Chemical Biology: Contribution to Molecular Therapeutic Innovation A New Role for Chemistry? Report from the Thematic SymposiumOrganized by the SCT (French Medicinal Chemistry Society),November 26th, 2013Frederic Schmidt,*, Pascal George, and Janos Sapi

SCT Communication Ocer; Institut Curie, Research Center, CNRS UMR3666, INSERM U1143, 26 rue dUlm, F-75248 Paris,FranceSCT President, Independent Scientic Expert and AdviserSCT Vice-President; UMR CNRS 7312, Universite de Reims-Champagne-Ardenne, 51 rue Cognacq-Jay, F- 51096 Reims cedex,France

AIM OF THE SYMPOSIUMIn the postgenomic era marked by an ever-growing under-standing of biological phenomena, chemical tools to modulatecomplex biological processes have become essential to moderndrug discovery. The aim of the symposium was to illustratevarious aspects of chemical biology approaches with anemphasis on the pivotal role of chemists in this area. Chemicalbiology1,2 pairs chemistry and biology to dissect biologicalprocesses in organisms and cells by designing highly specicand tightly binding small molecules and to reveal proteinfunctions. These studies lead to the identication of new drugtargets,3 new lead compounds, new biomarkers, and newdiagnostic tools.Therapeutic innovation drives the pharmaceutical industry to

discover and develop new molecular targets. Chemical biologysupports this endeavor with increasing comprehension ofmolecular mechanisms and intracellular processes.

THE PLACE: BIOCITECHThe symposium took place in the Biocitech technology park forlife sciences, located on the outskirts of Paris (20 min from thecity center). The site was created in 1909 by Gaston Roussel.Formerly a research center for pharmaceutical companies suchas Roussel-UCLAF (then part of Aventis), it was successfullyrestructured in 2003 as a technology park. Biocitech currentlyhosts twenty-ve companies in various elds such as drugdiscovery, chemistry, genetics, and computing technology.

THE AUDIENCEAttendees from academia and industry were well represented.Most of the 200 participants were French, but over 10% of theparticipants hailed from other countries.

CONFERENCESThe meeting consisted of six plenary lectures. Dr. MarkBronstrup, Head of the Chemical Biology Department at theHelmholtz Centre for Infection Research in Braunschweig,Germany, gave the introductory lecture.Prof. Bronstrup highlighted several aspects of modern drug

discovery and therapeutic innovation using chemical biologyapproaches. For instance, between 1999 and 2008 phenotypicscreening let to the discovery of more FDA-approved rst-in-

class small-molecule drugs than target-based approaches.4

Researchers rely on chemical biology to elucidate the modeof action of the drug. The old model of one compound, onetarget, one eect is simplistic, and it is necessary to take intoaccount the molecular signature of compounds, biophysicalinteractions with their targets, and indirect regulation of theirpathways. Chemical biology can add value to drug discoverythrough in vivo and cellular imaging, intracellular trac andsignaling, and transport across biological barriers. Theavailability of appropriate biological assays and a shortage ofdiversity oriented chemical libraries is often a bottleneck foraccelerated advancement of drug discovery. The developmentof new screening methods and the availability of diverse,dispersed collections of chemical entities may provide answersto new challenges of modern drug discovery, topics Prof.Marcel Hibert discussed in his talk.Prof. Marcel Hibert (Faculty of Pharmacy, Strasbourg,

France): Screening in academic environments: scientic andtherapeutic outcome.

Published: April 18, 2014

Copyright by Biocitech. Used with permission.

Figure 1. The amphitheater at Biocitech, venue of the meeting.

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Medicinal chemistry has entered a new era after thedeciphering of the human genome. Several thousands ofnovel proteins have now been identied that may representimportant targets for drug discovery. The medicinal chemist isnow challenged to rationalize and accelerate the discovery ofpotent and specic ligands acting at these targets to providebiologists with physiopathological research tools and preclinicalcandidates.Prof. Hiberts group had anticipated this evolution since they

decided 14 years ago to develop several convergent medicinalchemistry strategies to produce novel ligands as eciently aspossible in the academic environment. High throughputscreening represented clearly a means to accelerate thediscovery of original ligands for target molecules. In 1999they set up an open academic screening platform, gathered acollection of molecules and natural extracts produced bygenerations of scientists in academic laboratories (the FrenchChimiotheque Nationale),5 and developed several generic assaysto address issues such as target deorphanization, allostericligand discovery, or ultraminiaturization. For example, a FRET-based assay has been set up and validated as an alternative toscintillation assays allowing the specic detection of ligandsbinding to target proteins in a complex environment, such as G-protein coupled receptors. For soluble puried proteins,uorescence anisotropy has been used to detect ligand binding.For both types of targets, they designed and prepared librariesof uorescent frequent hitters that can be directly screened todiscover the very rst ligands of orphan receptors (receptordeorphaning) or molecules binding to allosteric sites offunctional relevance on known receptors. The uorescent hitsdiscovered in these primary screenings can then be used asanity probes to screen more drug-like libraries for furtherdevelopment.Prof. Nicolas Winssinger (University of Geneva, Switzer-

