Interfacing Chemical Biology and Drug Discovery: Report from the

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Interfacing Chemical Biology and Drug Discovery: Report from the 50th International Conference on Medicinal Chemistry of the SCT (French Medicinal Chemistry Society), July 2−4, 2014, Rouen, France Janos Sapi,*,† Frédéric Schmidt,‡ Luc Van Hijfte,# and Pascal George§ †

SCT Vice-President, UMR CNRS 7312, Université de Reims-Champagne-Ardenne, 51 rue Cognacq-Jay, F-51069 Reims Cedex, France ‡ SCT Communication Officer, Institut Curie, Research Center, CNRS UMR3666, INSERM U1143, 26 rue d’Ulm, F-75248 Paris, France # NovAliX, BioParc, 850 Blvd Sébastien Brant, BP 30170, F-67405 Illkirch Cedex, France § SCT President, Independent Scientific Expert and Adviser, F-78730 Longvilliers, France

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Rounding up the scientific program were two poster sessions of over 100 posters each. The scientific sessions began on Wednesday, July 2, 2014, with Prof. Karl-Heinz Altmann’s (ETH, Zürich, Switzerland) Paul Ehrlich Prize Lecture (sponsored by Janssen-Cilag). This was a stimulating talk on the synthesis and biological evaluation of macrolide-type natural products (epothilones A/B, zampanolide, rhizoxin F) and their analogs,1 acting as tubulin modulators. Prof. Altmann’s presentation covered the main aspects of synthetic chemistry, diverse macrocyclization strategies, and structure-antitumor activity relationship studies in particular. High resolution X-ray crystallographic experiments of protein−ligand complexes furnished fundamentally new insights into the molecular mechanism of action of both microtubule-stabilizing agents, such as epothilones or zampanolide, as well as tubulin polymerization inhibitors, such as rhizoxin F.2 Dr. Jean-Christophe Harmange (Constellation Pharmaceuticals, US) followed Prof. Altmann with a lecture on the discovery and optimization of a novel series of small molecule EZH2 (Enhancer of Zeste Homologue 2) inhibitors.3 The histone methyltransferase EZH2 is widely implicated in cancer, with recurrent mutations in B-cell lymphomas and melanoma, and overexpression in several malignant diseases including prostate or breast cancers. Lead compounds inhibiting EZH2 with nanomolar potency suppressing global histone H3-lysine 27 methylation and their further optimization to achieve in vivo efficacy after oral administration was discussed.4 Recent progress made in the field of stabilized peptides was highlighted by Dr. Peter Timmerman (Pepscan Therapeutics, The Netherlands), inventor of Pepscan’s 2-CLIPS Technology. 2-CLIPS peptides are highly constrained bicyclic peptides displaying antibody-like affinities and selectivities.5 Dr. Timmerman’s talk was focused on how combining 2-CLIPS technology with Pepscan’s peptide array technology platform enables the optimization of lead 2-CLIPS peptides using parallel synthesis and the development of screening libraries of replacement variants of lead 2-CLIPS binders.6 The second lecture in the stabilized peptides section was delivered by Prof. John Robinson (University of Zürich,

he 50th International Conference on Medicinal Chemistry, RICT (Rencontres Internationales de Chimie Thérapeutique) 2014, focused on “Interfacing Chemical Biology and Drug Discovery” and was co-organized by the French Medicinal Chemistry Society (Société de Chimie Thérapeutique, SCT) and the University of Rouen (Figure 1). Held on July 2−

Photo credit - Fabien Venturi

Figure 1.

4, 2014, in the modern building of the Faculty of Law, walking distance from the historical city of Rouen (Normandy), France, the symposium attracted more than 470 attendees from 40 countries and five continents. Approximately half of the attendees were from industry. The main topics of this Golden Jubilee meeting included the identification of new targets and pathways as well as the development of predictive tools and novel approaches/probes to better understand biological pathways for medicinal chemistry applications. In addition, new methods for the exploration of molecular space and recent results in the field of peptides/peptidomimetics were also discussed. The Scientific Advisory Board, composed of internationally recognized scientists, selected 25 plenary lectures, including two award lectures and four short oral communications, from submitted speaker proposals. Speakers were from academia and industry and spanned Europe, Asia, and North America. © XXXX American Chemical Society

