Morten Jorgensen - PDE2 Inhibitors: Novel therapies for CNS-disorders ? Medicinal chemistry highlights from a drug discovery project

The discovery of two screening hits from high-throughput screening and two different lead optimization strategies will be presented. The hit-to-lead campaign for the first hit was performed in a ‘classic’ potency-centric sense with an extensive Med.Chem program while the second hit series was optimized using structure-based drug design with an emphasis on Ligand Lipophilicity Efficiency.1 The consideration of physico-chemical properties lead to a compound series with a much improved overall profile as compared to the results obtained using the original strategy.The superior profile of the 2nd generation of compounds was evident when cosidering Lipiniski’s Rule-of-Five2 and when looking at the location of the compounds in a plot of MW vslogD (the so-called Golden Triangle analysis).3 The lessons learned in this and many other projects were instrumental in a fundamental change to the company’s compound acquisition and screening strategies that will be presented as a poster at this conference.4

 

[1] PD Leeson, B Springthorpe Nature Rev. Drug Discov. 20076, 881.

[2] CA Lipinski et al. Adv. Drug. Deliv. Rev. 199723, 3.

[3] DW Johnson, KR Dress, M Edwards Bioorg. Med. Chem. Lett. 200919, 5560.

[4] M Marigo, AG Sams, M Langård, L David, M Jørgensen ’Methods for Clean-up and Enrichment of Coporate Screening Collections’



Thierry Kogej - Screening collection enhancement through open-innovation

High-throughput screening (HTS) is one of the main tool for finding hits for drug discovery projects. The success of a HTS campaign relies on the wealth of the screening collection. Different open innovation strategies followed at AstraZeneca to ensure a continuous enrichment of the corporate collection will be presented.

Dr. Päivi Tammela Bioreporters in screening and characterization of novel antimicrobial agents against Gram-negative bacteria

According to a recent report by the WHO, a post-antibiotic era is a very real possibility for the 21st century. Antimicrobial resistance (AMR) has reached such alarming levels that available treatment options for common infections and minor injuries are becoming ineffective unless global actions across several sectors are taken. However, no first-in-class antibiotics against Gram-negative bacteria (GNB) have been developed for more than 40 years. Very worryingly, the emergence of E. coli carrying a new gene, MCR-1, providing resistance to colistin (the last resort antibiotic to treat multiple drug-resistant E. coli infections) has recently been reported and accentuates the urgent need for novel antimicrobials especially against GNB. To respond to this need, we have recently developed cell-based screening strategies for antimicrobial drug discovery by using E. coli bioreporter strains cloned with lux genes. These bioreporter-based assays are sensitive, allow automation, completion of assays in couple of hours, and monitoring of antimicrobial action of compounds in whole-cell context. We have demonstrated the functionality of this approach with screening of compound libraries, but also in studying natural product extracts. In summary, our results demonstrate that bioreporters are powerful tools both in HTS as well as in follow-up characterisation of novel antimicrobial agents. 

 


Moderators
avatar for Thomas Lundbäck

Thomas Lundbäck

Associate Director - Mechanistic Biology & Profiling, AstraZeneca
Thomas Lundbäck is Associate Director within the global Discovery Sciences organisation at AstraZeneca, providing reagent, assay development and screening services. Dr. Lundbäck also serves as an affiliate of the Karolinska Institutet, supporting the national chemical biology i... Read More →

Speakers
avatar for Mikael Elofsson

Mikael Elofsson

Umeå University
In 1996 Mikael Elofsson obtained his Ph.D. in in synthetic organic chemistry at the Lund Institute of Technology, Lund, Sweden. In the lab of Prof. Jan Kihlberg he worked with synthesis of glycosylated amino acids and their application in solid-phase synthesis of MHC class II binding glycopeptides. Thereafter he spent three years as postdoc in the lab of Prof. Craig M. Crews at Yale University, CT, USA working primarily on epoxyketone proteasome inhibitors. The work eventually led to the drug Kyprolis (Carfilzomib) that was approved by FDA in 2012. In 1999 Mikael was recruited to the Department of Chemistry at... Read More →
avatar for Morten Jørgensen