land): Following the lead from Nature, synthesis and discoveryof covalent inhibitors.Prof. Nicolas Winssinger presented his work on the design

and discovery of inhibitors that can interact covalently withtheir target. While covalent inhibitors have a long history astherapeutics and are abundant among bioactive naturalproducts, most have been discovered serendipitously andoften a posteriori. Sequence analysis across therapeuticallyrelevant protein families suggest that accessible cysteines can beengaged for covalent inhibition in a useful proportion of targets(2040%). This strategy was illustrated with case studiestargeting kinases,68 transcription factors,9 and bromodomains.To streamline the discovery of covalent inhibitors, a novelapproach using a DNA template to pair PNA-encoded smallmolecules10 with reactive functionality was presented.Dr. Ed Tate (Imperial College, London, U.K.): Chemical

biology and chemical proteomics: powerful tools to tackle drugtargets involved in posttranslational modication.Dr. Ed Tate focused on the elds of chemical proteomics11

and chemical biology. His group has taken diverse approachesin design and application of chemistry-driven ways to exploreand manipulate posttranslational modication (PTM) andproteinprotein interactions (PPIs) in living systems. Hispresentation highlighted recent progress in understanding post-translational protein lipidation using chemical biology and thediscovery of novel targets of PTMs such as GPI anchors andprotein acylation using tools including peptide and proteinsynthesis, inhibitor design and discovery, activity-basedproling, and proteomics. He went on to describe a specic

example of how these tools have been used to identify, validate,and exploit N-myristoyltransferase (an acyl transferase)12,13 as adrug target in malaria, resulting in potent, orally active leadswith a well-dened mode of action.Prof. Jens Hasserodt (Ecole Normale Superieure, Lyon,

France): Magnetogenic and uorogenic probes that respond to(bio)chemical analytes.It is widely recognized that modern drug development will

greatly benet from the availability of molecular probes forminimally invasive in vivo imaging modalities. For example, thesemiquantitative imaging of biomarker expression of certaintypes of cancer allows for evaluation of new drug candidates.The communication comprised two lines of probes respondingspecically to selected enzyme activity. Targeting enzymes asbiomarkers benets from increased detection sensitivity bycatalytic (enzymatic) signal amplication, provided that probesare designed that act as true substrates and demonstratemultiple turnover. O-on enzyme-responsive probes generatethe signal from zero background, i.e., the imaging probes areinvisible prior to encounter of the target enzyme, thus ensuringmaximum detection sensitivity and allowing easier imageinterpretation. Prof. Hasserodt proposed a general, highlymodular three-component probe design for peptidases14 wherethe probe releases a phenolic uorophore of ones choice foruorescence imaging. His group demonstrated the designsusefulness by an invisible probe (o) targeting intracellularaminopeptidase activity and releasing a solid-state, ESIPT-typeuorophore that precipitates as highly uorescent (on),photostable crystals in the cytoplasm (unpublished data).Second, he introduced the rst line of truly magnetogenicprobes15,16 for magnetic readout, for in vitro detection ofparamagnetism in a biological uid or potential in vivo detectionby MRI. The probes are diamagnetic (invisible, o) and robustunder physiological conditions and become paramagnetic (on)after irreversible transformation by the target analyte, either achemical reactant or an enzyme.Dr. Nicolas Guilbaud (Institut de Recherches Pierre

Fabre, Toulouse, France): Polyamine vectorization for theselective delivery of antineoplastic agents: From design strategyto F14512 early clinical developmentDespite the successful development of ecient antibody-

drug conjugates (ADC) a number of challenges remain to betackled for their widespread application in anticancer therapy.As an alternative tool small molecule-drug conjugates (SMDC)have recently emerged. Among numerous strategies that havebeen proposed to target drugs to tumors and improve theirecacy, the Polyamine Transport System (PTS), generallyhyperactive in cancer cells, seems to be a suitable molecularentry gate for polyamine-based drug delivery. F14512 isconsidered the most promising anticancer drug in this category,being selected from a large series of compounds derived froman epipodophyllotoxin core and tethered to natural andunnatural polyamines with a variable spacer. This noveltopoisomerase II inhibitor features all the required propertiesof the optimal polyamine drug conjugate: higher solubility,increased cytotoxicity and DNA-binding ability over its parentcompound, uptake via the PTS, and therefore, reduction intoxicity when used in vivo. A comprehensive set of preclinicalstudies validated the rationale of tumor targeting, and stronglysupport F14512 clinical development particularly in onco-hematology.1720

