DOI: 10.1002/ijch.201600132 Conference Report: Chemical ...techmail.technion.ac.il/174b977c982518db8fb2037a... · future issues in the series of Rosarium Philosophorum will be dedicated

DOI: 10.1002/ijch.201600132

Conference Report: Chemical Synthesis and DrugDiscovery: ICS Symposium Honoring Wolf Prize LaureatesK. C. Nicolaou and Stuart L. Schreiber, June 1, 2016,Technion – Israel Institute of Technology, Haifa, IsraelEhud Keinan*[a]

The Annual Wolf Prize Symposia of the ICS havebecome a permanent part of the scientific landscape ofthe Israeli community of chemists. These highly attendedevents take place almost every year in late May or earlyJune, just before the Wolf Prize award ceremony in theKnesset. Every symposium features a busy day of excel-lent lectures presented by the Wolf Prize Laureates andother speakers who are active in the field of the prizeand/or related to the laureates� research groups. Theseone-day symposia take place at one of the university cam-puses. For example, on May 14, 2012, we honored A.Paul Alivisatos and Charles M. Lieber in the symposium

entitled Celebrating Nanochemistry, which took place inTel Aviv University (Figure 1). On May 7, 2013, we helda symposium entitled New Biomaterials for Therapy inhonor of Robert Langer, and on June 2, 2014, the Schu-lich Faculty of Chemistry of the Technion hosted Chi-Huey Wong in a symposium, entitled Chemical Biologyand Biomedical Science. We skipped the year of 2015, be-cause no Wolf Prize in Chemistry was awarded in thatyear.

On June 1, 2016, the Technion hosted again the WolfPrize symposium, entitled Chemical Synthesis and DrugDiscovery, in honor of the Prize Laureates K. C. Nicolaou

and Stuart L. Schreiber (Figure 2 and Figure 3). Theevent was organized by the ICS President Ehud Keinanand Project Manager Liraz Maanit, and was generouslysponsored by the Technion, the Schulich Faculty ofChemistry, and several global pharmaceutical companies,

[a] E. KeinanThe Schulich Faculty of ChemistryTechnion – Israel Institute of TechnologyHaifa 32000 (Israel)e-mail: [email protected]

Figure 1. Announcement posters of Wolf Prize Symposia: 2012, 2013, and 2014.

Isr. J. Chem. 0000, 00, 1 – 14 � 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim &1&

These are not the final page numbers! ��

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including Teva Pharmaceutical Industries Ltd., Israel;Merck Sharp & Dohme (MSD) Corporation, USA;Bayer Pharma, Berlin, Germany; Synaffix BV, the Neth-erlands; and Stemcentrx Inc., San Francisco, USA.

Opening Session

Prof. Ehud Keinan opened the symposium by welcomingthe fresh Wolf Prize Laureates, the speakers, and the au-dience in the jam-packed auditorium of the Schulich Fac-

Figure 2. Announcement poster of the 2016 Wolf Prize Symposium autographed by all 11 speakers and 4 chairpersons.

Isr. J. Chem. 0000, 00, 1 – 14 � 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.ijc.wiley-vch.de &2&


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http://www.ijc.wiley-vch.de

ulty of Chemistry. He explained why the prize of thisyear is so important. Both the Wolf and the Nobel prizesare different from most other scientific prizes in that theyprimarily recognize and highlight a certain topic or a spe-cific discovery and then distinguish the pioneers who de-serve the credit for this advance. This year the prize inchemistry was important not only for the community oforganic synthesis, but also for the entire community ofchemists. Many people may not fully understand theformal citation of either Nicolaou, “for advancing thefield of chemical synthesis to the extremes of molecularcomplexity, linking structure and function and expandingour dominion over the interface of chemistry, biology,and medicine” or Schreiber “for pioneering chemical in-sights into the logic of signal transduction and gene regu-lation that led to important, new therapeutics, and for ad-vancing chemical biology and medicine through the dis-covery of small-molecule probes.” Even those who under-stand the words may not comprehend the significance oforganic synthesis to human health and wellbeing.

First of all, the 2016 prize highlights the science of or-ganic synthesis. In the past, particularly at the times ofRobert Woodward and Sir Robert Robinson, there wasno need to explain why organic synthesis was important.It was not necessary to apologize for practicing organicsynthesis and justify it by explaining that organic synthe-sis can benefit other disciplines. In our time, however,almost every review article and every research proposalthat focuses on organic synthesis starts with an explana-tion that the field is important for solving important prob-lems in other fields and therefore it should be supported.This apologetic tone is no longer needed after the Wolfprize of 2016.

Secondly, the prize of this year is immensely importantfor the improvement of the public image of chemistry.Too many people believe that chemistry is polluting, poi-soning, causing diseases or just ugly, evocative of chemi-cal weapons, synthetic ingredients in food, and everythingthat should be avoided. We know that commercial adver-tisements of consumer products truly reflect the commondenominators of people�s culture and beliefs. And manyof these ads promote food, cosmetics, dyes, detergents,and even pesticides and insecticides, all free of chemicals.Everyone in this audience would agree that there is noother scientific discipline that is so relevant to our every-day life, our wellbeing and our life expectancy thanchemistry. Yet, most people do not realize that chemistryis responsible the doubling of our average life expectancyfrom 47 years to over 85 in merely 100 years. Most peopletake it for granted that in our times most wounded sol-diers don�t die, whereas the huge military graveyards ofWorld War I show that only 5 % died in combat. Chemis-try should take most of the credit for the fact that ourworld is so different from that of our parents.

