In Focus pubs.acs.org/acschemicalbiology
Chemical Biology: Contribution to Molecular Therapeutic Innovation − A New Role for Chemistry? Report from the Thematic Symposium Organized by the SCT (French Medicinal Chemistry Society), November 26th, 2013 Frédéric Schmidt,*,† Pascal George,‡ and Janos Sapi§ †
SCT Communication Officer; Institut Curie, Research Center, CNRS UMR3666, INSERM U1143, 26 rue d’Ulm, F-75248 Paris, France ‡ SCT President, Independent Scientific Expert and Adviser § SCT Vice-President; UMR CNRS 7312, Université de Reims-Champagne-Ardenne, 51 rue Cognacq-Jay, F- 51096 Reims cedex, France
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AIM OF THE SYMPOSIUM In the postgenomic era marked by an ever-growing understanding of biological phenomena, chemical tools to modulate complex biological processes have become essential to modern drug discovery. The aim of the symposium was to illustrate various aspects of chemical biology approaches with an emphasis on the pivotal role of chemists in this area. Chemical biology1,2 pairs chemistry and biology to dissect biological processes in organisms and cells by designing highly specific and tightly binding small molecules and to reveal protein functions. These studies lead to the identification of new drug targets,3 new lead compounds, new biomarkers, and new diagnostic tools. Therapeutic innovation drives the pharmaceutical industry to discover and develop new molecular targets. Chemical biology supports this endeavor with increasing comprehension of molecular mechanisms and intracellular processes.
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Copyright by Biocitech. Used with permission.
Figure 1. The amphitheater at Biocitech, venue of the meeting.
THE PLACE: BIOCITECH The symposium took place in the Biocitech technology park for life sciences, located on the outskirts of Paris (20 min from the city center). The site was created in 1909 by Gaston Roussel. Formerly a research center for pharmaceutical companies such as Roussel-UCLAF (then part of Aventis), it was successfully restructured in 2003 as a technology park. Biocitech currently hosts twenty-five companies in various fields such as drug discovery, chemistry, genetics, and computing technology.
class small-molecule drugs than target-based approaches.4 Researchers rely on chemical biology to elucidate the mode of action of the drug. The old model of one compound, one target, one effect is simplistic, and it is necessary to take into account the molecular signature of compounds, biophysical interactions with their targets, and indirect regulation of their pathways. Chemical biology can add value to drug discovery through in vivo and cellular imaging, intracellular traffic and signaling, and transport across biological barriers. The availability of appropriate biological assays and a shortage of diversity oriented chemical libraries is often a bottleneck for accelerated advancement of drug discovery. The development of new screening methods and the availability of diverse, dispersed collections of chemical entities may provide answers to 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: scientific and therapeutic outcome.
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THE AUDIENCE Attendees from academia and industry were well represented. Most of the 200 participants were French, but over 10% of the participants hailed from other countries.
■
CONFERENCES The meeting consisted of six plenary lectures. Dr. Mark Brönstrup, Head of the Chemical Biology Department at the Helmholtz Centre for Infection Research in Braunschweig, Germany, gave the introductory lecture. Prof. Brönstrup highlighted several aspects of modern drug discovery and therapeutic innovation using chemical biology approaches. For instance, between 1999 and 2008 phenotypic screening let to the discovery of more FDA-approved first-in© 2014 American Chemical Society
Published: April 18, 2014 849
dx.doi.org/10.1021/cb500173s | ACS Chem. Biol. 2014, 9, 849−852
ACS Chemical Biology
In Focus
example of how these tools have been used to identify, validate, and exploit N-myristoyltransferase (an acyl transferase)12,13 as a drug target in malaria, resulting in potent, orally active leads with a well-defined mode of action. Prof. Jens Hasserodt (Ecole Normale Supérieure, Lyon, France): Magnetogenic and fluorogenic probes that respond to (bio)chemical analytes. It is widely recognized that modern drug development will greatly benefit from the availability of molecular probes for minimally invasive in vivo imaging modalities. For example, the semiquantitative imaging of biomarker expression of certain types of cancer allows for evaluation of new drug candidates. The communication comprised two lines of probes responding specifically to selected enzyme activity. Targeting enzymes as biomarkers benefits from increased detection sensitivity by catalytic (enzymatic) signal amplification, provided that probes are designed that act as true substrates and demonstrate multiple turnover. Off-on enzyme-responsive probes generate the signal from zero background, i.e., the imaging probes are invisible prior to encounter of the target enzyme, thus ensuring maximum detection sensitivity and