Morten Jørgensen

Discovery Chemistry and DMPK, Neuroscience Drug Discovery, H. Lundbeck
Dr. Morten Jørgensen has been working as a medicinal chemist at H. Lundbeck A/S for 14 years. Morten received his  PhD in  carbohydrate and organometallic chemistry from the Technical University of Denmark under the supervision of Professor Robert Madsen. Since then he has been working at H. Lundbeck A/S on a range of drug discovery projects within depression and anxiety... Read More →
avatar for Thierry Kogej

Thierry Kogej

Associate Principal Scientist, AstraZeneca
Thierry Kogej obtained his Ph.D in Physical-Chemistry at the University of Mons-Hainaut in Belgium in 1998. Worked at UCB Pharma as a medicinal computational chemist to support discovery projects in CNS and rhino-inflammatory (1998-2003). Got a Master in Drug Design at University of Lille (France) in 2000. Joined AstraZeneca... Read More →
avatar for Päivi Tammela

Päivi Tammela

Academy Research Fellow, Adjunct professor, University of Helsinki
Päivi Tammela received her Ph.D. in Pharmacy in 2004 (University of Helsinki, Finland). She has served as University Lecturer in Pharmaceutical Biology (2005-2007) at the University of Helsinki; and obtained Adjunct Professorship in Pharmaceutical Biology in 2005. Since 2008, she has served as University Researcher and Group Leader at the Faculty of Pharmacy where she currently leads the Bioactivity Screening Group. In 2011, Dr. Tammela completed a research visit at the University of Cambridge, UK. Currently, she holds the Academy of Finland Research Fellow position (2014-2019). Dr. Tammela has authored more than 60 peer-reviewed publications and 7 patents/patent applications. Tammela has received awards from the American Society of Pharmacognosy Foundation (Jack L. Beal Award, 2009) and from the Finnish Pharmaceutical Society (Albert Wuokko Award, 2006). Dr. Tammela actively participates in... Read More →


Tuesday June 6, 2017 16:30 - 18:00
Auditorium 4

18:00

19:00

Dinner
Tuesday June 6, 2017 19:00 - 22:00
Novo Nordisk Room
 
Wednesday, June 7
 

09:00

Plenary Lecture - PNA-programmed Self Assemblies in Chemical Biology - Nicolas Winssinger

PNA-programmed Self Assemblies in Chemical Biology

The programmable nature of nucleic acid hybridization has inspired a number of applications beyond their natural function in heredity.  Peptide Nucleic Acids (PNA) are endowed with attractive properties for this endeavor as they are more robust and form more stable duplex than their natural counter parts. Several applications from our laboratory to program self-assemblies of small molecules, template chemical reactions or display multimeric ligands will be presented.


Speakers
avatar for Nicolas Winssinger

Nicolas Winssinger

Professor, University of Geneva
Nicolas Winssinger is professor at the university of Geneva.  He began his independent career in 2002 at the Institut de Science et Ingénierie Supramoléculaires, Strasbourg.  He carried out his PhD under the guidance of K.C. Nicolaou (The Scripps Research Institute) and postdoctoral training with P.G. Schultz (NIH postdoctoral fellow). An important theme is the use of natural product synthesis to aid in the development of chemical biology probes, with a particular emphasis on natural product that inhibit their target through covalent interactions. Another important theme throughout his research is the use of unnatural nucleic acid (PNA) to encode molecules, program spatial organization of ligands and direct reactions. A long-term objective is to extend these principles towards complex systems which can emulate some of the fundamental features of living... Read More →


Wednesday June 7, 2017 09:00 - 10:00
Auditorium 4

10:00

Keynote Lecture - Compound Management and Hit Discovery for the 2020’s - Steve Rees

Compound Management and Hit Discovery for the 2020’s

Steve Rees, Vice-President, Screening Sciences and Sample Management

Success in drug discovery requires the rapid identification of multiple tractable hit series for every target.  This requires innovation in the quality and composition of compound collections, innovative ways of accessing novel chemistry, the implementation of advanced screening automation and assay platforms, and the development of new ways of working between and across pharma and academia.  From 2018, AstraZeneca’s hit discovery capabilities will be located within the AZ Medical Research Council UK Centre for Lead Discovery at the AstraZeneca research campus in Cambridge.  The centre will support up to 50 academic and pharma hit discovery projects each year with scientists from AstraZeneca, the Medical Research Council and Cancer Research UK working side by side.  In this presentation I will describe the vision for the UK Centre for Lead Discovery, the technology innovations being implemented in Compound Management and High Throughput Screening to create new capability, and the strategies being adopted to enrich the quality and diversity of the compound library to meet the aspiration of multiple quality hit series for every drug target.