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dx.doi.org/10.1021/cb5009469 | ACS Chem. Biol. XXXX, XXX, XXX−XXX

ACS Chemical Biology

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Prof. Ernest Giralt (University of Barcelona, Spain) presented some recent applications of relatively rigid peptide peptidomimetics as PPI inhibitors. His talk covered D-linear peptides as β-amyloid aggregation modulators, the synthesis of cyclic hexapeptides libraries for protein surface recognition, and the design of cell permeable photoswitchable PPI inhibitors.19 In the second talk of the protein−protein interactions session, Prof. Shaomeng Wang (University of Michigan, USA) reported on some efficient strategies for the conversion of low affinity PPI probe compounds into high quality, potent, and specific drug candidates for use in the treatment of human cancers. In the first part of his talk, Prof. Wang described the structure-based design and optimization of small-molecule Smac mimetics that target inhibitors of apoptosis proteins this led to the discovery of a candidate that has over 100-fold higher affinity than the natural Smac peptide and demonstrates excellent oral bioavailability and safety profiles in human clinical trials.20 In the second part of his talk, Prof. Wang presented the structure-based de novo design approach he used to obtain a new class of nonpeptide small-molecule inhibitors that block the MDM2-p53 interaction. This approach resulted in a clinical candidate which binds to MDM2 over 1000-times better than the p53 protein, with optimized pharmacological properties, including oral bioavailability.21 Safety-related issues are one of the major causes of drug attrition in (pre)clinical development. To overcome this challenge, we need new, reliable, and cost-effective predictive technologies that enable the early determination of the safety profile of drug candidates. The first talk of this safety session was given by Prof. Richard Walmsley (University of Manchester/Gentronix Ltd., U.K.) and focused on the importance of genotoxicity screening in lead optimization and safety assessment. The expression of GADD45alpha protein in response to DNA damage has been exploited to develop two in vitro microplate assays, Green Screen HC and Blue Screen HC, for the detection of genotoxic stress via the production of Green Fluorescent Protein or Gaussia luciferase, respectively.22,23 Case studies have further illustrated the utility and the performance of these assays.24 The second talk of the session, by Prof. Arthur Brown (ChanTest, USA), described “Recent Advances in Predicting Cardiac Risk during Drug Development.” The regulatory paradigm for testing the effects of nonantiarrhythmic drugs on cardiac safety is shifting. The present guidelines have focused on delayed repolarization rather than serious adverse events such as the Torsade de Pointes arrhythmia. The FDA favors the Comprehensive in vitro Proarrhythmia Assay (CiPA) to focus on proarrhythmia and to provide a more complete and accurate assessment of potential effects on human cardiac electrophysiology; ChanTest is implementing CiPA by testing multiple ion channel effects in cell lines, arrhythmias in stem cell-derived ventricular myocytes using MEA, and modeling the human ventricular action potential in silico.25 The first lecture of the oncology session entitled “Targeting BAX for Cancer Therapy: from Computer Screen to Mouse” was delivered by Prof. Luciana Marinelli (University of Napoli, Italy). The most potent small molecule that directly activates BAX, a pro-apoptotic member of the BCl-2 family, was identified through a computer-aided design. It opens up the opportunity to ascertain the real anticancer potential of BAX direct activators. A panel of different tumor cell lines and a mouse model of non-small-cells lung carcinoma were used for in vitro and in vivo studies, respectively. The reported in situ