Prof. George Whitesides of Harvard University oncesaid, “We as chemists think of ourselves as experts inquarrying blocks from granite; we have not thought it ourjob to build cathedrals from them.” Most chemists consid-er themselves expert reductionists, keeping away fromthe big issues, letting others build the cathedrals. TheWolf prize of 2016 is important because Nicolaou andSchreiber have demonstrated that chemists can buildmonumental scientific cathedrals for the benefit of hu-mankind. The scientific program of this symposium con-veys an important advice to the young generation: if youwish to change the world in biology and medicine, don�tstart with biology and medicine, but with chemistry. Thisassures that rigorous analysis of problems and observa-tions is done with high precision for better understandingthe less rigorous domains.

Keinan also mentioned that in addition to this symposi-um and other events of this Wolf Prize week, the IsraelJournal of Chemistry will celebrate the prize by a specialissue titled Advancing Science through Synthetic Chemis-try and Chemical Biology, with Professors Scott Snyderand John Porco serving as guest editors. In addition, twofuture issues in the series of Rosarium Philosophorumwill be dedicated to organic synthesis and biologicalchemistry.

Finally, Keinan acknowledged the sponsors of this sym-posium, including MSD, Stemcentrx, Inc., Synaffix BV,Bayer AG, Teva Pharmaceutical Industries Ltd., theTechnion, and the Schulich Faculty of Chemistry. Hethanked the ICS Project Manager, Ms. Liraz Maanit, thelecturers, the session chairs, Prof. Doron Shabat of TelAviv University, Wolf Prize Laureate Prof. Meir Wilchekof the Weizmann Institute of Science, and Dr. AdrianGilbert, VP CMC, Teva Pharmaceutical Industries Ltd.

Figure 3. Group photo of all lecturers and chairpersons. From left:Doron Shabat, Manfred T. Reetz, Adrian Gilbert, Ehud Keinan,Marcus Bauser, K. C. Nicolaou, Roderich S�ssmuth, Stuart L.Schreiber, Floris L. van Delft, Shlomo Rozen, Doron Pappo, JuliaGavrilyuk, Philippe G. Nantermet, Meir Wilchek, and Peter J. Stang.Photograph by Avia Haberman.



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Prof. Peretz Lavie, President of the Technion, con-gratulated the Prize Laureates and referred to Keinan�scomment about the apologetic tone that is no longer rele-vant. It reminded him of the early days of the Technionin 1924, when the institute opened its gates with a class of17 students, including one woman. The keynote speakerin the opening ceremony was the mining engineer Mena-hem Usishkin, whose name appears on many streets inmajor cities around Israel. Usishkin started his speechwith the claim that applied research and basic sciencerepresent two sides of the same coin. Therefore, weshould not apologize for what we do, neither for quarry-ing granite nor for building cathedrals. Lavie expressedhis delight realizing that both laureates excel not only inscience, but also in science education.

Prof. Lavie made another point that both laureates areknown for the interdisciplinary nature of their science,combining chemistry with biology and medicine. Thefuture of science depends on interdisciplinary science,and for more than a decade, the Technion has been tryingto encourage this trend by establishing the nanotechnolo-gy center, the energy center, the life sciences and engi-neering center, and the center of autonomous systems, allbridging different fields of science. He said that he hadjust come from another symposium, honoring the HarveyPrize Laureate, Prof. Emanuel Bloch of Electrical Engi-neering. That symposium also bridged several fields ofscience, including quantum physics, materials, and engi-neering. Multidisciplinary research represents the futureof science, and the industrial revolution in which we areliving now, relies on people like the Wolf Prize Laureatesof 2016.

Prof. Noam Adir, Dean of the Schulich Faculty ofChemistry, indicated that the Schulich Faculty of Chemis-try is honored again to celebrate the Wolf Prize inChemistry with the laureates and the fantastic group ofscientists. “In the past we have been honored to have sim-ilar symposia for Sam Danishefsky, Gilbert Stork, Ri-chard A. Lerner, Peter G. Schultz, Richard N. Zare, AdaYonath, George Feher, Chi Huey Wong and others.Almost five billion years of evolution have enabled thebiosynthesis of almost every compound possible andevery molecule necessary for life�s various needs. Overthe last thousands of years, mankind has utilized many ofthese compounds for a variety of needs, especially astreatments for various ailments. The use of natural com-pounds was based on trial and error, without knowledgeof the actual molecular agent, or the mechanism ofaction. Over the past 150 years, scientists isolated thecompounds, characterized them and started learning howto make them synthetically. The following step has startedrelatively recently, and it includes the identification ofnew compounds, which are potential therapeutic agents,but were not yet found in nature. The Wolf Prize of thisyear celebrates the achievements of two remarkable sci-entists for their contribution to synthetic chemistry and

chemical biology, to the development of novel syntheticmethods and the use of such novel compounds to probethe control over biological systems. This symposium joinsan additional Schulich Symposium on Chemical Biologyorganized by Prof. Ashraf Brik, and both symposia bringchemical biology to the forefront. I congratulate the lau-reates and wish all participants an enjoyable symposium.”

Prof. Stuart Schreiber followed up on thoughts ex-pressed by previous speakers, saying that Prof. Nicolaouand he wanted to convey two major messages. “First, it istrue that this is now a remarkable period of time for bio-medical research. Biology has made great strides towardsunderstanding the origin of diseases. Yet, our society isexpecting us, scientists, to mitigate suffering and deathfrom diseases, and we have to realize that we are stillvery far from these goals. Sometime, the world of biologygets a little bit ahead with too much exuberance. It isquick to describe the mechanisms of disease, but to trans-late this understanding to make real advances is a problemthat is fundamental to chemical and chemical biologyproblems. Secondly, the upside of this picture is my enor-mous enthusiasm and optimism about the future. When Ilook at the young generation in Israel my optimism is en-hanced. Israel has a fantastic culture of valuing education,encouraging intellectual creativity and innovation and Isee the desire among the young generation to change theworld.”