Speakers
avatar for Steve Rees

Steve Rees

VP, Screening Sciences and Sample Management, AstraZeneca
Steve Rees is Vice-President of Screening Sciences and Sample Management at AstraZeneca with global responsibility for Compound Management, the human tissue BioBank, Hit Discovery and Lead Optimisation biology support to preclinical discovery projects. | | Prior to joining AstraZeneca, Steve worked at GlaxoSmithKline for 24 years in various... Read More →


Wednesday June 7, 2017 10:00 - 10:45
Auditorium 4

10:45

11:20

Session 3

Lari Lehtiö - Discovery of chemical probes for human mono ADP-ribosyltransferases

Human mono ADP-ribosyltransferases (mARTDs) of the PARP/ARTD family regulate biological activities through ADP-ribosylation of target proteins. They only transfer a single ADP-ribose unit to the target residue in contrast to e.g. founding member of the family, DNA damage response enzyme PARP1/ARTD1. Until very recently there were no selective inhibitors available for any of the mARTDs and I will describe our efforts to discover first inhibitors for ARTD10, an enzyme involved in cell death, NF-kB signaling and S-phase DNA repair. The chemical probe rescues the cells from ARTD10 induced apoptosis and sensitizes the cells to the hydroxyurea-induced genotoxic stress. The chemical scaffold, OUL35, and its new binding mode to the active site open up a path towards discovery of chemical tools to study also other mARTDs of the family. 

Guillaume Médard - Chemoproteomics-aided drug discovery

 In this presentation, EPHA2 will be used as a prototypical example of a therapeutically interesting protein kinase, with no dedicated inhibitor, for which chemical proteomics has been instrumental along the discovery pipeline. It will be shown how chemical proteomics has been used to establish the therapeutic relevance of this target (target selection and validation), how we used another flavour of this approach to establish its inhibition landscape (screening), how it helped us design a medicinal chemistry campaign (lead selection), and how we used it to assess the affinity and selectivity of each synthetized inhibitor candidate during the medicinal chemistry efforts (lead optimization). 

Katrine Qvortrup - Design and Synthesis of New Linkers for Antibody-Drug Conjugates