Switzerland), who detailed the design and applications of protein epitope mimetics (PEMs).7 PEMs mimic key folded epitopes involved in protein−protein or protein−nucleic acid interactions. The transfer of the epitope to a synthetic macrocyclic scaffold allows the optimization of their target affinity/selectivities as well as their physicochemical properties. An interesting example that was presented was one of a new class of β-hairpin-shaped peptides with potent antimicrobial activities against Pseudomonas via specific targeting of the βbarrel of the outer membrane protein LptD, essential for lipopolysaccaride transport. In the opening lecture of day two, Prof. Erick Carreira (ETH Zürich, Switzerland) took attendees on an “excursion in uncharted structural space.” The lecture demonstrated how a synthetic chemist could contribute to drug discovery via the design of new chemical entitiesthese have the potential to increase accessible molecular space and molecular diversity, with the aim of enabling modulation of physicochemical properties. Diverse synthetic strategies leading to spiro[3,3]heptane-, spiro[3,4]octane-, or spiro[3,5]nonane-type scaffolds were described.8 As illustrated by ciprofloxacin, nilotinib, thalidomide, etc., replacement of six-membered heterocycles (such as piperazine, morpholine, and pyridone) with their homospirocyclic counterparts allowed the modulation of PK properties, improved metabolic stability, and, in certain cases, enhanced activity.9,10 Following Prof. Carreira was a series of short communications, organized into two parallel sessions. Prof. Philippe Belmont (University of Paris Descartes, France) reported on the design, optimization, and metabolic stability of trimethylsilyl-containing tetrahydrocyclopenta[c]acridinone-type derivatives as potent CDK2/cycline A inhibitors. A cobalt catalyzed Pauson-Khand reaction afforded diastereoselectivity of targeted molecules,11 while a fine-tuned optimization to get nanomolar range inhibitors was supported by X-ray crystallography and molecular modeling.12 Prof. Nicolas Moitessier (McGill University, Canada) then discussed the development of potent covalent prolyl oligopeptide enzyme inhibitors by an elegant combination of advanced synthetic methodologies and in-house developed computational tools.13 Prof. Muriel Amblard (University of Montpellier, France) focused her talk on the design and optimization of cell penetrating constrained dipeptide mimics14,15 as vectors for intracellular delivery of pepstatin, a highly potent but poorly internalized Cathepsin D inhibitor. The obtained bioconjugates displayed potent antiproliferative activity, resulting from their intracellular Cathepsin D inhibitory effect, and altered the cell cycle by triggering apoptosis in vitro. When tested in vivo in mice xenografted with breast cancer cells, the most potent bioconjugate was able to delay tumor emergence and growth.16 In the fourth oral communication, Dr. Dominique Bonnet (University of Strasbourg, France) described the use of fluorescent-based assays as powerful tools for the understanding of GPCR functional architecture and for the investigation of ligand−GPCR interactions by HTS. For example, fluorescent probes have been developed to detect oxytocin/vasopressin GPCRs (fluorescent “turn-on” approach), their homo- and heterodimers (time-resolved FRET strategy)17 on the surface of living cells, or to find nonpeptide agonists of the apelin receptor (Generic FRET-based assay).18 Day two also featured a special session on recent developments in the field of protein−protein interactions. B