allowing easier image interpretation. Prof. Hasserodt proposed a general, highly modular three-component probe design for peptidases14 where the probe releases a phenolic fluorophore of one’s choice for fluorescence imaging. His group demonstrated the design’s usefulness by an invisible probe (off) targeting intracellular aminopeptidase activity and releasing a solid-state, ESIPT-type fluorophore that precipitates as highly fluorescent (on), photostable crystals in the cytoplasm (unpublished data). Second, he introduced the first line of truly magnetogenic probes15,16 for magnetic readout, for in vitro detection of paramagnetism in a biological fluid or potential in vivo detection by MRI. The probes are diamagnetic (invisible, off) and robust under physiological conditions and become paramagnetic (on) after irreversible transformation by the target analyte, either a chemical reactant or an enzyme. Dr. Nicolas Guilbaud (Institut de Recherches Pierre Fabre, Toulouse, France): Polyamine vectorization for the selective delivery of antineoplastic agents: From design strategy to F14512 early clinical development Despite the successful development of efficient antibodydrug conjugates (ADC) a number of challenges remain to be tackled for their widespread application in anticancer therapy. As an alternative tool small molecule-drug conjugates (SMDC) have recently emerged. Among numerous strategies that have been proposed to target drugs to tumors and improve their efficacy, the Polyamine Transport System (PTS), generally hyperactive in cancer cells, seems to be a suitable molecular entry gate for polyamine-based drug delivery. F14512 is considered the most promising anticancer drug in this category, being selected from a large series of compounds derived from an epipodophyllotoxin core and tethered to natural and unnatural polyamines with a variable spacer. This novel topoisomerase II inhibitor features all the required properties of the optimal polyamine drug conjugate: higher solubility, increased cytotoxicity and DNA-binding ability over its parent compound, uptake via the PTS, and therefore, reduction in toxicity when used in vivo. A comprehensive set of preclinical studies validated the rationale of tumor targeting, and strongly support F14512 clinical development particularly in oncohematology.17−20
Medicinal chemistry has entered a new era after the deciphering of the human genome. Several thousands of novel proteins have now been identified that may represent important targets for drug discovery. The medicinal chemist is now challenged to rationalize and accelerate the discovery of potent and specific ligands acting at these targets to provide biologists with physiopathological research tools and preclinical candidates. Prof. Hibert’s group had anticipated this evolution since they decided 14 years ago to develop several convergent medicinal chemistry strategies to produce novel ligands as efficiently as possible in the academic environment. High throughput screening represented clearly a means to accelerate the discovery of original ligands for target molecules. In 1999 they set up an open academic screening platform, gathered a collection of molecules and natural extracts produced by generations of scientists in academic laboratories (the French Chimiothèque Nationale),5 and developed several generic assays to address issues such as target deorphanization, allosteric ligand discovery, or ultraminiaturization. For example, a FRETbased assay has been set up and validated as an alternative to scintillation assays allowing the specific detection of ligands binding to target proteins in a complex environment, such as Gprotein coupled receptors. For soluble purified proteins, fluorescence anisotropy has been used to detect ligand binding. For both types of targets, they designed and prepared libraries of fluorescent frequent hitters that can be directly screened to discover the very first ligands of orphan receptors (receptor deorphaning) or molecules binding to allosteric sites of functional relevance on known receptors. The fluorescent hits discovered in these primary screenings can then be used as affinity probes to screen more drug-like libraries for further development. Prof. Nicolas Winssinger (University of Geneva, Switzerland): Following the lead from Nature, synthesis and discovery of covalent inhibitors. Prof. Nicolas Winssinger presented his work on the design and discovery of inhibitors that can interact covalently with their target. While covalent inhibitors have a long history as therapeutics and are abundant among bioactive natural products, most have been discovered serendipitously and often a posteriori. Sequence analysis across therapeutically relevant protein families suggest that accessible cysteines can be engaged for covalent inhibition in a useful proportion of targets (20−40%). This strategy was illustrated with case studies targeting kinases,6−8 transcription factors,9 and bromodomains. To streamline the discovery of covalent inhibitors, a novel approach using a DNA template to pair PNA-encoded small molecules10 with reactive functionality was presented. Dr. Ed Tate (Imperial College, London, U.K.): Chemical biology and chemical proteomics: powerful tools to tackle drug targets involved in posttranslational modification. Dr. Ed Tate focused on the fields of chemical proteomics11 and chemical biology. His group has taken diverse approaches in design and application of chemistry-driven ways to explore and manipulate posttranslational modification (PTM) and protein−protein interactions (PPIs) in living systems. His presentation highlighted recent progress in understanding posttranslational protein lipidation using chemical biology and the discovery of novel targets of PTMs such as GPI anchors and protein acylation using tools including peptide and protein synthesis, inhibitor design and discovery, activity-based profiling, and proteomics. He went on to describe a specific 850
