The International Chemical Biology Society's Global Mission

Jan 17, 2014 - Konnichiwa! Biology probed with chemical tools was the talk of the town from October 7–9, 2013, as researchers from across the world ...
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In Focus pubs.acs.org/acschemicalbiology

The International Chemical Biology Society’s Global Mission Crystallizes in Kyoto Brandon Findlay† and Margaret A. Johns*,‡ †

University of Alberta, Edmonton, AB T6G 2R3, Canada Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, United States

‡

K

onnichiwa! Biology probed with chemical tools was the talk of the town from October 7−9, 2013, as researchers from across the world gathered in beautiful Kyoto, Japan for the second annual meeting of the International Chemical Biology Society, ICBS2013. Set among Kyoto’s ancient sites, such as the Imperial Palace and the Kinkaku-ji golden pavilion, the Shirankaikan conference hall (Kyoto University) is steeped in history, though research presented by local colleagues revealed a determined focus on the future. ICBS2013 was the first annual meeting of the International Chemical Biology Society (ICBS) outside of North America. It was cohosted by the Japanese Society for Chemical Biology (JSCB) and was organized by Chair Masatoshi Hagiwara (Kyoto University, Japan), co-Chair Lixin Zhang (Chinese Academy of Science, China), and a conference organizing committee.5 Researchers came from nearly 20 countries and every sector to discuss their work, from which the global nature of the chemical biology field became readily apparent. The research of young investigators was highlighted throughout the conference with many invited presentations, a session dedicated to 1 minute flash poster presentations, and a “Global Rising Stars” program finale. A free preconference educational workshop,6 sponsored by JSCB, provided a solid foundation for the meeting and underscored the educational mission of the ICBS. The fledgling society is beginning to serve as a point of contact for chemical biologists, with representatives from the Japanese, Chinese, Indian, and European regional societies in attendance to meet, collaborate, and discuss trends in research the world over. Keynote speaker Shuh Narumiya, a pioneer in academic−industrial alliances and Imperial Prize recipient, perhaps captured the value of collaborative forums like ICBS2013. In his talk, Narumiya noted the cyclical nature of scientific discoveries, which he called the “reproductive cycle of science”. In this cycle, basic science discoveries become seeds for industry and feed into a continuous cycle of industrial production (such as new therapeutics) and then new academic innovations and biological insights (Figure 1). This cycle involves both pharmacologic insights, how chemicals affect bodily function, and chemical biologic insights, how chemicals affect biological processes. With a mission to bring together cross-disciplinary scientists from all sectors, the annual ICBS meetings promise to serve as a central axis for this cycle, as a forum for distributing “seeds” of ideas and trends among all participants. Some of the trends evident at ICBS2013 included challenging targets, chemical matters, cellular complexity, and neglected diseases. © 2014 American Chemical Society

Figure 1. The reproductive cycle of pharmacology, described by keynote speaker Shuh Narumiya, is facilitated by events such as ICBS2013, which serves as a forum to distribute “seeds” of ideas among participants from around the world and all different sectors.

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CHALLENGING TARGETS The unveiling of the Human Genome Sequence has opened large new target spaces for development of chemical probes and has driven a significant trend in target-based research and “gene-to-medicine” drug discovery. However, many of these new targets are considered difficult and “undruggable” based on factors such as featureless binding sites, highly conserved active sites (hindering selectivity), conformationally transient binding sites, and poor lead bioavailability. As highlighted by keynote speaker James Wells (UCSF, USA), challenging targets “provide tremendous opportunities for drug discovery but require novel approaches and state-of-the-art chemistry, biophysics, and cell biology.” Several ICBS2013 presentations were focused on challenging targets, including protein−protein interactions and phosphatases. Other target-based projects for chemical probe and therapeutic discovery were presented throughout conference sessions. In the first keynote lecture, James Wells demonstrated the potential for HTS against what have been traditionally thought of as difficult to access targets: protein−protein interactions (PPIs). In a series of scientific vignettes, Wells described work in his lab on three such targets, IL-2, PDK-1, and caspase-3. To interrogate the difficult protein−protein interaction interface, Wells’ group has developed a site-directed fragment-based discovery approach, known as tethering, which results in stable linkage of disulfide-containing small molecules to engineered cysteine residues at putative interaction surfaces. Using this technique with IL-2 and its interaction with the IL-2 alpha Published: January 17, 2014 21