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BAX activation, massive reduction of tumor burden in vivo, and no signs of gross toxicity all evoke a feasible future clinical application of BAX direct activators in humans.26 In his talk, Dr. Masanori Okaniwa (Takeda Pharmaceutical Co, Japan) presented Takeda’s drug discovery program involving the pan-RAF inhibitor, TAK-632.27,28 Given its potent pan-RAF inhibition (IC50: BRAFV600E 2.4 nM, CRAF 1.4 nM) and slow dissociation (koff) profile, TAK-632 demonstrated potent antitumor activities in both A375 (BRAFV600E) and HMVII (NRASQ61K) xenograft models in rats.28,29 These results raise the possibility of using pan-RAF inhibitors such as TAK-632 for the treatment of human cancers harboring either BRAFV600E or NRAS mutations. Over the past decade, Surface Plasmon Resonance (SPR) has become a widely used biophysical tool in drug discovery. The first talk in this special session, given by Prof. Helena Danielson (Uppsala University, Sweden), demonstrated how SPR could be implemented in the drug discovery process, from screening to lead optimization.30 The efficiency of this method has been exemplified by relevant case studies involving fragment-based drug discovery, membrane-bound target evaluation, and investigation of protein−protein interactions. Although SPR is a biophysical tool used in all phases of (fragment based) drug discovery, assay formats relying on the immobilization of the target protein on the sensor surface carry the risk of introducing artifacts if the protein target is unstable, or if the fragment analytes are not sufficiently soluble. In his talk, Dr. Thomas Neumann (NovAliX, France) disclosed that the “reverse” format of High Throughput Chemical Microarray SPR (HT-CM-SPR), where the fragment is immobilized, sidesteps potential problems by keeping the target protein in solution under near native conditions. However, the presentation of fragments to the target is affected.31 With over 9000 sensor fields per microarray, the platform simultaneously generates affinity data for more than 3000 immobilized fragments (24 000 fragments in total) in triplicate. Pros and cons of “channel based” SPR formats and HT-CMSPR were discussed, and two case studies (MMP, PIM, out of more than 110 targets screened) were presented.32,33 Dr. Saadi Khochbin (University of Grenoble/INSERM, France) presented a talk entitled “Cell Identity Loss in Cancer: a Source of New Biomarkers and Therapeutic Targets.” Largescale and systematic ectopic activation of tissue-restricted genes have been shown to occur in all cancers and provide an important source of new cancer biomarkers.34 Dr. Khochbin found that detailed functional analyses of the out-of-context activity of “epigenetic” male germ cell-specific factors in various cancers revealed new and unexpected therapeutic strategies and drug targets.35,36 Dr. Dafydd Owen (Pfizer, USA) in his lecture pointed out how high quality active chemical probes could accelerate medicinal chemistry research by offering better insight into the role of epigenetics in various diseases.37 In his talk, “Applications of Native Mass Spectrometry in Drug Discovery,” Dr. Luc Van Hijfte (NovAliX, France) provided an overview of the use of this technology to gain an understanding of molecular interactions. Native MS is a technique38 that allows visualization of noncovalently bound molecular entities, be it a protein−protein or a protein−ligand complex. The technology allows medium throughput screening and identification of binding affinities and provides the ability to define covalent vs. noncovalent interactions and determine,

qualitatively, the contribution of direct polar interactions (enthalpy of binding). It has been shown that the total duration of ligand−receptor interaction, residence time,39 coupled with kinetics of ligand− receptor association/dissociation has a crucial impact on the ligand’s in vivo efficacy, selectivity, and safety. In her lecture, Prof. Laura Heitman (Leiden University, The Netherlands) described the results of molecular dynamics stimulations combined with mutagenesis to investigate the dissociation of ZM-241385 from its adenosine A2A type receptor.40 A multistep dissociation pathway was evidenced via consecutive interactions with the topographically distinct domains of the receptor suggesting in f ine that such a multistep dissociation is common to other GPCRs. Prof. Klaus Müller (University of Basel/F. Hoffmann-La Roche, Switzerland) concluded day two of the symposium with his talk entitled “Polar Units and Dipolar Interactions Modulating Conformation, Lipophilicity, and other Physicochemical Properties.” He highlighted how polar and polarizing structural units may contribute to lower lipophilicity of a substance without enhancing its hydrogen bonding capacity. Numerous examples illustrated that fine-tune modulation of lipophilic character may affect conformation as well as physicochemical and pharmacokinetic properties.41 Day three of the symposium started with a lecture by Dr. Ulrich Lücking (Bayer HealthCare, Germany) on the discovery of the pan-CDK inhibitor BAY 1000394 (roniciclib). Lead optimization of an HTS hit led to the rapid identification of pan-CDK inhibitor ZK 304709, which displayed a promising preclinical profile. Unfortunately, ZK 304709 failed in phase I studies due to dose-limited absorption and high interpatient variability, which was attributed to limited aqueous solubility and off-target activity against carbonic anhydrases. Further lead optimization efforts addressing the off-target activity profile finally resulted in the introduction of a sulfoximine group, which remains a rather unconventional pharmacophore in medicinal chemistry. However, the sulfoximine series of compounds revealed very interesting properties, culminating in the identification of the nanomolar pan-CDK inhibitor BAY 1000394, which is currently being investigated in phase II clinical trials.42 The second presentation of the kinase session was from Dr. Juan-Miguel Jimenez (Vertex Pharmaceuticals, U. K.), who outlined the design and optimization of pyrazolo[3,4-b]pyridine-type PKC theta inhibitors for the treatment of autoimmune diseases like multiple sclerosis. A tedious but successful optimization process exploiting nonlipophilic substrate-PKC theta enzyme interactions provided a highly potent and selective inhibitor as compared to other PKC isoenzymes despite the almost identical ATP binding sites.43 Dr. Herbert Nar (Boehringer Ingelheim, Germany) discussed the identification, humanization, and in vitro and in vivo pharmacology of monoclonal antibody-based antidotes for dabigatran, a thrombin inhibitor and the first novel oral anticoagulant to enter the market since warfarin 50 years ago. Via a tight network of interactions, the FAB antidote idarucizumab achieves an affinity for dabigatran that is ∼350 times stronger than its affinity for thrombin. Despite the structural similarities in the mode of dabigatran binding, idarucizumab does not bind known thrombin substrates and has no activity in coagulation tests or platelet aggregation. Idarucizumab rapidly reverses the anticoagulant activity of dabigatran in vivo in a rat model of anticoagulation. This is the C