dx.doi.org/10.1021/cb500173s | ACS Chem. Biol. 2014, 9, 849−852
ACS Chemical Biology
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In Focus
ORGANIZING COMMITEE The meeting was organized by a group of scientists from SCT particularly interested in chemical biology: Dr. Pascal George (SCT president, independent scientific expert and adviser) Dr. Frédéric Schmidt (SCT communication officer, Institut Curie, Paris) Dr. Sébastien Papot (SCT councillor, Université de Poitiers) Dr. Frédéric Dollé (SCT councillor, CEA, Institut d’imagerie biomédicale, Orsay)
Dr. Yves Auberson (Novartis Institute for BioMedical Research, Basel, Switzerland): Medicinal chemistry for new imaging agents: Developing tools for therapeutic innovation. The remit of medicinal chemistry has significantly expanded over the past decade and now includes all stages of drug optimization, as well as the generation of tools for chemical biology and clinical imaging. Among others, several new PET and SPECT radioligands were developed recently, allowing visualization and quantification of targets that could not be imaged before. These imaging agents can be used to follow the distribution of a drug in the body, to measure target occupancy, or to image diseases and therapeutic effects. The understanding of properties that make a molecular imaging tracer successful is progressing, removing unknowns from optimization strategies. New analytical methods allow better prediction of nonspecific binding or the in vivo quantification of performance of tracer candidates without the need for early radiolabeling. Dr. Auberson illustrated how imaging agents offer opportunities for medicinal chemists to provide clinicians with tools for the early phases of clinical development, with the aim to address high medical needs with innovative drugs and most quickly bring them to patients.21−25
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CONCLUSION The first Chemical Biology Thematic Symposium provided a comprehensive overview of some special areas of chemical biology research. In his conclusion Prof. Jean Martinez (Faculty of Pharmacy, Montpellier, France) emphasized the importance of chemical biology in modern medicinal chemistry and the key role of proteins as targets for therapy.
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: [email protected].
ABOUT THE FRENCH MEDICINAL CHEMICAL SOCIETY (SCT) The French Medicinal Chemistry Society (Société de Chimie Thérapeutique, SCT, Web site: http://www.sct-asso.fr) was founded in 1966 as a nonprofit organization with the aim to disseminate scientific results and promote interdisciplinary knowledge in the major pharmaceutical research and development domains covering the whole panel of drug discovery and related sciences from target identification to drug registration. The SCT is also involved in advancing medicinal chemistry by initiating cooperation, networking, providing training, and rewarding scientific excellence. The SCT is interested in developing and maintaining scientific contacts with industrial and academic research groups, medicinal chemistry related associations, and federations, both on national and international levels. Each year, the SCT organizes four dedicated scientific events, including the ‘Rencontres Internationales de Chimie Thérapeutique (RICT)’ (International Meeting of Therapeutic Chemistry), an international congress devoted to the main scientific areas in drug discovery chemistry. Generally these highly successful meetings bring together more than 25 internationally recognized speakers from Europe, America, and Asia presenting outstanding results in every aspect of modern medicinal chemistry. Apart from the RICT, the French Medicinal Chemistry Society organizes two smaller thematic one-day meetings: for example, in April, 2013 a workshop dealt with biologically relevant molecular diversity while the Fall One-Day Meeting 2014 focused on chemical biology, especially its contribution to molecular therapeutic innovation. The fourth yearly organized event is “The Scientific Days” for young Ph.D. students and postdocs (Journées de Jeunes Chercheurs, JJC) offering the opportunity to present their results in oral communications and poster sessions. To acknowledge outstanding scientific results, SCT attributes every year with the support of its sponsor’s prestigious prizes (Ehrlich Prize, Prize for Vocation in Medicinal Chemistry, etc.), fellowships recognizing leading scientists, research teams, or young researchers.