Keinan concluded the opening session with a smallaward ceremony. Prof. Stuart Schreiber and Prof.Manfred Reetz received the recognition of an HonorableMembership of the ICS. Prof. K. C. Nicolaou and Prof.Peter Stang already received this recognition severalyears ago. In addition, both laureates, Nicolaou andSchreiber, received a gift of three souvenir leaves of theIsraeli stamps, which were produced in collaboration be-tween the Israel Philatelic Service and the ICS, commem-orating Nobel Prizes in Chemistry awarded to six Israeliscientists over the past decade.

Plenary Lectures

The scientific program included 11 plenary lectures,which were grouped into 4 sessions (Figure 4).

Prof. K. C. Nicolaou of Rice University delivered thefirst lecture on Total synthesis of natural and designedmolecules of biological and medical importance. Whilepresenting the speaker, Keinan mentioned that this washis third visit to Israel. Nicolaou first visited this countryin 1997 as a member a delegation of scientists from TheScripps Research Institute to the 62nd Annual Meeting ofthe ICS in the Technion. Skipping his long list of prizesand awards, as well as his specific scientific achievements,Keinan highlighted the fact that Nicolaou�s career servesas a role model for many young people worldwide. In par-ticular, Nicolaou inspires those who wrongly assume that



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only people who were born into the proper social envi-ronment would be able to reach the top in science. Hisrather unusual career exemplifies that everything is possi-

ble for talented people who are determined to achievetheir goals. K. C. Nicolaou was born 70 years ago in thesmall Greek town, Karavas, on the Northern shore of

Figure 4. Collage of photos from the Wolf Prize Symposium. The Schulich Faculty of Chemistry, Technion, June 1, 2016. Photographs byAvia Haberman.



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Cyprus, an area that suffered from continuous conflictsbetween Greek and Turks, and was later occupied by theTurkish army in 1974. Obviously, this is not the idealbackground for a young person to become a world leaderin science. In 1964, at age 18, he travelled to London andspent his first two years there, learning English and pre-paring for the entrance exams to the university, makinghis living from various jobs, including selling fish andchips on the street. In 1969, this young immigrant re-ceived his B.Sc. degree in chemistry, First Class Honors,from the University of London, and the rest is history:Ph.D. in 1972 from University College under Franz Sond-heimer and Peter J. Garratt; postdoc at Columbia Univer-sity (1972–1973) under Thomas J. Katz and then at Har-vard University (1973–1976) under E. J. Corey; and thenclimbing up the ladder all the way to a professor ofchemistry at the University of Pennsylvania (1978–1989).In 1989, when Richard Lerner, President of The ScrippsResearch Institute, decided to create a department ofchemistry from scratch in the shortest possible time, heknew who could do the job. Nicolaou accepted the offerat Scripps, along with a joint appointment at the UC SanDiego. In less than a decade, Nicolaou and Lerner man-aged to build one of the best chemistry departmentsworldwide. This legendary success story has becomea lesson and a model for all university presidents aroundthe world. In 2013, Nicolaou moved on to the next phaseof his career by accepting an offer from Rice University.

In his lecture, Prof. Nicolaou covered a number oftopics dealing with total synthesis, molecular design, andbiological testing of complex molecules relevant to biol-ogy and medicine, including the antibiotics viridicatum-toxin B and CJ-16,264, and antitumor agents N14-desace-toxytubulysin H, D12-prostaglandin J3, shishijimicin A, un-cialamycin, and trioxacarcin C.

Prof. Stuart L. Schreiber of the Howard Hughes Medi-cal Institute, Broad Institute of Harvard and MIT, deliv-ered the second lecture on Chemistry towards novelmechanism-of-action compounds in probe and therapeu-tics discovery. While presenting the speaker, Keinan cited

David Ogilvy who said, “the secret of long life is doublecareers; one to about age sixty, then another for the nextthirty years.” This advice may not be relevant to Schreib-er who has just turned 60, because he has already accom-plished several amazing careers during his first 60 years.After studying at the University of Virginia, he workedunder Robert B. Woodward at Harvard University, andfollowing Woodward’s death, continued with YoshitoKishi. In 1980, he started his independent career at YaleUniversity and later moved back to Harvard and also tothe Broad Institute. He has been a pioneer in chemicalbiology for over two decades. Long ago, Schreiber had re-alized that small molecules are not only useful tools toaffect biological targets, but they are also associated withdynamic flow of information in biological systems, andtherefore, can be used as probes in biology and medicine.He went a long way from the field of total synthesis tochemical biology and drug discovery, and on the way,coined many concepts and terms that we all use very fre-quently. They are all based on the recognition that mole-cules are the language of nature to convey information.

In his lecture, Schreiber focused on the role of modernasymmetric synthesis in generating 3-D compoundshaving novel mechanisms of action (nMoA) in probe andtherapeutics discovery. His group hypothesized that sp3-rich chiral compounds are especially well suited to bindthe topographically complex binding sites of proteins andRNA than traditional, sp2-rich, generally more flat com-pounds. Improving their ability to access a greater rangeof binding sites leads to compounds having novel MoAs,which is key to tackling many problems in biomedicaland translational research today. For example, human ge-netics and biochemical studies of variant proteins canprovide a blueprint for the activities that drugs shouldconfer on the more common versions of the proteins, inthe context of human physiology and prior to launchinga drug-discovery effort, in order to be safe and effica-cious. However, the activities suggested by these experi-ments of nature are challenging and often unfamiliar tothe historical path towards drug discovery. For the mostpart, drugs don�t yet exist that have these suggestedMoAs. Thus, they demand nMoA compounds. In the areaof microbial therapeutics, nMoA compounds are powerfulprobes of pathogen�s biology and key to overcoming thegeneral problem of resistance. Schreiber also introducedthe concept of chemistry driving the discovery of com-pounds having novel mechanisms of action. After illus-trating the synthetic paths they use to create 3-D chiralcompounds and their ability to yield nMoA compounds,including as microbial therapeutics, he ended by describ-ing their efforts to achieve real-time biological annotationof synthetic compounds using thousands of multiplexedmeasurements of the actions of compounds on cells. Hestated that if real-time biological annotation of syntheticcompounds could become a routine aspect of syntheticorganic chemistry in the future, it could provide a means



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to increase the potential of chemistry to impact biologyand medicine.