Antibody Drug Conjugates (ADCs) are monoclonal antibodies attached to biologically active drugs by chemical linkers with labile bonds. ADCs hold considerable promise as anticancer agents, offering the potential of specific delivery of cytotoxic agents to tumour cells (targeted therapy),[1,2] thereby avoiding the dose-limiting toxicity of chemotherapy that occurs as a result of its effects on normal cells. Background: ADCs are comprised of three parts: a monoclonal antibody, a cytotoxic agent (the ‘warhead’) and a structural moiety that joins the two together (the ‘linker’), Figure A. The antibody of the ADC is selected or engineered to bind to a tumour cell-specific antigen or to an antigen that is over-expressed on the surface of tumour cells. Thus, the antibody guides the ADC selectively to target tumour cells. Upon binding, the ADC is internalised and the cytotoxic agent is released from the antibody to perform its cell-killing function.[2-5] Recent years have witnessed tremendous interest in ADCs; two are already on the market as anticancer agents (Roche’s Kadcyla and Seattle Genetics’ Adcetris) and there are now a further 33 ADCs in clinical trials.[7] The development of new linkers by synthetic chemists will be crucial to the further advancement of the field and the emergence of next generation ADCs. Aim: We now wish to report the design and development of novel linker technologies for ADC chemotherapeutics. Indeed, linker technology is known to profoundly impact upon ADC potency, specificity and safety.[3,7] The knowledge and insights gained can potentially be applied to other synergistic therapeutic modalities. The research is conducted in collaboration with Professor David Spring, Cambridge University. All new ADCs produced are continuously being evaluated as chemotherapeutics in collaboration with GlaxoSmithKline. Methodology: There are two key aspects of ‘linker technology’: (1) the chemical method of attachment of the linker to the antibody and warhead and (2) the nature (and thus properties) of the linker (Figure A). We have worked to further develop both aspects of linker technology by conducting the following activities: (1) Design and synthesise new linkers and evaluate with a range of agents to make new conjugates. (2) Develop novel site-specific attachment strategies. Linker composition: There are two general classes of linkers: cleavable and non-cleavable. Cleavable linkers rely on processes that occur within the cell to liberate the warhead.[9] Non-cleavable linkers require catabolic degradation of the antibody; this results in release of the warhead still bound to the linker, which in turn is bonded to the amino acid through which it was attached to the antibody.[2,3,6,9] In the current project, we have examined a variety of bioorthogonal warhead de-attachment strategies. Specifically, we have developed novel light and enzymatically cleavage strategies, allowing for the mild release of bioactive compounds (examples are presented in Figure B). Site-specific conjugation: Conjugation of the linker to the antibody is generally achieved by reaction with functional groups of naturally occurring lysine and cysteine amino acids in the antibody (Figure B).[2] There is an inherent lack of sophistication with the ‘traditional’ attachment approach in that it is pseudorandom: in theory, any of the targeted amino acids within the antibody can be modified.[9] Consequently, the ADCs generated using this approach will be heterogeneous in terms of the number of drug molecules incorporated and their locations on the antibody.[9] Recent years have witnessed considerable interest in developing linker technologies that are ‘site-specific’; that is, where sites of attachment of the linker (and thus the warhead) to the antibody are defined. Site-specific conjugation is expected to yield more consistent ADCs, with improved stability, efficacy and safety.[2,5,6,8] In the current project, we examine the application of two bioorthogonal methodologies[10] to the synthesis of site-specific ADCs. Specifically, we have developed novel site-specific conjugation strategies, where reactivity depends on the synergistic interaction of two or more naturally occurring amino acids. (Figure B). References: [1] Nicolaou, K. Angew. Chem. Int. Ed. 2014, 53, 9128. [2] Ducry, L.; Stump, B. Bioconjugate Chem. 2010, 21, 5. [3] Chari, R. V. J. et al. Angew. Chem. Int. Ed. 2014, 53, 3796. [4] Ducry, L.; Stump, B. Bioconjugate Chem. 2010, 21, 5. [5] Flygare, J. A. et al. Chem. Biol. Drug. Des. 2013, 81, 113. [6] Kitson, S. L. et al., Chimica Oggi-Chemistry Today, July/August 2013, 31. [7] Thayer, A. M. Chemical & Engineering News 2014, 92, 13. [8] Challenger, C. BioPharma International 2014, 27, 22. [9] Ritter, A., Pharmaceutical Technology 2012, 42. [10] Sletten, E. M.; Bertozzi, C. R. Angew. Chem. Int. Ed. 2009, 48, 6974.

Kristian Strømgaard - Targeting Protein-Protein Interactions

Protein-protein interactions (PPIs) are essential to vital cellular processes, and serve as potential targets for therapeutic intervention. We are particularly interested in the PPIs between integral membrane proteins and their intracellular protein partners. We have developed peptide-based inhibitors of the PSD-95/glutamate receptor interaction, by exploiting that PSD-95 contains a tandem PDZ1-2 domain. So we designed and synthesized dimeric peptides with low nanomolar affinities,1 and have demonstrated that these ligands are potential treatment for ischemic stroke.2 For the same PPI, we examined the importance of backbone hydrogen bond by employing amide-to-ester mutations in peptide ligands3 and proteins.4 Finally, we have exploited the principle of dimeric peptide-based ligands to perturb the PPI between the scaffolding protein gephyrin and glycine/GABAA receptors.5,6 Most recently we have developed high affinity, cell-permeable peptides and demonstrated how these can modulate receptors and used to label synapses.7


Moderators
avatar for Krister Wennerberg

Krister Wennerberg

FIMM-EMBL Group Leader, Institute for Molecular Medicine Finland (FIMM)
Krister Wennerberg, Ph.D. is a FIMM-EMBL Group Leader at the Institute for Molecular Medicine Finland (FIMM), University of Helsinki since 2010.  He received his Ph.D. in biochemistry from Uppsala University, Sweden and got his postdoctoral training at the University of North Carolina at Chapel... Read More →