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Figure 2. The yin and yang of the chemical biology toolbox. The interdisciplinary nature of chemical biology weaves together the strengths and weaknesses of chemical tools and biological techniques. In chemical space, scaffold diversity must be balanced with possibility of reactive chemical promiscuity in the design of tools. In biological space, target promiscuity (polypharmacology) must be balanced with desire for specificity of action in the design of assays. The choice of chemical tools and biological assays are intimately connected, and decisions must ultimately be based on the final goals of a project, such as chemical probe development or therapeutics. Adapted with permission from.1−4

receptor, they identified both rigid and flexible subsites in the IL-2 binding groove that bound to small molecules. Their finding that many more compounds bound the adaptive site than the rigid site underscored the limitations of using standard “static” computational methods for structure−activity prediction.7 Wells also described use of the tethering technique to search for allosteric modulators of PDK1. Based on a model of a homologous binding interaction between PIFtide (a PDK1 interacting peptide) and its kinase, PDK1, the Wells’ group used their tethering technique to discover “hit” fragments that regulate PDK1 activity. Positive hits were discovered that could turn PDK1 “on” (6-fold activation) or “off” (70% inhibition), even though the fragments bound to the same site.8 Another HTS by the Wells group turned up a compound with a rather unusualand serendipitousmode of action. Compound 1541 was identified in a small molecule screen of potential procaspase-3 activators, with early results suggesting selective activation via binding to an allosteric site in procaspase-3. Further characterization confirmed the selectivity but revealed that under the assay conditions 1541 was not a monomer; instead, it rapidly formed thin tendrils up to 1 μm long. These fibrils appeared to co-localize procaspase-3 with trace amounts of activated caspase-3 that was spontaneously formed under the assay conditions, greatly enhancing activation.9 Wells ended with the following thoughts: “PPI targets are challenging but do-able, allosteric sites are new target opportunities, and be prepared for unexpected opportunities when attacking these challenging targets.” Zhong-Yin Zhang’s (Indiana University School of Medicine, USA) presentation focused on a different challenging target space: protein tyrosine phosphatases (PTPs). While more than two dozen kinase inhibitors have made it to the clinic, the directly opposing PTPs, linked to numerous human diseases, have not yet been therapeutically exploited. Zhang noted the active sites of PTPs are highly conserved and positively charged, and traditionally strong inhibitors of PTPs show large cross-reactivity and poor bioavailability, limiting their utility. To address these issues, his group utilized a fragment-based

approach to target both the PTP active site and nearby unique peripheral binding pockets, creating PTP inhibitors with both high potency and selectivity. Identification of these specific inhibitors not only opens new windows into the biology regulated by each of these PTPs but also offers potential leads for novel therapeutics. Of particular note was a highly selective and efficacious inhibitor of PTP-MEG2.10 Zhang’s lab demonstrated that inhibition of PTP-MEG2 augments insulin signaling and promotes insulin sensitivity and glucose homeostasis in diet-induced obese mice. He also described a new bicyclic salicylic acid-based inhibitor of the oncogenic phosphatase, SHP2, with anti-cancer properties.11,12 Inhibition of SHP2 impaired AKT and ERK signaling in a leukemia model, resulting in decreased tumor growth and increased survival of treated mice. ICBS2013 featured many additional presentations on targetbased chemical biology projects, including kinases, the Bcl-2 family, and others. In the first session of the conference, Shudong Wang (University of South Australia, Australia) discussed her research on targeting protein kinases in cancer. She noted that use of molecularly targeted therapies has resulted in therapeutic responses in the clinic, but the responses are almost always followed by relapse due to activation of alternate pathways in tumors. She presented data on identification of drug candidates that synergistically target key pathways in cancer, including the CDK and Aurora kinase families.13,14 The high interest in the potential of kinase DYRK1 as a therapeutic target for Alzheimer’s Disease, stem cell fate, and cancer was evident from the number of research presentations focused on this target. Laurent Meijer (ManRos Therapeutics, France) presented an HTS screening strategy for DYRK1A inhibitors that has led to identification of leucettines, a class of marine natural product-based lead compounds with promising activity in cognitive impairment models;15 Isao Kii (Kyoto University, Japan) presented work on a novel inhibitor that targets the folding intermediate of DYRK1A; graduate student Stephanie Bellmaine (University of Melbourne, Australia) used ID-8 as a chemical probe to study the role of 22

