Meeting Highlights

Report on the 10th Anniversary ofInternational Drug DiscoveryScience and TechnologyConference, 8 -- 10 November2012, Nanjing, ChinaJeremy R EverettUniversity of Greenwich, School of Science, Chatham Maritime, Kent, UK

The 10th Anniversary of International Drug Discovery Science and Technology

(IDDST) Conference was held in Nanjing, China from 8 to 10 November 2012.

The conference ran in parallel with the 2nd Annual Symposium of Drug Deliv-

ery Systems. Over 400 delegates from both conferences came together for the

Opening Ceremony and Keynote Addresses but otherwise pursued separate

paths in the huge facilities of the Nanjing International Expo Centre. The

IDDST was arranged into 19 separate Chapters covering drug discovery

biology, target validation, chemistry, rational drug design, pharmacology

and toxicology, drug screening technology, ‘omics’ technologies, analytical,

automation and enabling technologies, informatics, stem cells and regenera-

tive medicine, bioprocessing, generics, biosimilars and biologicals and seven

disease areas: cancer, CNS, respiratory and inflammation, autoimmune,

emerging infectious, bone and orphan diseases. There were also two sessions

of a ‘Bench to Bedside to Business’ Program and a Chinese Scientist

programme. In each period of the IDDST conference, up to seven sessions

were running in parallel. This Meeting Highlight samples just a fraction of

the content of this large meeting. The talks included have as a link, the use

of new approaches to drug discovery. Many other excellent talks could have

been highlighted and the author has necessarily had to be selective.

Keywords: 10th Anniversary IDDST Conference, 2012, China, drug discovery, meeting

highlights, Nanjing

Expert Opin. Drug Discov. (2013) 8(3):357-361

The Keynote sessions were opened by Nobel Laureate, Professor Jean-Marie Lehn,ISIS, ULP, Paris, France, who spoke on ‘From Supramolecular Chemistrytowards Adaptive Chemistry -- Bio-Organic and Drug Discovery Aspects’.Supramolecular chemistry [1,2] was defined as the world beyond the molecules andin particular the study of interactions between molecules mediated by non-covalentbonds. This is necessarily a dynamic chemistry because of the reversibility ofnon-covalent interactions. Dynamics in chemistry is typically considered in termsof molecular reactions and molecular motions. However, dynamics can be intro-duced into molecular chemistry via the incorporation of unstable covalent bondsto give constitutional dynamic chemistry (CDC) as a third element of chemicaldynamics. CDC has numerous applications, including in drug discovery. Forinstance, chemical libraries can be made that are dynamic and that can respond tothe binding requirements of the receptor. This was illustrated with the selectionof a novel carbonic anhydrase inhibitor from a library of ligands (made frommultiple fragments) that interconverted via imine chemistry. Selection pressure

10.1517/17460441.2013.762353 © 2013 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X 357All rights reserved: reproduction in whole or in part not permitted

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was placed on the library by the addition of the receptorwhich, by Le Chatelier’s principle, biased the library to thosemolecules that were able to bind strongly to the receptor. Thisapproach combines the power of combinatorial chemistrywith the specificity of the demands of the receptor’sbinding site.Dr Dan Marquess, VP Medicinal Chemistry, Therav-

ance, Inc., spoke on ‘Integrating Multivalent Design withBiological Insight to Create Theravance’s Pipeline ofDifferentiated Medicines’. Theravance’s pipeline includesdrugs that utilise multi-valent approaches to drug--receptorinteractions, that is, the incorporation of two distinct bindingmoieties into the same drug so that a single molecule caninteract with two completely different receptors. This multi-valent approach is typically achieved by joining two distinctdrug moieties together via a linker. A downside of thisapproach is that high molecular weight can mean that oraldrug delivery may not be possible. An upside is that the lossof entropy for the drug on binding to the second receptor ismuch smaller than it would be for a univalent drug and thisis therefore less unfavourable for binding. The antibacterialTD-1792 [3] is a cephalosporin and glycopeptide heterodimer(Figure 1) with activity against Gram-positive bacteria. It hassignificantly increased potency with respect to either theseparate ‘monomer’ agents or a combination of the twoseparate ‘monomers’. The glycopeptide portion allows thecephalosporin to find its active sites in the bacteria:penicillin-binding proteins 2 and 2a, and thus acts as atargeting agent [4]. Phase II studies are underway.Dr Kalpana Merchant, CSO, Translational Science, Eli