Speakers
avatar for Lari Lehtiö

Lari Lehtiö

Academy of Finland research fellow, University of Oulu
Lari Lehtiö is a structural biologist who got PhD training in University of Helsinki after which he worked as a crystallographer at the Structural Genomics Consortium  in Stockholm. He started his research group at Åbo Akademi University in 2009 and moved to the University of... Read More →
avatar for Guillaume Médard

Guillaume Médard

Group Leader Chemical Proteomics Lehrstuhl für Proteomik und Bioanalytik, Technische Universität München
Guillaume Médard studied organic chemistry in the Ecole Nationale Supérieure de Chimie de Montpellier and in the University of Strasbourg. His PhD in University College London was dedicated to different strategies to synthesize Astrogorgiadiol, a natural marine 9,10-secosteroid. After four years in a drug discovery company in England (Argenta Discovery), where he specialized in kinase inhibitors, Guillaume moved back to the continent to twist his medicinal chemistry know-how for chemical proteomics. Appointed as a group leader by Bernhard... Read More →
avatar for Katrine Qvortrup

Katrine Qvortrup

Senior Research Scientist, Technical University of Denmark, Department of Chemistry
Following more than eight of chemical research in academic institutions, I have a strong in-depth knowledge of biological chemistry. I have a high passion for chemistry projects that involve teamworkers/collaborators from a diverse range of backgrounds. By teaming up with complementary research groups one can combine the collective expertise and gain synergy. The challenges are substantial in interdisciplinary projects, and they continue to inspire me to perform the best. It is rewarding to conceive creative scientific ideas, to do the critical experiments, and feel the excitement when hypotheses are proven. Current research focuses on various fields of chemical biology: site-selective peptide and protein labeling, library design and generation, identification of novel biological targets, screening for biological activity and assay... Read More →
avatar for Kristian Strømgaard

Kristian Strømgaard

Professor, University of Copenhagen
Professor Kristian Strømgaard graduated from the Royal Danish School of Pharmacy (1999), with part of the studies carried out at H. Lundbeck A/S and did his postdoctoral training at Columbia University (USA). He was appointed assistant professor at University of Copenhagen, and t... Read More →


Wednesday June 7, 2017 11:20 - 12:40
Auditorium 4

12:40

13:40

Session 4

Dominic Hoepfner - Chemogenomics with CRISPR – Old Tricks but New Dogs

Chemogenomic profiling is a powerful and unbiased approach to elucidate pharmacological targets and the mechanism of bioactive compounds. Until recently, genome-wide, high-resolution experiments of this nature have been limited to fungal systems due to lack of mammalian genome-wide deletion collections. With the example of a novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitor and a novel antiviral compound of natural origin, we demonstrate that the CRISPR/Cas9 system enables the generation of transient homo- and heterozygous deletion libraries and allows for the identification of efficacy targets and pathways mediating hypersensitivity and resistance relevant to the compound mechanism of action.

Niclas Nilsson - Enabling scientific exploration using a truly open innovation platform – Pharma collaborations with no strings attached

 

  • Why the Industry and Academic research mutually benefits from opening up

  • How this is done, exemplified by LEO Pharma’s concrete and unique open innovation platform

  • What opportunities can come from truly changing the way we work together

Connecting targets and compounds - the European Lead Factory experience - Kristina M. Orrling, PhD

The European Lead Factory (ELF) is a public–private partnership supported by the Innovative Medicines Initiative (IMI).It provides researchers in Europe with a unique platform for translation of innovative biology and chemistry into high-quality starting points for drug discovery. It combines high-throughput screening (HTS) infrastructure and hit follow-up capabilities with an exceptional collection of small molecules to advance research projects from both private companies and publicly funded researchers. Established in 2013, its unique collaborative model has so far resulted in >6,000 hit compounds with a defined biological activity from over 100 successfully completed HTS and hit evaluation campaigns, >145,000 novel innovative screening compounds that complement the 327,000 compounds contributed by the big pharma, >30 protein–ligand structures, two patents and two start-up biotechs. Intrinsic to its setup, ELF enables breakthroughs in areas with unmet medical and societal needs, where no individual entity would be able to create a comparable impact in such a short time.