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synthesis (DOS), significantly impacting drug development and chemical biology. He presented a number of research projects catalyzed by C−H functionalization, including research focused on discovery of human cytochrome P450 aromatase inhibitors (AIs). AIs are currently used in the clinic as frontline therapy for postmenopausal women with estrogen receptor positive breast cancer. Davies’ group has utilized new insights into the molecular mechanisms of AI action and recent publication of the aromatase crystal structure to guide development of novel aromatase inhibitors that are highly potent and inhibit breast cancer line viability in vitro.20 Natural products form a core element of chemical biology research in Japan; thus, it was only fitting that the conference featured a session on global natural product resources for diverse chemical libraries. Resources from Australia, Japan, China, and the USA were highlighted, as was the important role natural products have played in development of top-selling drugs. Ron Quinn (Griffith University, Australia) shared recent advances at Nature Bank, a complete collection of all known Queensland plants, plus marine invertebrates from the Great Barrier Reef, and samples from Tasmania, China, and Papua New Guinea. This resource consists of >200,000 semipurified samples plus additional extracts and pure compounds and is available for discovery partnerships. Quinn described ongoing work utilizing this diverse chemical resource for anti-malarial research.1 Hiroyuki Osada (RIKEN, Japan) presented the Natural Product Depository (NPDepo).21 Systematic isolation of minor components in their fractions has led to the discovery of new natural products and scaffolds, while also offering a means of quickly determining the active component in a HTS hit. Lixin Zhang (Chinese Academy of Sciences, China) discussed the current status of chemical biology research in China. Effort underway calls for development of an integrated platform covering the “Reading”, “Writing”, and “Arithmetic” of natural product research to maximize discovery capabilities. Zhang provided an example of his work for anti-tuberculosis discovery focused on the transcriptional-based mechanism of action of chrysomycins leading to dysregulation of Mycobacterium tuberculosis genes and taking advantage of abyssomicins’ thioether Michael addition for potential antitubercular prodrugs.22 Hakim Djaballah (Memorial Sloan-Kettering Cancer Center, USA) provided an overview of natural product research at MSKCC in the USA, including research vignettes on identification of compounds that are radiation protectants23 and use of natural product libraries for discovery of novel agents that synergize with resveratrol for treatment of retinoblastoma.24 He noted that the pharmaceutical industry has nearly abandoned natural product research due to cost of synthesis and challenges with assignment of intellectual property. Compound promiscuity, which forms the molecular basis for polypharmacology, is a core concept in chemical biology studies. It is well-known that many active compounds exert their effect by acting on multiple targets, dependent on concentration or dose. Thus, a debateable question in drug discovery is where along the spectrum of “specificity” versus “promiscuity” the most efficacious compounds will lie (Figure 2). In a discussion-provoking talk, Jürgen Bajorath (University of Bonn, Germany) presented a computational investigation of promiscuity using currently available compound activity data.25,26 He found that, on average, a bioactive compound interacts with close to 3 targets, whereas a drug interacts with close to 7 targets. A subset of highly promiscuous drugs is