Lilly spoke on ‘How does Translational Science Improvethe Quality of Drug Candidates and Provide Benefit forIndividual Patients’. She advocated the use of translationalscience (TS) to find targets for drug discovery, as TS connectstargets to disease and drugs to targets in individual patient pop-ulations. Use of TS should decrease project failure, itself drivenby poor target selection [5]. The scientific case given was that:i) we need to understand patient populations individually, thatis, diabetes in Brazil cannot necessarily be treated in the sameway as diabetes in China, ii) we need much greater understand-ing of human physiology in normal and diseased states, under-pinned by much greater academic/industrial collaboration inareas such asmetabonomics, proteomics, genomics and imaging.A future, more successful drug discovery world would have:i) patient diagnosis based on molecular pathways and not onpatient symptoms, ii) research projects informed by clinical asopposed to pre-clinical results and iii) drug discovery companiescompeting against each other on generating drugs againstvalidated targets: target discovery and validation would benon-competitive and done in concert with academia.Dr Francois Iris, Chairman and CSO, Bio-Modelling

Systems, France discussed ‘The Discovery of InnovativeTherapeutic Approaches: Looking under the Streetlightis not Necessarily the Right Place to Search’. Francoisdescribed two key problems for drug discovery: i) the

integration of a mass of disparate information and ii) thefact that therapeutic success arises from the coherent manipu-lation of a physiological system as a whole, not just the spe-cific modulation of one particular pathway. The currentparadox is that we have no choice but to use tools andapproaches that will not enable us to reach our goals, as theyare not sufficiently sophisticated or comprehensive to do so.Dr Iris discussed an event-driven analytical approach basedon falsification of hypotheses. This alternative approach iscalled computer-assisted deductive integration (CADI) andit associates algorithmics and heuristics at a systems level toprovide a least-biased view of a biological system. A key con-cept discussed was that specific biological events do not occurbecause they are fated to: they arise because other events couldnot. It is therefore critical to understand what is forbidden. Anexample was given of the modelling of prion-infected neuronsand their interactions with astrocytes and glial cells, whichproduced several testable hypotheses that were later verifiedin vivo [6].

Dr Harren Jhoti, President Astex Pharmaceuticals USA,spoke on ‘Discovering Allosteric Inhibitors usingFragment-based Drug Discovery’. Harren gave examples ofthe use of fragment screening approaches combined withstructural information from X-ray crystallography (sometimessolving hundreds of complexed structures) to discover novelallosteric inhibitors. For full-length hepatitis C virus (HCV)NS3 [7], allosteric inhibitors were discovered in a new, highlyconserved binding site that stabilise an inactive conformationof HCVNS3. These allosteric inhibitors prevented the proteinfrom opening up properly in order to effect its protease andhelicase functions and they represent a new class of antiviralagents. Another example focused on the M2 isoform ofpyruvate kinase (PKM2) [8], a complex tetrameric proteinthat is overexpressed in cancer cells. Structural studies showedthat PKM2 has many fragment binding sites, including anamino acid binding pocket. Serine was shown to be able toactivate PKM2 and fragment leads were developed againstthis pocket.

Professor Jeremy Everett, University of Greenwich, UK,spoke about ‘From Metabonomics to Pharmacometabo-nomics’. Metabonomics is a well-established technology forthe understanding of metabolic processes in systems rangingfrom cell cultures to humans. It was defined in 1999 as ‘Thestudy of the metabolic response of organisms to disease, envi-ronmental change or genetic modification’ [9]. Metabonomicshas important applications in disease diagnosis and treatment,drug metabolism, toxicology, environmental studies, popula-tion studies and many other areas. Pharmacometabonomicsis a new development in which mathematical models of pre-dose biofluid profiles are used to predict the outcome ofdrug administration [10]. In this talk, more recent examplesof pharmacometabonomics were described. In one example,the post-dose ratio of the sulphate to glucuronide metabolitesof paracetamol (acetaminophen) in human urine was shownto be related to the pre-dose urine levels of para-cresol

J. R. Everett

358 Expert Opin. Drug Discov. (2013) 8(3)

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sulphate (PCS, Figure 2) [11]. This is a remarkable result, asapart from being the first demonstration of pharmacometabo-nomics in humans, it shows that gut microbiome-derivedmolecules, such as PCS, can have a significant influence onhuman drug metabolism.