ACKNOWLEDGMENTS Dr. Jean-François Boussard (Biocitech President) is acknowledged for logistic facilities and hosting the meeting. REFERENCES
(1) Huryn, D. M., Resnick, L. O., and Wipf, P. (2013) Contributions of academic laboratories to the discovery and development of chemical biology tools. J. Med. Chem. 56, 7161−7176. (2) Bucci, M., Goodman, C., and Sheppard, T. L. (2010) A decade of chemical biology. Nat. Chem. Biol. 6, 847−854. (3) Bunnag, M. E., Chekler, E. L., and Jones, L. H. (2013) Target validation using chemical probes. Nat. Chem. Biol. 9, 195−199. (4) Swinney, D. C., and Anthony, J. (2011) How were new medicines discovered? Nat. Rev. Drug Discovery 10, 507−519. (5) Hibert, M. F. (2009) French/European academic compound library initiative. Drug Discovery Today 14, 723−725. (6) Leproult, E., Barluenga, S., Moras, D., Wurtz, J. M., and Winssinger, N. (2011) Cysteine mapping in conformationally distinct kinase nucleotide binding sites: Application to the design of selective covalent inhibitors. J. Med. Chem. 54, 1347−1355. (7) Barluenga, S., Jogireddy, R., Koripelly, G. K., and Winssinger, N. (2010) In vivo efficacy of natural product-inspired irreversible kinase inhibitors. ChemBioChem 11, 1692−1699. (8) Zambaldo, C., Sadhu, K. K., Karthikeyan, G., Barluenga, S., Daguera, J. P., and Winssinger, N. (2013) Selective affinity-based probe for oncogenic kinases suitable for live cell imaging. Chem. Sci. 4, 2088−2092. (9) Duplan, V., Serba, C., Garcia, J., Valot, G., Barluenga, S., Hoerlé, M., Cuendet, M., and Winssinger, N. (2013) Synthesis of sesquiterpene-inspired derivatives designed for covalent binding and their inhibition of the NF-κB pathway. Org. Biomol. Chem. 12, 370− 375. (10) Daguer, J. P., Ciobanu, M., Alvarez, S., Barluenga, S., and Winssinger, N. (2011) DNA-templated combinatorial assembly of small molecule fragments amenable to selection/amplification cycles. Chem. Sci. 2, 625−632. (11) Storck, E. M., Serwa, R. A., and Tate, E. W. (2013) Chemical proteomics: a powerful tool for exploring protein lipidation. Biochem. Soc. Trans. 41, 56−61. (12) Goncalves, V., Brannigan, J. A., Whalley, D., Ansell, K. H., Saxty, B., Holder, A. A., Wilkinson, A. J., Tate, E. W., and Leatherbarrow, R. J. (2012) Discovery of Plasmodium vivax N-myristoyltransferase
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inhibitors: screening, synthesis, and structural characterization of their binding mode. J. Med. Chem. 55, 3578−3582. (13) Wright, M. H., Clough, B., Rackham, M. D., Kaveri, R., Brannigan, J., Grainger, M., Moss, D. K., Bottrill, A. R., Heal, W. P., Broncel, M., Serwa, R. A., Brady, D., Mann, D. J., Leatherbarrow, R. J., Tewari, R., Wilkinson, A. J., Holder, A. A., and Tate, E. W. (2014) Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach. Nat. Chem. 6, 112− 121. (14) Thorn-Seshold, O., Vargas-Sanchez, M., McKeon, S., and Hasserodt, J. (2012) A robust, high-sensitivity stealth probe for peptidases. Chem. Commun. 