Prof. Manfred T. Reetz of the Philipps-University, Mar-burg, and Max-Planck-Institut f�r Kohlenforschung, M�l-heim, Germany, presented the third lecture on Directedevolution of oxidoreductases for difficult stereoselective re-actions. He explained that since its conception some timeago, the idea of directed evolution of stereoselective en-zymes as a novel approach to asymmetric catalysis hasbeen generalized by his and other research groups to in-clude essentially all enzyme types. It involves recursivecycles of gene mutagenesis and screening, which buildsup “evolutionary pressure”, quite different from develop-ing selective transition-metal catalysts or organocatalysts.Since the screening step is the bottleneck of Darwinianlaboratory evolution, the real challenge is to obtainmutant libraries of highest quality requiring a minimumof screening effort. His group has proposed iterative satu-ration mutagenesis (ISM), which is the key to a prolificsource of catalysts. It has been refined to include whatthey call triple code saturation mutagenesis (TCSM).Recent applications concern the control of regio- and ste-reoselectivity of P450-catalyzed late-stage oxidative hy-droxylation of steroids and of purely synthetic nonnaturalcompounds, and ADH-catalyzed asymmetric reduction of“difficult-to-reduce” ketones, including the creation ofstereoselective E. coli designer cells for cascade process-es.

Dr. Philippe Nantermet of the MRL DiscoveryChemistry, Merck and Co., lectured on Accelerating drugdiscovery: integration of chem-informatics, drug-like re-agent collections and screening automation to improvesuccess rate. He illustrated the principles of an emergingcapability with the potential for being truly transforma-tional in their efforts to improve efficiency in drug discov-ery. Recent advances in several discrete scientific andtechnological areas have enhanced their ability to mine,fuse, and analyze large data sets, model relevant drug-likechemical space, and enhance their ability to execute inmedicinal chemistry and in vitro pharmacology. Harness-ing these aptitudes, they have developed an integrated“design cycle”, which is an iterative, data driven processenabled by the following components: 1) a parallel designtool enabling virtual enumeration and in silico evaluationof tens of thousands of theoretical drug candidates(ALDaS, Automated Library Design and Synthesis); 2)visualization and sampling from bio- and chemo-similarsubgroups of this virtual space (MPO, Multi-ParameterOptimization); 3) rapid, parallel nano-scale pre-screeningof reaction conditions; 4) rapid parallel synthesis ofa small subset of the most relevant candidates (PMC, Par-allel Medicinal Chemistry); and finally, 5) facile genera-tion and analysis of biological data (e.g., ALIS, Automat-ed Ligand Identification System), which in turn, informsthe subsequent design cycle. Nantermet presented several

examples of drug discovery projects enabled by this ap-proach.

Prof. Shlomo Rozen of Tel Aviv University lectured onImpossible organic transformations carried out with ele-mental fluorine. He explained that for almost a century,F2 was considered to be a most destructive element. Awhile ago, his group started to show that under certainconditions, the opposite is true. It has been used for veryselective fluorinations and for some oxygen transfer reac-tions, which cannot be achieved by any other agent. Theyused F2 for the activation of inactive sites in organic mol-ecules, opening the field of true electrophilic substitutionson saturated centers. Elemental fluorine adds in a synmode across double bonds via the extremely unstable a-fluorocarbocation. A highly unusual support for thatnotion was mentioned. They also synthesized AcOF andMeOF, which were theoretically predicted to be impossi-ble to make. Among other unique characteristics, thesereagents were found useful for the PET technology asa source for 11C labeling. HOFCMeCN complex, madeeasily by passing F2 through aqueous acetonitrile, wasfound to be the best oxygen transfer reagent in organicchemistry. He presented few examples where compoundswere made for the first time, despite literature claims thatthey are impossible to make.

Dr. Floris L. van Delft of Synaffix BV, the Netherlands,lectured on Metal-free click chemistry to enable the nextgeneration of antibody-drug conjugates. He explained thatthe precise modulation of protein structure and functionby covalent functional modification is a powerful tool inproteome-based research, biomedical applications, and di-agnostics. Moreover, biological therapeutics based onprotein conjugation has gained prominence in the fightagainst HIV, cancer, malaria, enzyme replacement thera-py, and others. Unfortunately, site-specific modification ofa single amino acid in a protein amongst a plethora ofcompeting side chains (lysines, cysteines) remains a greatchallenge, and typically mixtures of products are ob-tained. Most recently, his group has contributed to thefield by the fully controlled modification of proteinsbased on a two-stage strategy: 1) site-specific introductionof a specific abiotic functionality, followed by 2) fast andselective chemical conjugation of a functionality of inter-est by metal-free click chemistry. Several approacheswere presented for the incorporation of a 1,3-dipole (e.g.,azide or nitrone), which serves as a suitable anchor pointfor the subsequent conjugation by a strain-promoted cy-cloaddition. Particular attention was given to a versatilestrategy for the site-specific modification of N-glycopro-teins, by means of a two-stage chemoenzymatic conjuga-tion via the glycan. The latter approach, called GlycoCon-nect�, was presented as a powerful tool in the generationof antibody-drug conjugates (ADCs), a promising newgeneration of anticancer drugs. Moreover, a versatilepolar linker technology called HydraSpace� was present-ed, which further lifts the potential of glycan conjugation



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in terms of efficiency, antibody stability, and potency. Ex-cellent in vivo efficacy and high tolerability is demon-strated, thus paving the way for the next generation ofADCs with an improved therapeutic index.