In a further example, pharmacometabonomic predictionsof the metabolism and toxicity of isoniazid were describedin a pre-clinical experiment [12].

Dr Jeog Cheng Ra, President Stem Cell ResearchCenter, RNL Bio Co. Ltd., Korea, gave a remarkable talkon ‘The Safety and Efficacy of Systemic Infusion ofAutologous, Adipose Stem Cells in Humans’. Stem celltherapy was demonstrated [13] by using human adipose stemcells (hASCs, Figure 3) obtained from individual patients,which are then administered back to that same donor patientto treat a wide variety of conditions. Surgical removal of 5 g ofadipose tissue from the patient leads to the isolation of over500,000 hASCs, which are then cultured over 3 weeks to gen-erate over 1 billion hASCs, which can be stored and bankedfor repeat injections. Checks have been carried out for safetyafter single or multiple doses of hASCs in mice and humans.Dr Ra himself has had multiple doses of his own hASCssince 2008.

Evidence was shown of efficacy of hASCs against severalconditions in humans including: i) critical limb ischaemiavia intramuscular injection of hASCs, where regeneration ofblood vessels was observed after 6 months, ii) diabetic ulcervia intramuscular injection of hASCs into the foot, leadingto significant reduction in the ulcer after 4 months, whereup until now the only treatment was amputation andiii) osteoarthritis, where intra-articular injection of hASCsled to reduction of arthritis scoring from K-L grade 4 toK-L grade 3, after 6 months in a Phase II study in South

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Figure 1. The chemical structure of TD-1792 illustrating the bivalent nature of the drug: the glycopeptide left hand side of the

molecule is joined to the cephalosporin on the right hand side by a linker to the oxime moiety.

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Pre-dose PCS/creatinine integral ratio (I.R.)

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Figure 2. The ratio of paracetamol sulphate to paracetamol

glucuronide metabolites (S/G) in the post-dose urine of

99 human volunteers plotted against the pre-dose urine

integral ratio of para-cresol sulphate (PCS)/creatinine. The

figure clearly shows that when pre-dose ratios of PCS/creatinine

are high (> 0.06), the post-dose S/G ratios are low (< 0.8).Reproduced from [11] with permission of the National Academy of Sciences, USA.

Report on the 10th Anniversary of Conference, 8 -- 10 November 2012, Nanjing, China

Expert Opin. Drug Discov. (2013) 8(3) 359

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Korea. A remarkable set of images taken with a keyholecamera showed the regeneration of articular cartilage. Unlikesome other stem cells, hASCs can maintain their activityeven in patients up to 100 years old. Although controversialin some respects, this therapy seems to hold promise.Dr Jean-Claude Dussaule, University Pierre et Marie

Curie, Paris, spoke on ‘Discoidin Domain Receptor 1 is aMajor mediator of Inflammation and Fibrosis duringVascular and Renal Injuries’. Discoidin domain receptor1 (DDR-1) is a tyrosine kinase receptor activated by collagentypes I to IV and is widely expressed and pathologically over-expressed in cancer of the breast, ovary, lung and oesophagus,as well as in atherosclerosis and inflammatory and fibrotic pro-cesses in the kidney and lung. A series of elegant experimentsin mice demonstrated that: i) DDR-1 is a major mediator ofinflammation and fibrosis, ii) DDR-1 expression is inducedin the site affected independent of cell type and iii) mice lack-ing DDR-1 are protected from vascular and renal diseases [14].It is expected that DDR-1 will be a significant drug target forvascular and renal disease in humans.Dr Michael Hennig, VP Drug Discovery Technologies,