48, 6253−6255. (15) Hasserodt, J., Kolanowski, J. L., and Touti, F. (2014) Magnetogenesis in water induced by a chemical analyte. Angew. Chem., Int. Ed. 53, 60−73. (16) Touti, F., Maurin, P., and Hasserodt, J. (2013) Magnetogenesis under physiological conditions with probes that report on (bio)chemical stimuli. Angew. Chem., Int. Ed. 52, 4654−4658. (17) Barret, J. M., Kruczynski, A., Vispe, S., Annereau, J. P., Brel, V., Guminski, Y., Delcros, J. G., Lansiaux, A., Guilbaud, N., Imbert, T., and Bailly, C. (2008) F14512, a potent antitumor agent targeting topoisomerase II vectored into cancer cells via the polyamine transport system. Cancer Res. 68, 9845−53. (18) Annerea, J. P., Brel, V., Dumontet, C., Guminski, Y., Imbert, T., Broussas, M., Vispé, S., Bréand, S., Guilbaud, N., Barret, J. M., and Bailly, C. (2010) A fluorescent biomarker of the polyamine transport system to select patients with AML for F14512 treatment. Leuk. Res. 34, 1383−1389. (19) Brel, V., Annereau, J. P., Vispé, S., Kruczynski, A., Bailly, C., and Guilbaud, N. (2011) Cytotoxicity and cell death mechanisms induced by the polyamine-vectorized anti-cancer drug F14512 targeting topoisomerase II. Biochem. Pharmacol. 82, 1843−1852. (20) Kruczynski, A., Pillon, A., Créancier, L., Vandenberghe, I., Gomes, B., Brel, V., Fournier, E., Annereau, J. P., Currie, E., Guminski, Y., Bonnet, D., Bailly, C., and Guilbaud, N. (2013) F14512, a polyamine-vectorized anti-cancer drug, currently in clinical trials exhibits a marked preclinical anti-leukemic activity. Leukemia 11, 2139−48. (21) Ametamey, S. M., Kessler, L. J., Honer, M., Wyss, M. T., Buck, A., Hintermann, S., Auberson, Y. P., Gasparini, F., and Schubiger, P. A. (2006) Radiosynthesis and preclinical evaluation of 11C-ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5. J. Nucl. Med. 47, 698−705. (22) Hintermann, S., Vranesic, I., Allgeier, H., Brülisauer, A., Hoyer, D., Lemaire, M., Moenius, T., Urwyler, S., Whitebread, S., Gasparini, F., and Auberson, Y. P. (2007) ABP688, a novel selective and high affinity ligand for the labeling of mGlu5 receptors: identification, in vitro pharmacology, pharmacokinetic and biodistribution studies. Bioorg. Med. Chem. 15, 903−914. (23) Ametamey, S. M., Treyer, V., Streffer, J., Wyss, M. T., Schmidt, M., Blagoev, M., Hintermann, S., Auberson, Y. P., Gasparini, F., Fischer, U. C., and Buck, A. (2007) Human PET studies of metabotropic glutamate receptor subtype 5 with 11C-ABP688. J. Nucl. Med. 48, 247−252. (24) Briard, E., Orain, D., Beerli, C., Billich, A., Streiff, M., Bigaud, M., and Auberson, Y. P. (2011) BZM055, an iodinated radiotracer candidate for PET and SPECT imaging of myelin and FTY720 brain distribution. ChemMedChem 6, 667−677. (25) Deschwanden, A., Karolewicz, B., Feyissa, A. M., Treyer, V., Ametamey, S. M., Johayem, A., Burger, C., Auberson, Y. P., Sovago, J., Stockmeier, C. A., Buck, A., and Hasler, G. (2011) Reduced metabotropic glutamate receptor 5 density in major depression determined by [(11)C]ABP688 PET and postmortem study. Am. J. Psychiatry 168, 727−734.