Prof. Doron Pappo of Ben-Gurion University of theNegev, Beer-Sheva, lectured on Natural phenolic productsas inspiration for developing new C�C bond forming reac-tions. He explained that iron-catalyzed oxidative cross-coupling reactions provide an environmentally friendlystrategy to form new C�C bonds directly from two C�Hbonds. This chemistry is widely used by plants to producethe complex natural phenolic oligomeric and polymericcompounds that are essential for growth and protection.In the laboratory, the biomimetic oxidative cross-couplingof phenolic components suffers from a lack of selectivity,making the cross-coupling of two nonidentical reactantsat specific sites difficult to obtain. To address the selectiv-ity issue in these reactions, his group has developed a setof highly selective iron-catalyzed oxidative cross-couplingreactions that follow district coupling mechanisms, there-by enabling efficient synthesis of specific phenolic archi-tectures in high degree of chemo-, regio-, and enantiose-lectivity.

Dr. Julia Gavrilyuk of Stemcentrx Inc., South SanFrancisco, lectured on Selection of the optimal payload forantibody-drug conjugates. She mentioned that Stem-centrx, which was founded in 2008, combines state-of-the-art research and GMP manufacturing capabilities. Thishas allowed them to advance from target discovery intheir laboratory to treating patients in clinical trials at anaccelerated pace. They are investigating many of the larg-est and most lethal cancers through their proprietary plat-forms, which identify cancer stem cells and discover noveltargets, and then engineer and manufacture antibodiesand antibody drug conjugates for those targets. She pre-sented an example of their evaluation process that leadsto the selection of linker-payload for clinically useful anti-body drug conjugates. In particular, she focused on syn-thetic aspects and lessons learned from the synthesis ofpyrrolobenzodiazepine linker-payload used in rovalpitu-zumab tesirine (Rova-T�; SC16LD6.5). Stemcentrx�smost advanced drug rovalpituzumab tesirine (Rova-T;SC16LD6.5) is addressing SCLC and other neuroendo-crine cancers, such as large-cell neuroendocrine carcino-ma. Rova-T has received orphan drug designation fromthe FDA for treatment of small-cell lung cancer.

Prof. Roderich D. S�ssmuth of the Technische Univer-sit�t Berlin, lectured on Chemical biology of peptide natu-ral products – structures, syntheses and bioactivities. Heexplained that infectious diseases are a threat to humanhealth worldwide. In this context, peptides, natural prod-ucts from bacteria and fungi, have proved importantsource of new drugs. Pathways for peptide synthesis arethe ribosomal peptide synthesis rendering ribosomallysynthesized and posttranslationally modified peptides(RiPPs), as well as non-ribosomally synthesized peptides

(NRPs). He reported on the quest for new peptide drugsby classical screening and genome mining approaches:the discovery of RiPPs, e.g., plantazolicin from Bacillusamyloliquefaciens and the antiallodynic and antiviral lab-yrinthopeptins from Actinomyces species. Likewise,pathogenic microorganisms producing toxins to insects orplants are also exceptional sources for novel peptidestructures: examples are the bacterium Xanthomonas al-bilineans, which synthesizes the anti-Gram negativegyrase inhibitor albicidin, causing leaf scald diseases insugar cane, as well as the honey bee pathogenic bacteri-um Paenibacillus larvae causing the American foulbrood(AFB). Unprecedented biosynthesis pathways of com-pounds produced by these organisms were shown and anassessment of their bioactivity and a putative role inpathogenesis were highlighted.

Dr. Marcus Bauser of Bayer Pharma Aktiengesell-schaft, BPH-DD-TRG-ONCII, Oncology II, Berlin, lec-tured on Discovery of selective probes for oncology re-search and beyond. He pointed out that with recent ad-vances in chemical biology, the opportunity to understandand treat human disease has substantially increased. Togenerate meaningful results, high quality small-moleculetool compounds are needed. Therefore, Bayer has joinedforces with the Structural Genomics Consortium (SGC)to generate chemical probes that fulfill stringent potencyand selectivity criteria as confirmed by independent re-viewers. All chemical probes are open access and willhelp scientists in academia and in pharmaceutical re-search to identify and validate new targets to treat severediseases. He presented two recent case reports: TheSMYD2 (SET and MYND domain-containing protein 2)is a protein lysine methyltransferase (PKMT), which wasinitially described as a histone H3K36 and H3K4 methyl-transferase involved in transcriptional regulation. Giventhe reports of overexpression in certain cancers alsolinked to poor prognosis, SMYD2 is proposed to be anoncogene and an attractive cancer drug target. He report-ed the discovery of a novel potent and selective SMYD2inhibitor, by high throughput screening and extensive bio-physical validation. Further optimization generated BAY-598, which shows improved low nanomolar potency andis selective against kinases and other PKMTs. Further-more, BAY-598 specifically inhibits SMYD2 methylationactivity in a cellular assay with similar potency and re-duces methylation of the tumor suppressor protein p53.BAY-598 was found to be a promising selective andpotent SMYD2 inhibitor in vitro and in vivo, possiblyproviding new treatment options for combination thera-pies of cancers, showing up with SMYD2-mediated inacti-vation of the p53 tumor suppressor. Increased glycolysisrates combined with an insufficient cellular respiration intumor cells have been known for decades as the Warburgeffect (1930). One of the key players in this metabolic al-teration of cancer cells is glucose transporter 1 (orGLUT-1), which facilitates the transport of glucose across



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the plasma membranes of mammalian cells. Based ona high throughput screen (HTS) using a kinetic readoutof constitutive expressing luciferase H1299 cells, theyidentified new potent lead structures with unique selectiv-ity against the other members of the GLUT-1 family(GLUT-2, -3, and -4). Extensive SAR elaboration by syn-thesizing more than 1600 new derivatives of the leadstructure clearly revealed the essential moieties for highactivity, potency, and selectivity. He reported the preclini-cal profile of the very potent and highly selective GLUT-1 inhibitor BAY-876, showing 2nM inhibition againstGLUT-1 and more than 100-fold selectivity towardsGLUT-2, -3, and -4. In addition, a preliminary in vivostudy showed additive antitumor efficacy of BAY-876, incombination with radiation, underlining GLUT-1 inhibi-tion as new therapeutic concept.