DYRK1A in stem cell renewal; and well-known DYRK1A authority, Pamela Lochhead (Babraham Institute, U.K.), used chemical probe AZ191 to characterize the role of DYRK1B in the cell cycle for cancer.16 Other target-based presentations included Zaneta Nikolovska-Coleska (University of Michigan, USA) and Guillaume Lessene (Walter & Eliza Hall Institute of Medical Research, Australia), who are both targeting Bcl-2 family members. Nikolovska-Coleska described new validation data for Mcl-1 as a target for pancreatic cancer based on research with promising new chemical probes with improved Mcl-1 binding and selectivity properties. Lessene described a large-scale HTS for Bcl-XL inhibitors and detailed the structure activity for promising new potent and selective compounds.17 Jiang Wu’s (Lanzhou University, China) lab began with anacardic acid, linking it and other molecules to coenzyme A with the goal of creating inhibitors of Tip60. Yukihiro Itoh’s lab (Kyoto Prefectural University of Medicine, Japan) began with an irreversible but poorly selective inhibitor of lysine-specific demethylase 1 (LSD1), PCPA, coupling it first to natural LSD1 substrates and then to a variety of analogues to improve activity and prevent off-target binding. Tapas Kundu (Jawaharial Nehru Centre, India) discussed targeting TTK21, a specific activator of histone acetyltransferase CBP/p300. TTK21 is a promising target for Alzheimer’s but requires small molecule activators to cross the blood brain barrier. His group addressed this challenge by utilizing TTK21 conjugated glucose nanospheres. They demonstrated that these conjugated nanospheres distribute throughout the brains of adult mice following intraperitoneal injection, with no observed toxicity. Treated mice did not have improved retention of recent memories but instead showed increased neurogenesis and sustained long-term memory storage.18

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CHEMICAL MATTERS The interdisciplinary nature of chemical biology weaves together the strengths and weaknesses of chemical tools and biological techniques in a complex interplay (Figure 2). In chemical space, Jonathan Baell discussed the dangers of reactive compounds (PAINS) during the educational workshop and noted the many published “false starts” resulting from current high-throughput screening efforts. His talk highlighted an open debate in the chemical biology community about the usefulness and definition of “problematic” compounds and the correct balance between library diversity and promiscuity. Such discussions flourished throughout the conference and underscored the importance of chemical matters. Innovative and streamlined chemical synthesis technologies can play a transformative role in chemical biology research by providing compounds that are otherwise difficult or impossible to prepare. During the “Cutting Edge Medicinal Chemistry and Tool Compounds” session, Huw Davies (Emory University, USA) presented the development of a “paradigm shifting” synthetic strategy, the ability to derive molecules by altering reactive sites at C−H centers, known as “C−H Functionalization”.19 Davies’ group is a member of the NSF Center for Selective C−H Functionalization, the goal of which is to establish a “toolbox of catalysts and reagents” to allow “generally programmable and controllable methods” for functionalization of complex systems, efficiently building compounds that would traditionally require a prohibitive number of synthetic steps to access. This fundamental development in chemistry allows novel diversity-oriented 23

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The advancement of phenotypic screening to the highthroughput screening arena has brought new challenges and complexities to light. One critical technical challenge highlighted by Djaballah is the slow time for image acquisition. In addition, developing physiologically relevant predictive assays for use in microwell plates adds new layers of complexity, as covered during a lecture given by Terry Riss (Promega, USA) during the pre-meeting workshop on cell-based assay development. Riss noted “the importance of cells in cell-based assays.” Cells are never static, and over time they will form subpopulations, reacting to the steady consumption of nutrients and production of waste products. Reproducibility is a significant concern, reflected in the need for extensive standard operating procedures and the increasing trend for journals to require evidence of cell line authentication prior to publication. Riss reviewed the many assays now available for measuring cell cytotoxicity, including newer peroxide sensor and stress response reporter technologies. He predicted the future “path forward” for cell-based assays includes increased emphasis on 3D culture models, real time measurements, and multiplexed assays. Horst Flotow (Experimental Therapeutics Centre, Singapore) discussed the complexities and showed the possibilities of whole organism phenotypic screens using a Caenorhabditis elegans model to identify antimicrobial agents for Burholderia pseudomallei, the causative agent of melioidosis. Biochemical fluorescent tracers, which stained all worms red and dead worms green, were used to track C. elegans survival following infection. However, as noted by Djaballah, it was the image acquisition and processing step that was perhaps the most challenging. For example, automation of image processing required novel algorithm development to address issues such as overlap of worms and nonuniform staining. His talk also highlighted a challenge common to all high-throughput phenotypic screens, the balance between time for image acquisition (and thus, image resolution) and the need for throughput. Arguing that the shortcomings of target-based approaches for drug discovery, such as the nonpredictive nature of target choice and therapeutic strategies, are responsible for the current failure rates in drug development, Ulf Nehrbass (Institute Pasteur Franco-German Advanced Translational Center, France) gave a high level talk highlighting a large-scale phenotypic screening approach for therapeutic agents underway at Institute Pasteur, which he termed “phenomics”. Starting from a reverse translational approach with a clinically relevant starting point and a target-free phenotypic assay system, this image-based discovery method allows identification of both efficacious compounds and, subsequently, the underlying target that most effectively impacts on the clinically relevant readout. Overall, he argued this approach is faster, generates innovative therapies, and has a higher chance of success. Using this approach he discussed discovery of the potent clinical antituberculosis candidate Q203,30,31 which targets the cytochrome bc1 complex. He also cited a phenotypic senescence-based project for anti-cancer agents that led to a new therapeutic target previously thought undruggable.