Roche, Basel, Switzerland, gave a talk on ‘Screening andStructural Methods to Facilitate Drug Discovery’. Aftercovering aspects of Roche’s HTS (high-throughput screening)and screening file strategy, examples were given of the success-ful use of an integrated array of technologies to accelerate drugdiscovery. The goal of the Roche lead identification group isto ‘generate ideas to inspire chemistry’, a great goal! Insulindegrading enzyme (IDE) is key to the degradation ofb-amyloid and is therefore a potential target in the fightagainst Alzheimer’s disease. An enzyme activator was requiredby the project but no internal or external lead matter wasavailable so a full-file HTS was run using a proprietaryprotease assay with fluorescent detection. An equivalentassay was run against neprilysin (NEP) in order to assesscompound selectivity: selective activators were found for

IDE but not for NEP. Biacore competition experimentswere used to map the binding sites of the ligands and thesewere then investigated with X-ray-based structural biologyexperiments that demonstrated the presence of an allostericbinding site. This was explored with a chemistry program,resulting in a tool compound to use in a pre-clinical proof-of-concept study. The talk closed with a tour de force exampleof the successful use of an emerging technology: structuralbiology of membrane proteins. Very recently, Brian K.Kobilka and Robert J. Lefkowitz were awarded the 2012Nobel Prize in Chemistry for studies on G-protein coupledreceptors, a very important membrane protein family [15].The Roche group solved the structure of a member of anotherclass of membrane proteins, the H+-gated sodium channelASIC1a, which is important in a number of central nervoussystem (CNS) indications. The structure of ASIC1a boundto the gating modifier toxin Psalmotoxin 1 (PCTX1, fromSouth American tarantula) was solved at 3 A resolution andthis enabled a structure-based approach to drug discoveryagainst that target [16].

Expert opinion

The 10th Anniversary of IDDST was a large and generallywell-run meeting that brought together academics, pharma-ceutical and biotechnology representatives, clinicians and ven-dors for 3 intense days of presentations and interactions on allaspects of drug discovery. The key themes that emerged fromthe meeting are as follows. First, a systems biology approachto drug discovery is necessary, even though the tools to effectthis are yet imperfect and still emerging. Genomics, proteo-mics, metabonomics and informatics all have important rolesto play in this regard. Second, drug discovery projects need tobe targeted against important diseases that are defined accord-ing to their molecular mechanisms, as opposed to patients’symptoms. Third, it is increasingly clear that human geneticson its own will struggle to define, understand and help treathuman disease and that much more attention needs to bepaid to the interaction between the human genome and thehuman microbiome. Fourth, biological approaches to drugdiscovery, especially new regenerative medicine approachesusing stem cells, while still at a very early stage, hold a greatdeal of promise and we wait eagerly to see if this promisetranslates into broad patient benefit in the decades to come.Although the global pharmaceutical industry is in a state ofturmoil and rapid change, it is still an exciting time to beinvolved in drug discovery. The patient is still waiting!

Declaration of interest

JR Everett has no financial connection with any of the thirdparties whose talks are covered in this Meeting Highlights.JR Everett is a co-inventor on a recently granted patent onmetabolic phenotyping that concerns pharmacometabonomics(EP1540560).

Figure 3. A photomicrograph of human adipose stem cells.Courtesy of Cyagen, Inc., www.cyagen.com.

J. R. Everett

360 Expert Opin. Drug Discov. (2013) 8(3)

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BibliographyPapers of special note have been highlighted as

either of interest (�) or of considerable interest(��) to readers.

1. Lehn J-M. From supramolecular

chemistry towards constitutional dynamic

chemistry and adaptive chemistry.

Chem Soc Rev 2007;36(2):151-60.. Key review of

supramolecular chemistry.

2. Lehn J-M. Constitutional dynamic

chemistry: bridge from supramolecular

chemistry to adaptive chemistry. In:

Barbolu M, editor. Constitutional

dynamic chemistry. Springer-Verlag

Berlin, Heidelberger Platz 3, D-14197

Berlin, Germany; 2012. p. 1-32.. Key review of CDC.

3. Stryjewski ME, Potgieter PD, Li YP,

et al. TD-1792 versus vancomycin for

treatment of complicated skin and skin

structure infections.