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Chemical Biology: Contribution to Molecular Therapeutic Innovation − A New Role for Chemistry? Report from the Thematic Symposium Organized by the SCT (French Medicinal Chemistry Society), November 26th, 2013 Frédéric Schmidt,*,† Pascal George,‡ and Janos Sapi§ †
SCT Communication Officer; Institut Curie, Research Center, CNRS UMR3666, INSERM U1143, 26 rue d’Ulm, F-75248 Paris, France ‡ SCT President, Independent Scientific Expert and Adviser § SCT Vice-President; UMR CNRS 7312, Université de Reims-Champagne-Ardenne, 51 rue Cognacq-Jay, F- 51096 Reims cedex, France
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AIM OF THE SYMPOSIUM In the postgenomic era marked by an ever-growing understanding of biological phenomena, chemical tools to modulate complex biological processes have become essential to modern drug discovery. The aim of the symposium was to illustrate various aspects of chemical biology approaches with an emphasis on the pivotal role of chemists in this area. Chemical biology1,2 pairs chemistry and biology to dissect biological processes in organisms and cells by designing highly specific and tightly binding small molecules and to reveal protein functions. These studies lead to the identification of new drug targets,3 new lead compounds, new biomarkers, and new diagnostic tools. Therapeutic innovation drives the pharmaceutical industry to discover and develop new molecular targets. Chemical biology supports this endeavor with increasing comprehension of molecular mechanisms and intracellular processes.
■
Copyright by Biocitech. Used with permission.
Figure 1. The amphitheater at Biocitech, venue of the meeting.
THE PLACE: BIOCITECH The symposium took place in the Biocitech technology park for life sciences, located on the outskirts of Paris (20 min from the city center). The site was created in 1909 by Gaston Roussel. Formerly a research center for pharmaceutical companies such as Roussel-UCLAF (then part of Aventis), it was successfully restructured in 2003 as a technology park. Biocitech currently hosts twenty-five companies in various fields such as drug discovery, chemistry, genetics, and computing technology.
class small-molecule drugs than target-based approaches.4 Researchers rely on chemical biology to elucidate the mode of action of the drug. The old model of one compound, one target, one effect is simplistic, and it is necessary to take into account the molecular signature of compounds, biophysical interactions with their targets, and indirect regulation of their pathways. Chemical biology can add value to drug discovery through in vivo and cellular imaging, intracellular traffic and signaling, and transport across biological barriers. The availability of appropriate biological assays and a shortage of diversity oriented chemical libraries is often a bottleneck for accelerated advancement of drug discovery. The development of new screening methods and the availability of diverse, dispersed collections of chemical entities may provide answers to 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: scientific and therapeutic outcome.
■
THE AUDIENCE Attendees from academia and industry were well represented. Most of the 200 participants were French, but over 10% of the participants hailed from other countries.
■
CONFERENCES The meeting consisted of six plenary lectures. Dr. Mark Brönstrup, Head of the Chemical Biology Department at the Helmholtz Centre for Infection Research in Braunschweig, Germany, gave the introductory lecture. Prof. Brönstrup highlighted several aspects of modern drug discovery and therapeutic innovation using chemical biology approaches. For instance, between 1999 and 2008 phenotypic screening let to the discovery of more FDA-approved first-in© 2014 American Chemical Society
Published: April 18, 2014 849
dx.doi.org/10.1021/cb500173s | ACS Chem. Biol. 2014, 9, 849−852
ACS Chemical Biology
In Focus
example of how these tools have been used to identify, validate, and exploit N-myristoyltransferase (an acyl transferase)12,13 as a drug target in malaria, resulting in potent, orally active leads with a well-defined mode of action. Prof. Jens Hasserodt (Ecole Normale Supérieure, Lyon, France): Magnetogenic and fluorogenic probes that respond to (bio)chemical analytes. It is widely recognized that modern drug development will greatly benefit from the availability of molecular probes for minimally invasive in vivo imaging modalities. For example, the semiquantitative imaging of biomarker expression of certain types of cancer allows for evaluation of new drug candidates. The communication comprised two lines of probes responding specifically to selected enzyme activity. Targeting enzymes as biomarkers benefits from increased detection sensitivity by catalytic (enzymatic) signal amplification, provided that probes are designed that act as true substrates and demonstrate multiple turnover. Off-on enzyme-responsive probes generate the signal from zero background, i.e., the imaging probes are invisible prior to encounter of the target enzyme, thus ensuring maximum detection sensitivity and allowing easier image interpretation. Prof. Hasserodt proposed a general, highly modular three-component probe design for