Prof. Peter J. Stang of the University of Utah, SaltLake City, presented the last lecture, on Abiological self-assembly: predesigned metallacycles and metallacages viacoordination. He explained that the use of just two typesof building blocks, linear and angular, in conjunction withsymmetry considerations, allows the rational design ofa wide range of metallocyclic polygons and polyhedra viathe coordination motif. His group has used this approachto self-assemble a variety of 2-D supramolecular poly-gons, such as triangles, rectangles, squares, hexagons, etc.,as well as a number of 3-D supramolecular polyhedra:truncated tetrahedra, trigonal prisms, cuboctahedra, anddodecahedra. More recently, they have functionalizedthese rigid supramolecular scaffolds with different elec-troactive, host-guest, dendritic, and hydrophobic/hydro-philic moieties, and have investigated the properties ofthese multifunctionalized supramolecular species. Theyhave also begun to explore the self-assembly of 2-D poly-gons and 3-D polyhedra on a variety of surfaces, with theaim of developing their potential to be used in device set-tings. These novel, supramolecular ensembles were char-acterized by physical and spectral means. The designstrategy, formation, characterization, and potential usesof these novel metallocyclic assemblies were discussed,along with their recent results in crystal engineering.

An Evening in Savyon with Opera Singer JessyeNorman

Shortly after the closing ceremony, most of the speakersand chairpersons travelled together to the village ofSavyon near Tel Aviv for a special evening with the WolfPrize Laureate in Music, soprano Jessye Norman. TheWolf Foundation and the Arthur Rubinstein InternationalMusic Society jointly organized the event. Roni Feingoldof Savyon hosted the guests at her home, and Ms. IdithZvi, Artistic Director of the Rubinstein Competition,moderated the interview with Ms. Norman. The audience

watched this personal interview along with famous videorecordings from her key performances.

The 70-year-old American-born iconic opera singer ar-rived in Israel to accept the Wolf Prize for Music, whichshe was due to receive in 2015, together with Americanpianist Murray Perahia. Last year she was unable totravel due to a health problem.

Ms. Jessye Norman has become the first female musi-cian to receive the Wolf Prize in the Arts. She is one ofthe world�s leading singers, blessed with a unique voicethat excels in dramatic operas by Wagner, in works ofSchubert and Strauss, as well as light Italian and Frenchoperas, jazz music, etc. She grew up in Augusta, Georgia,and by the age of four, she was already singing gospelsongs at the local Baptist church. Following an impromp-tu audition at school at age 16, she was offered a fullmusic scholarship and earned a music degree from theHoward University in Washington, DC. She continuedher studies at the Peabody Institute in Baltimore and atthe University of Michigan, where she earned a master�sdegree, consolidating her command of music theory andvocal technique.

Over the past 50 years, Norman has constantly amazedaudiences around the world at Carnegie Hall, La Scala,Covent Garden, and the Berlin Opera, to mention buta few top venues. In 1996, Norman became the fourthclassical singer to receive the Grammy Award for Life-time Achievement, thus joining Enrico Caruso, MarianAnderson, and Leontyne Price. In 2010, she received theNational Medal of the Arts from President BarackObama. Although Norman no longer tours the world asa regular working opera singer, her acclaimed recordingsof works by the likes of Wagner, Richard Strauss, andMozart continue to delight many, along with her warmthand graciousness.

In 2003, she opened, in her hometown, Augusta, theJessye Norman School of the Arts, which runs free after-school programs, giving talented middle school studentsthe opportunity to study music, drama, dance, and art.Norman serves on the boards of Carnegie Hall and theNew York Public Library, as well as the Elton John AIDSFoundation, the Lupus Foundation, and the Partnershipfor the Homeless. She is also a proud lifetime member ofthe Girl Scouts of America. In her interview, she offeredher advice to the young generation: “You have to putyour heart and your soul into what you are doing, wheth-er you are playing the piano or singing or writing poetry,you are sharing that with the outside world.”

Jessye Norman interacted with a variety of audiencesin multiple events throughout her week in Israel, includ-ing a visit to the Israel Arts and Science Academy(IASA), high school for gifted students, in Jerusalem, thefestive reception in the residence of Rafi Mehoudar inTel Aviv (Figure 5), the evening in Savyon, interviewswith the Israeli TV, and on top of it all, the memorableWolf Prize ceremony in the Knesset and the following re-



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ception at the President�s House. It was a pleasant andexciting surprise for everybody at the President�s housewhen Jessye Norman performed the song He’s Got theWhole World in His Hands. For many of us who attendedthis enchanted performance, it seemed like she was aboutto fly out of her wheelchair.

The Wolf Prize Ceremony, June 2, 2016

Many consider the Wolf Prize, nicknamed “Israel�s NobelPrize”, a strong predictor of the Nobel, since a considera-ble number of Wolf Laureates have later received theNobel. Since 1978, five or six prizes have been awardedannually in the fields of agriculture, chemistry, mathemat-ics, medicine, and physics, whereas the arts prize rotatesannually among architecture, music, painting, and sculp-ture. The prize in each field consists of a certificate anda monetary award of $100,000. In the event of two orthree recipients sharing the prize, the honorarium is di-vided equally. International prize committees in eachfield, comprising renowned experts, select the Wolf Prizewinners. Prize committees are appointed every year, andtheir proceedings, minutes and recommendations are keptconfidential. To date, a total of 253 scientists and artistsfrom 23 countries have been honored. All laureates re-ceive their awards from the President of the State ofIsrael and Minister of Education.