Antimicrob Agents Chemother

2012;56(11):5476-83

4. Hegde SS, Okusanya OO, Skinner R,

et al. Pharmacodynamics of TD-1792, a

novel glycopeptide-cephalosporin

heterodimer antibiotic used against

gram-positive bacteria, in a neutropenic

murine thigh model.

Antimicrob Agents Chemother

2012;56(3):1578-83

5. Paul SM, Mytelka DS, Dunwiddie CT,

et al. How to improve R&D

productivity: the pharmaceutical

industry’s grand challenge. Nat Rev

Drug Discov 2010;9(3):203-14. Important analysis of pharmaceutical

R&D productivity and ways of

improving it.

6. Iris F. Psychiatric systems medicine:

closer at hand than anticipated but not

with the expected portrait.

Pharmacopsychiatry 2012;45(S1):S12-21. Important paper describing how

modelling approaches using both

heuristics (top-down) and algorithmic

(bottom-up) modelling strategies,

together with input from clinician

networks can help address

psychiatric disorders.

7. Saalau-Bethell SM, Woodhead AJ,

Chessari G, et al. Discovery of an

allosteric mechanism for the regulation of

HCV NS3 protein function.

Nat Chem Biol 2012;8(11):920-5. Important paper describing the

discovery of a new conserved binding

site at the protease and helicase

domain interface of HCV NS3 protein.

Leads discovered from fragment

screening that bind at this site

represent a new class of

antiviral agents.

8. Chaneton B, Hillmann P, Zheng L,

et al. Serine is a natural ligand and

allosteric activator of pyruvate kinase

M2. Nature 2012;491(7424):458-62

9. Lindon J, Nicholson J, Holmes E,

Everett J. Metabonomics: metabolic

processes studied by NMR spectroscopy

of biofluids. Concepts Magn Reson

2000;12(5):289-320.. Key paper that introduces and defines

the concept of metabonomics.

10. Clayton T, Lindon J, Cloarec O, et al.

Pharmaco-metabonomic phenotyping

and personalized drug treatment. Nature

2006;440(7087):1073-7.. Key paper providing the first

demonstration

of pharmacometabonomics.

11. Clayton TA, Baker D, Lindon JC, et al.

Pharmacometabonomic identification of

a significant host-microbiome metabolic

interaction affecting human drug

metabolism. Proc Natl Acad Sci USA

2009;106:14728-33.. Key paper demonstrating

pharmacometabonomics in humans for

the first time.

12. Cunningham K, Claus SP, Lindon JC,

et al. Pharmacometabonomic

characterization of xenobiotic and

endogenous metabolic phenotypes that

account for inter-individual variation in

isoniazid-induced toxicological response.

J Proteome Res 2012;11(9):4630-42

13. Kang SK, Shin IS, Ko MS, et al. Journey

of mesenchymal stem cells for homing:

strategies to enhance efficacy and safety

of stem cell therapy. Stem Cells Int

2012;2012:1-11.. Key review of mesenchymal stem cell

(MSC) migration and strategies for

enhancing the migration of MSCs to

injured tissues.

14. Kerroch M, Guerrot D,

Vandermeersch S, et al. Genetic

inhibition of discoidin domain receptor

1 protects mice against crescentic

glomerulonephritis. FASEB J

2012;26(10):4079-91

15. Linse SS. Studies of G-Protein-Coupled

Receptors. Scientific Background on the

Nobel Prize in Chemistry. 2012.

Available from: http://www.nobelprize.

org/nobel_prizes/chemistry/laureates/

2012/advanced.html [Cited

12 November 2012]

16. Dawson RJP, Benz J, Stohler P, et al.

Structure of the acid-sensing ion channel

1 in complex with the gating modifier

psalmotoxin 1. Nat Commun

2012;3:936.. Key paper that provides a new general

concept for gating modifier toxin

binding to ion channels.

AffiliationJeremy R Everett

Professor,

University of Greenwich,

School of Science,

Medway Campus, Central Avenue,

Chatham Maritime, Kent, ME4 4TB, UK

Tel: + 44 208 331 8323;

E-mail: j.r.everett@greenwich.ac.uk

Report on the 10th Anniversary of Conference, 8 -- 10 November 2012, Nanjing, China

Expert Opin. Drug Discov. (2013) 8(3) 361

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