peptidases14 where the probe releases a phenolic fluorophore of one’s choice for fluorescence imaging. His group demonstrated the design’s usefulness by an invisible probe (off) targeting intracellular aminopeptidase activity and releasing a solid-state, ESIPT-type fluorophore that precipitates as highly fluorescent (on), photostable crystals in the cytoplasm (unpublished data). Second, he introduced the first line of truly magnetogenic probes15,16 for magnetic readout, for in vitro detection of paramagnetism in a biological fluid or potential in vivo detection by MRI. The probes are diamagnetic (invisible, off) and robust under physiological conditions and become paramagnetic (on) after irreversible transformation by the target analyte, either a chemical reactant or an enzyme. Dr. Nicolas Guilbaud (Institut de Recherches Pierre Fabre, Toulouse, France): Polyamine vectorization for the selective delivery of antineoplastic agents: From design strategy to F14512 early clinical development Despite the successful development of efficient antibodydrug conjugates (ADC) a number of challenges remain to be tackled for their widespread application in anticancer therapy. As an alternative tool small molecule-drug conjugates (SMDC) have recently emerged. Among numerous strategies that have been proposed to target drugs to tumors and improve their efficacy, the Polyamine Transport System (PTS), generally hyperactive in cancer cells, seems to be a suitable molecular entry gate for polyamine-based drug delivery. F14512 is considered the most promising anticancer drug in this category, being selected from a large series of compounds derived from an epipodophyllotoxin core and tethered to natural and unnatural polyamines with a variable spacer. This novel topoisomerase II inhibitor features all the required properties of the optimal polyamine drug conjugate: higher solubility, increased cytotoxicity and DNA-binding ability over its parent compound, uptake via the PTS, and therefore, reduction in toxicity when used in vivo. A comprehensive set of preclinical studies validated the rationale of tumor targeting, and strongly support F14512 clinical development particularly in oncohematology.17−20
Medicinal chemistry has entered a new era after the deciphering of the human genome. Several thousands of novel proteins have now been identified that may represent important targets for drug discovery. The medicinal chemist is now challenged to rationalize and accelerate the discovery of potent and specific ligands acting at these targets to provide biologists with physiopathological research tools and preclinical candidates. Prof. Hibert’s group had anticipated this evolution since they decided 14 years ago to develop several convergent medicinal chemistry strategies to produce novel ligands as efficiently as possible in the academic environment. High throughput screening represented clearly a means to accelerate the discovery of original ligands for target molecules. In 1999 they set up an open academic screening platform, gathered a collection of molecules and natural extracts produced by generations of scientists in academic laboratories (the French Chimiothèque Nationale),5 and developed several generic assays to address issues such as target deorphanization, allosteric ligand discovery, or ultraminiaturization. For example, a FRETbased assay has been set up and validated as an alternative to scintillation assays allowing the specific detection of ligands binding to target proteins in a complex environment, such as Gprotein coupled receptors. For soluble purified proteins, fluorescence anisotropy has been used to detect ligand binding. For both types of targets, they designed and prepared libraries of fluorescent frequent hitters that can be directly screened to discover the very first ligands of orphan receptors (receptor deorphaning) or molecules binding to allosteric sites of functional relevance on known receptors. The fluorescent hits discovered in these primary screenings can then be used as affinity probes to screen more drug-like libraries for further development. Prof. Nicolas Winssinger (University of Geneva, Switzerland): Following the lead from Nature, synthesis and discovery of covalent inhibitors. Prof. Nicolas Winssinger presented his work on the design and discovery of inhibitors that can interact covalently with their target. While covalent inhibitors have a long history as therapeutics and are abundant among bioactive natural products, most have been discovered serendipitously and often a posteriori. Sequence analysis across therapeutically relevant protein families suggest that accessible cysteines can be engaged for covalent inhibition in a useful proportion of targets (20−40%). This strategy was illustrated with case studies targeting kinases,6−8 transcription factors,9 and bromodomains. To streamline the discovery of covalent inhibitors, a novel approach using a DNA template to pair PNA-encoded small molecules10 with reactive functionality was presented. Dr. Ed Tate (Imperial College, London, U.K.): Chemical biology and chemical proteomics: powerful tools to tackle drug targets involved in posttranslational modification. Dr. Ed Tate focused on the fields of chemical proteomics11 and chemical biology. His group has taken diverse approaches in design and application of chemistry-driven ways to explore and manipulate posttranslational modification (PTM) and protein−protein interactions (PPIs) in living systems. His presentation highlighted recent progress in understanding posttranslational protein lipidation using chemical biology and the discovery of novel targets of PTMs such as GPI anchors and protein acylation using tools including peptide and protein synthesis, inhibitor design and discovery, activity-based profiling, and proteomics. He went on to describe a specific 850