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first specific antidote for a next-generation anticoagulant that may become a valuable tool in patients that require emergency procedures.44 In his lecture, Prof. Hirosaki Suga (University of Tokyo, Japan) described the development of a genetic code reprogramming technology that enables the expression of natural-product inspired nonstandard peptides45 or pseudonatural products. This approach involves macrocyclizations, incorporation of non-natural amino acids, and reliable synthesis of highly complex compound libraries. Coupled with an in vitro display system (Random nonstandard Peptide Integrated Discovery, RaPID), the libraries were screened efficiently with various drug targets affording for example macrocyclic, Nmethyl amino acid-containing ubiquitin ligase inhibitors46 and drug transporters. Dr. José-Manuel Bartalomé-Nebreda (Janssen R&D, Spain) focused on phosphodiesterase 10A (PDE10A) inhibitors, identified as potential enzyme targets for the treatment of schizophrenia. HTS hit identification followed by optimization experiments provided a series of imidazopyrazine-type derivatives inhibiting PDE10A-mediated cAMP hydrolysis in vitro and proved to be efficient in preclinical models of schizophrenia.47 Dr. Guiseppe Cecere (F. Hofmann La Roche, Switzerland) followed with a discussion on the identification of selective TAAR1 partial agonists to enable the preclinical validation of TAAR1 as a promising CNS drug target. Starting with 2-benzyl imidazolines screening hits, extensive investigations led to the discovery of RO5073012 as a potent and selective TAAR1 ligand.48 While this compound had a favorable PK profile and showed in vivo activity in behavioral mice models, its potential for clinical development was hampered by DDI and reactive metabolite risk. An alternative series of TAAR ligands was identified using the SOSA approach49 starting from known adrenergic compounds (e.g., Servier S18616). Optimization of TAAR1 affinity against other aminergic GPCRs was demonstrated and resulted in the identification of highly promising compounds within the 2-amino-oxazoline series (e.g., RO5203648).50 The closing lecture was delivered by Prof. Sébastien Papot (University of Poitiers, France), winner of the “Pierre Fabre Award for Therapeutic Innovation,” an award in memory of Pierre Fabre, founder of Laboratoires Pierre Fabre. Dr. Papot presented the study of novel “smart” drug delivery systems designed to enhance the selectivity of cancer chemotherapies. These compounds are programmed to allow (1) the efficient recognition of malignant specificities located either at the surface of cancer cells51 or in the tumor microenvironment52 and (2) the controlled release of the parent drug exclusively at the tumor site. These innovative molecular systems exhibit remarkable anticancer activities on various tumors in mice, including orthotopic mammary and pancreatic models.53 Two poster prizes for Vocation in Medicinal Chemistry (sponsored by Servier Institute for Research) and nine free registrations offered by the SCT for the next “RICT 2015” meeting, to be held on July 1−3, 2015 in Avignon (Provence), France, wrapped up this very successful symposium on “Interfacing Chemical Biology and Drug Discovery.”

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ACKNOWLEDGMENTS We thank the members of the Scientific Advisory Board, the RICT Executive Board and the Local Organizing Committee for preparation of the scientific program, local organization and hosting the meeting.

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REFERENCES

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Corresponding Author

*E-mail: [email protected]. D



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Interfacing Chemical Biology and Drug Discovery: Report from the

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