Every year, the ceremony takes place in the ChagallState Hall of the Knesset Building (Israel�s Parliament),in Jerusalem. The hall was designed and decorated by theJewish artist Marc Chagall (1887–1985), who designed forthat hall 12 floor mosaics, one wall mosaic, and three Go-belin tapestries. The tapestries were ordered in 1965, andwere produced over a period of four years. The work ispresented in the form of a triptych, in which each of theparts is both part of the whole and a separate unit. They

represent a sort of concise and poetic expression to thefatefulness of the Jewish people.

President Reuven Rivlin presented the prizes to alleight laureates, assisted by Education Minister and WolfFoundation chairman Naftali Bennett and KnessetMember Yehiel Bar, Deputy Speaker of the Knesset:(Figure 6). A video of the entire ceremony is available onthe Wolf Foundation website: http://www.wolffund.org.il/index.php?dir= site&page=content&cs=3124&lang-page=heb.

Architect Phyllis Lambert, Canada, received the 2016Wolf Prize in Architecture “for being vigorously involvedin the realization of seminal innovative buildings, exem-plary urban regeneration projects and leading research in-stitutes.”

Prof. Trudy Frances Charlene Mackay of the Depart-ment of Biological Sciences, North Carolina State Univer-sity, NC, USA, received the 2016 Wolf Prize in Agricul-ture “for pioneering studies on the genetic architecture ofcomplex traits and the discovery of fundamental princi-ples of quantitative genetics with broad applications foragricultural improvements.”

Prof. Kyriacos C. Nicolaou of the Department ofChemistry, Rice University, Houston, Texas, USA, andProf. Stuart L. Schreiber of the Department of Chemistryand Chemical Biology, Harvard University, Cambridge,MA, USA, shared the 2016 Wolf Prize in Chemistry. Nic-olaou received the prize “for advancing the field of chem-ical synthesis to the extremes of molecular complexity,linking structure and function and expanding our domin-ion over the interface of chemistry, biology and medi-cine.” And Schreiber received the prize “for pioneeringchemical insights into the logic of signal transduction andgene regulation that led to important, new therapeutics,and for advancing chemical biology and medicine throughthe discovery of small-molecule probes.”

Figure 5. Left: The Wolf Prize Laureates at a festive reception in the residence of Rafi Mehoudar, Tel Aviv, May 30, 2016. From left: Prof.Lewis Cantley, Prof. Trudy Mackay, Prof. C. Ronald Kahn, Ms. Jessye Norman, Prof. Stuart L. Schreiber, Prof. K. C. Nicolaou, Prof. Yoseph Imry,Prof. Mina Teicher of the Wolf Council, Dr. Liat Ben David, CEO of the Wolf Foundation, Architect Phyllis Lambert, Mr. Rafi Mehoudar, andProf. Dan Shechtman, current Chairman of the Wolf Council. Right: Jessye Norman performs He’s Got the Whole World in His Hands at thePresident’s House in Jerusalem, June 2, 2016. Photographs by the Wolf Foundation and Ehud Keinan.



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Prof. Yoseph Imry of the Weizmann Institute of Sci-ence, Israel, received the 2016 Wolf Prize in Physics “forpioneering studies of the physics of mesoscopic andrandom systems.”

Prof. Lewis Cantley of the Weill Cornell Medical Col-lege, NY, USA, and Prof. C. Ronald Kahn of HarvardMedical School, USA, shared the 2016 Wolf Prize inMedicine. Cantley received the prize “for discovery ofphosphoinositide-3 kinases and their roles in physiologyand disease.” And Kahn received the prize “for pioneer-

ing studies defining insulin signaling and its alterations indisease.”

Jessey Norman, Soprano, received the 2015 Wolf Prizein Music “for her extraordinary performances worldwide,her educational activities and her devotion for health re-lated causes.”

In his address, President Reuven Rivlin welcomed therecipients for a special reception in their honor, held atthe President’s Residence. He congratulated the recipi-ents and said, “The Wolf Prize rewards professional and

Figure 6. Collage of photos from the Wolf Prize ceremony in the Knesset and the following reception at the President’s House. Jerusalem,June 2, 2016. Photographs by the Wolf Foundation and Ehud Keinan.



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academic achievements, however, it stands for muchmore. It celebrates humanity, it promotes solidarity, andit shows that cooperation in the fields of science can over-come barriers and borders, and bring people together.”

The President stressed, “We live in a world where poli-tics plays a major role. But we must be careful not to de-stroy science and art for the sake of politics. An academicboycott is not just bad for Israel, it is shameful for sci-ence. Cooperation, not boycott, is the way to go forward,to find new ways to build trust between Israelis and Pal-estinians.”

The President turned to the prize recipients and said,“You stand at the cutting edge of science, research, andcreativity. You dedicate your lives to discovery. You areworking to make this world a better place. On behalf ofthe citizens of Israel, I thank each and every one of you.”

The 80-year-old clarinet virtuoso Giora Feidman enter-tained the audience with an emotional performance ofklezmer music. Feidman�s background is as colorful as hismusic. He was born in Buenos Aires in 1936 to Jewish im-migrants from Bessarabia. Continuing his family traditionof music, at age 18, he became a clarinetist at the TeatroCol�n Symphony Orchestra. At age 21, he immigrated toIsrael and immediately became a member of the IsraelPhilharmonic Orchestra. Twenty years later, he began hissolo career, performing with the Berliner Symphoniker,the Kronos Quartet, the Polish Chamber Philarmonic, theMunich Chamber Philarmonic Orchestra, and the MunichRadio Orchestra. In addition, he found his way to theatri-cal works, musicals, operas, and films. Movie directorSteven Spielberg invited him to play the clarinet solos forthe soundtrack of Schindler’s List, which won sevenAcademy Awards. He also performed in The ComedianHarmonists and in Beyond Silence. In August 2005, hewas invited by Pope Benedict XVI to play before an audi-ence of more than 800,000 people at the vigil on WorldYouth Day in Cologne, Germany. “I don’t play the clari-net. I am a singer,” Giora Feidman once said. “I singthrough my instrument.” It is a timeless, very emotionalsong that doesn’t need any texts. Indeed, it was a movingmoment in the ceremony when Feidman invited the audi-ence to join him with the melody of Jerusalem of Gold,the song that became the informal hymn of the State ofIsrael since the 1967 war.