dx.doi.org/10.1021/cb500173s | ACS Chem. Biol. 2014, 9, 849−852
ACS Chemical Biology
■
In Focus
ORGANIZING COMMITEE The meeting was organized by a group of scientists from SCT particularly interested in chemical biology: Dr. Pascal George (SCT president, independent scientific expert and adviser) Dr. Frédéric Schmidt (SCT communication officer, Institut Curie, Paris) Dr. Sébastien Papot (SCT councillor, Université de Poitiers) Dr. Frédéric Dollé (SCT councillor, CEA, Institut d’imagerie biomédicale, Orsay)
Dr. Yves Auberson (Novartis Institute for BioMedical Research, Basel, Switzerland): Medicinal chemistry for new imaging agents: Developing tools for therapeutic innovation. The remit of medicinal chemistry has significantly expanded over the past decade and now includes all stages of drug optimization, as well as the generation of tools for chemical biology and clinical imaging. Among others, several new PET and SPECT radioligands were developed recently, allowing visualization and quantification of targets that could not be imaged before. These imaging agents can be used to follow the distribution of a drug in the body, to measure target occupancy, or to image diseases and therapeutic effects. The understanding of properties that make a molecular imaging tracer successful is progressing, removing unknowns from optimization strategies. New analytical methods allow better prediction of nonspecific binding or the in vivo quantification of performance of tracer candidates without the need for early radiolabeling. Dr. Auberson illustrated how imaging agents offer opportunities for medicinal chemists to provide clinicians with tools for the early phases of clinical development, with the aim to address high medical needs with innovative drugs and most quickly bring them to patients.21−25
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CONCLUSION The first Chemical Biology Thematic Symposium provided a comprehensive overview of some special areas of chemical biology research. In his conclusion Prof. Jean Martinez (Faculty of Pharmacy, Montpellier, France) emphasized the importance of chemical biology in modern medicinal chemistry and the key role of proteins as targets for therapy.
■ ■ ■
AUTHOR INFORMATION
Corresponding Author
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*E-mail: [email protected].
ABOUT THE FRENCH MEDICINAL CHEMICAL SOCIETY (SCT) The French Medicinal Chemistry Society (Société de Chimie Thérapeutique, SCT, Web site: http://www.sct-asso.fr) was founded in 1966 as a nonprofit organization with the aim to disseminate scientific results and promote interdisciplinary knowledge in the major pharmaceutical research and development domains covering the whole panel of drug discovery and related sciences from target identification to drug registration. The SCT is also involved in advancing medicinal chemistry by initiating cooperation, networking, providing training, and rewarding scientific excellence. The SCT is interested in developing and maintaining scientific contacts with industrial and academic research groups, medicinal chemistry related associations, and federations, both on national and international levels. Each year, the SCT organizes four dedicated scientific events, including the ‘Rencontres Internationales de Chimie Thérapeutique (RICT)’ (International Meeting of Therapeutic Chemistry), an international congress devoted to the main scientific areas in drug discovery chemistry. Generally these highly successful meetings bring together more than 25 internationally recognized speakers from Europe, America, and Asia presenting outstanding results in every aspect of modern medicinal chemistry. Apart from the RICT, the French Medicinal Chemistry Society organizes two smaller thematic one-day meetings: for example, in April, 2013 a workshop dealt with biologically relevant molecular diversity while the Fall One-Day Meeting 2014 focused on chemical biology, especially its contribution to molecular therapeutic innovation. The fourth yearly organized event is “The Scientific Days” for young Ph.D. students and postdocs (Journées de Jeunes Chercheurs, JJC) offering the opportunity to present their results in oral communications and poster sessions. To acknowledge outstanding scientific results, SCT attributes every year with the support of its sponsor’s prestigious prizes (Ehrlich Prize, Prize for Vocation in Medicinal Chemistry, etc.), fellowships recognizing leading scientists, research teams, or young researchers.
ACKNOWLEDGMENTS Dr. Jean-François Boussard (Biocitech President) is acknowledged for logistic facilities and hosting the meeting. REFERENCES
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