The presentation will reveal some cross-programme trends, further illustrated by a few case studies from the target programme portfolio.

Roger Olsson, Fish and Grasshoppers in the Service of MANkind: exploring new in vivo and in vitro models

The presentation will focus on the use of alternative animal models in drug discovery, phenotypic screening—profiling in zebrafish and evaluation of blood-brain barrier (BBB) permeation and drug metabolism in the brain using an ex vivo model based on grasshoppers. Is the zebrafish model sensitive enough to distinguish between structurally similar compounds with polypharmacological profiles, and is clozapine N-oxide used as an inert ligand in chemical genetics using the DREADD technology really inert, and is it readily penetrating the BBB?

 


 


Moderators
avatar for Per-Anders Enquist

Per-Anders Enquist

Senior research engineer at Department of Chemistry, Chemical Biology Consortium Sweden

Speakers
avatar for Dominic Hoepfner

Dominic Hoepfner

Novartis Institutes for Biomedical Research
Dominic did his Ph.D. in the lab of Prof. Peter Philippsen at the Biozentrum in Basel, Switzerland followed by a postdoc with Prof. Henk Tabak at the University of Utrecht Netherlands, where he helped to identify the fundamental biogenesis pathway of peroxisomes. Dominic joined... Read More →
avatar for Niclas Nilsson

Niclas Nilsson

Head of Open Innovation Research, LEO Pharma
Niclas is spearheading an initiative to use Open Innovation at the core of drug research with focus on science and external collaborations at LEO Pharma, a pharmaceutical company in Denmark focusing on dermatology and inflammatory skin disease. Prior to setting up the LEO Pharma... Read More →
avatar for Roger Olsson

Roger Olsson

Professor, Chemical Biology & Therapeutics, Lund University
Professor Olsson is a trained organic chemist, that learnt medicinal chemistry in the pharmaceutical industry. However, after returning to academia he is focusing on behavioral neuropharmacology using zebrafish. The main theme in the group is the focus on response profiles of drugs, connecting behaviour with neuronal signalling and drug distribution within the brain, rather than on receptor affinities and target-centered drug discovery... Read More →
avatar for Kristina Orrling

Kristina Orrling

Lygature
Kristina Orrling has worked more than 15 years with various aspects of drug discovery. Her scientific activities have focused on medicinal chemistry and infectious diseases. She holds a PhD in medicinal chemistry and a MSc Chemical Engineering with drug research specialization from Uppsala University, Sweden, as well as a... Read More →


Wednesday June 7, 2017 13:40 - 15:00
Auditorium 4

15:00

Plenary Lecture - John Sutherland - Origin of life, prebiotic chemistry, systems chemistry, protometabolism

By reconciling previously conflicting views about the origin of life – in which one or other cellular subsystem precedes, and then ‘invents’ the others – a new modus operandi for its study is suggested. Guided by this, a cyanosulfidic protometabolism is uncovered which uses UV light and the stoichiometric reducing power of hydrogen sulfide to convert hydrogen cyanide, and a couple of other prebiotic feedstock molecules which can be derived therefrom, into nucleic acid, peptide and lipid building blocks.Copper plays several key roles in this chemistry, thus, for example, copper(I)-copper(II) photoredox chemistry generates hydrated electrons, and copper(I) catalysed cross coupling and copper(II) driven oxidative cross-coupling reactions generate key feedstock molecules. Geochemical scenarios consistent with this protometabolism are outlined. Finally, the transition of a system from the inanimate to the animate state is considered in the context of there being intermediate stages of partial ‘aliveness’.

 

 

 

 

 


Speakers
avatar for John Sutherland

John Sutherland

John Sutherland studied chemistry at the University of Oxford, and then spent a spell as a Kennedy Scholar at Harvard with Jeremy Knowles. Upon return to the UK, he carried out his doctoral work with Jack Baldwin at Oxford, and then stayed in Oxford first as a Junior Research Fel... Read More →


Wednesday June 7, 2017 15:00 - 16:00
Auditorium 4