Prof. K. C. Nicolaou responded in the name of bothlaureates of the chemistry prize: “Mr. President, Distin-guished Guests, Stuart Schreiber and I would like to ex-press our deep gratitude and appreciation to the WolfFoundation and the selection committee for this highhonor and thank our students and mentors for their con-tributions and support that culminated in us standing infront of such a distinguished audience today.

Stuart would like to thank his wife Mimi and his familyfor their support and unconditional love; and I would liketo express my many thanks and gratitude to my wife,Georgette, and family for their unconditional love and

support and apologize to them for the times I was notthere when I should have.

I also personally like to acknowledge with pleasure thepresence in this special ceremony of the Ambassador ofCyprus and the Mayor of my town in Cyprus, Karavas,where I was born and raised – now unfortunately occu-pied. I am also happy to note the presence in the audi-ence of Mr. and Mrs. Takis and Louki Nemitsas who es-tablished, and currently preside over, the Nemitsas Foun-dation in Cyprus, whose mission is similar to that of theWolf Foundation.

This award is very special and touching to both StuartSchreiber and me, for it not only recognizes us, but it alsoreflects the collective contributions of our colleagues andfriends that resulted in the impressive advances in thefields of organic synthesis and chemical biology and theirenormous impact on chemistry, biology, and medicine inthe last few decades. These advances, and the myriadmolecules that resulted from them, enabled and facilitat-ed the discovery of new medicines for people and arepoised to exploit the latest discoveries in the life sciencesfor the benefit of science and society today and in thefuture.

Being honored in the Knesset in this magnificent cere-mony, and in front of this historic wall, I am sure I reflectthe sentiments of all the Wolf Laureates in expressing myadmiration and respect for the State of Israel and itspeople for their contributions to democracy, science, cul-ture, and civilization. On behalf of Professor Schreiberand myself, thank you all for honoring us today with yourpresence.”

Prof. Stuart L. Schreiber addressed the audience at thePresident�s House: “Mr. President Rivlin and distinguish-ed guests, I am delighted to offer a few words regardingscience and its influence on the quality and longevity oflife. I will restrict my comments to the area of science ofwhich I am most familiar – namely, the life sciences.

The fundamental pillar of life science is biomedical re-search, and biomedical research in the 20th and 21st centu-ries has led to an understanding of many of the basicprinciples of life, and in some cases, has enabled scientiststo mitigate suffering and death from infection and dis-ease.

In the 21st century we�ve seen the emergence of humanbiology – the ability to read and write DNA, to correlatevariation in DNA sequence with disease, and the abilityto reprogram human cells; for example, to take a skinsample from an individual and in the laboratory convertit into stem-like cells, and from there to neurons of thebrain or endocrine cells of the pancreas. This has enabledthe study of the biology of humans directly, rather thanrelying largely on inferences from simpler, model organ-isms – for example, flies and worms; fish and mice.

Correlating genetic variation with disease has led tothe discovery of variants of genes that confer risk andprotection to disease. Biochemical studies of the variant



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proteins are providing a blueprint for the activities thatdrugs should confer on their targets to be safe and effec-tive. These experiments of nature are all in the context ofhuman physiology so that, for the first time, we can knowthe consequence of turning on or off a gene, even beforea risky drug discovery effort is launched.

Nevertheless, there remains a gap between understand-ing disease and treating disease effectively. The blueprintsthat have emerged thus far are challenging and in generalunfamiliar to the historical process of drug discovery.

We will need to innovate the science that underliestherapeutics discovery. Chemistry, biology, physics, math,computer science, and engineering have a great challenge,a challenge of a lifetime, but I believe the field is up tothe challenge.

I�m especially confident because our young generationof scientists is fearless and hungry to change the world,and nowhere is that more evident than in the State ofIsrael. Israel is a world leader in terms of the value itplaces on education, and the unique combination of intel-lectual curiosity and creativity it so naturally fosters in itschildren.

This year�s Wolf Prizes in the Arts and Sciences haveshined a bright light on the need to close the gap betweenunderstanding and treating disease, and for that, myfellow laureates and I are extremely grateful. It�s alreadyhaving an impact, and when we combine this with thefearlessness of the young generation, the future of sciencecontributing to long and healthy lives is promisingindeed.”

It seems appropriate to end this report with a personalanecdote. In the relaxing time after the ceremony, StuartSchreiber shared with me some of his experience andemotions and what seemed to him an embarrassingmoment: “While standing on the stage, tears started roll-ing down my cheeks, and I was not sure whether or notwould it be appropriate to pull out my handkerchief inthe middle of the ceremony.” I responded: “Stuart, youwere not an exception. As far as I could see, everybodyin the audience, including myself, was in tears.”



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CONFERENCE REPORT

E. Keinan*

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Conference Report: ChemicalSynthesis and Drug Discovery: ICSSymposium Honoring Wolf PrizeLaureates K. C. Nicolaou and StuartL. Schreiber, June 1, 2016, Technion– Israel Institute of Technology,Haifa, Israel



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DOI: 10.1002/ijch.201600132 Conference Report: Chemical ...techmail.technion.ac.il/174b977c982518db8fb2037a... · future issues in the series of Rosarium Philosophorum will be dedicated