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Dr. Yves Auberson (Novartis Institute for BioMedicalResearch, Basel, Switzerland): Medicinal chemistry for newimaging agents: Developing tools for therapeutic innovation.The remit of medicinal chemistry has signicantly expanded

over the past decade and now includes all stages of drugoptimization, as well as the generation of tools for chemicalbiology and clinical imaging. Among others, several new PETand SPECT radioligands were developed recently, allowingvisualization and quantication of targets that could not beimaged before. These imaging agents can be used to follow thedistribution of a drug in the body, to measure target occupancy,or to image diseases and therapeutic eects. The understandingof properties that make a molecular imaging tracer successful isprogressing, removing unknowns from optimization strategies.New analytical methods allow better prediction of nonspecicbinding or the in vivo quantication of performance of tracercandidates without the need for early radiolabeling. Dr.Auberson illustrated how imaging agents oer opportunitiesfor medicinal chemists to provide clinicians with tools for theearly phases of clinical development, with the aim to addresshigh medical needs with innovative drugs and most quicklybring them to patients.2125

ABOUT THE FRENCH MEDICINAL CHEMICALSOCIETY (SCT)

The French Medicinal Chemistry Society (Societe de ChimieTherapeutique, SCT, Web site: http://www.sct-asso.fr) wasfounded in 1966 as a nonprot organization with the aim todisseminate scientic results and promote interdisciplinaryknowledge in the major pharmaceutical research and develop-ment domains covering the whole panel of drug discovery andrelated sciences from target identication to drug registration.The SCT is also involved in advancing medicinal chemistry byinitiating cooperation, networking, providing training, andrewarding scientic excellence. The SCT is interested indeveloping and maintaining scientic contacts with industrialand academic research groups, medicinal chemistry relatedassociations, and federations, both on national and internationallevels.Each year, the SCT organizes four dedicated scientic events,

including the Rencontres Internationales de Chimie Therapeutique(RICT) (International Meeting of Therapeutic Chemistry), aninternational congress devoted to the main scientic areas indrug discovery chemistry. Generally these highly successfulmeetings bring together more than 25 internationallyrecognized speakers from Europe, America, and Asia presentingoutstanding results in every aspect of modern medicinalchemistry.Apart from the RICT, the French Medicinal Chemistry

Society organizes two smaller thematic one-day meetings: forexample, in April, 2013 a workshop dealt with biologicallyrelevant molecular diversity while the Fall One-Day Meeting2014 focused on chemical biology, especially its contribution tomolecular therapeutic innovation. The fourth yearly organizedevent is The Scientic Days for young Ph.D. students andpostdocs (Journees de Jeunes Chercheurs, JJC) oering theopportunity to present their results in oral communications andposter sessions. To acknowledge outstanding scientic results,SCT attributes every year with the support of its sponsorsprestigious prizes (Ehrlich Prize, Prize for Vocation inMedicinal Chemistry, etc.), fellowships recognizing leadingscientists, research teams, or young researchers.

ORGANIZING COMMITEEThe meeting was organized by a group of scientists from SCTparticularly interested in chemical biology:Dr. Pascal George (SCT president, independent scientic

expert and adviser)Dr. Frederic Schmidt (SCT communication ocer, Institut

Curie, Paris)Dr. Sebastien Papot (SCT councillor, Universite de Poitiers)Dr. Frederic Dolle (SCT councillor, CEA, Institut dimagerie

biomedicale, Orsay)

CONCLUSIONThe rst Chemical Biology Thematic Symposium provided acomprehensive overview of some special areas of chemicalbiology research. In his conclusion Prof. Jean Martinez (Facultyof Pharmacy, Montpellier, France) emphasized the importanceof chemical biology in modern medicinal chemistry and the keyrole of proteins as targets for therapy.

AUTHOR INFORMATIONCorresponding Author*E-mail: frederic.schmidt@curie.fr.

ACKNOWLEDGMENTSDr. Jean-Francois Boussard (Biocitech President) is acknowl-edged for logistic facilities and hosting the meeting.

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