partly responsible for this increase. The probability of promiscuity for a particular compound varied only slightly between chemical databases but increased along the drug discovery path, though not much across different target families or for compounds with different molecular weights. Promiscuity cliffs were introduced: highly similar compounds pairs with a large difference in the number of binding partners. For example, under chemical microarray conditions, compounds with azocane rings in particular were found to be highly promiscuous, and replacement of this moiety significantly decreased the number of binding partners. While Bajorath noted that data sparseness generally leads to conservative promiscuity estimates, the power of computational chemical biology for such studies was evident. An expanding area and research strength for Japanese chemical biologists is chemical imaging. The old adage “a picture is worth a thousand words” holds true in biology, and synthetic chemistry applied to dyes and photoactive proteins provides new images of biological processes leading to novel insights into complex systems, as well as clinical tools. The “Chemical Imaging” session opened with a presentation by Yasuteru Urano (University of Tokyo, Japan). His presentation highlighted two exciting imaging projects: generation of novel cancer-specific fluorescent probes and chemical methods for super high resolution imaging. The cancer-specific fluorescent probe project focused on rational design of fluorescent probes by intramolecular spirocylization.27 Using hydroxymethyl rhodamine green (HMRG) as a novel scaffold, his group designed and synthesized fluorescent probes with spirocyclic structures that have extremely low background fluorescence until converted into highly fluorescent HMRG by target enzymes in cells. One use for this type of probe is intraoperative endoscopic detection of tiny tumor sites.4 Urano also presented ongoing and promising work focused on development of super high resolution images with intermittent, fluorescent dyes. In other chemical imaging work, Yuko Kamikawa and co-workers have been working to optimize interactions between a photoactive yellow protein (PYP) fused protein and a self-quenched cinnamic acid conjugate. Binding of PYP and the small molecule cleaves the quenching domain, resulting in a strong fluorophore that does not require washing because it has very little off-target activation. Christopher MacNevin described the development of a biosensor specific for the active state of calmodulin. Tracking fluorescence of the sensor allowed monitoring of calmodulin activity and localization in real time, both in cellular models and in whole animals. Seung Bum Park also presented development of the novel Seoul-Fluor platform for rational design of colorful ratiometric fluorescent pH sensors28 using 9aryl-1,2-dihydropyrrolo[3,4-b]indolizin-3-one as a scaffold.29

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CELLULAR COMPLEXITY Cell-based and phenotypic screening has its advantages, as highlighted by Djaballah during the educational workshop lecture “High Content Screening Technologies and Case Studies”. Hakim Djaballah noted that cell-based screening is one of the best ways to discover new, first-in-class drugs. Molecular knowledge of cellular pathways or targets is not a prerequisite for cell-based studies, and such screening often reveals new molecular targets. Additionally, good cell permeability is a prerequisite for hit activity, removing one of the major hurdles in lead optimization, and the presence of compensatory pathways is likewise built into the test system.

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NEGLECTED DISEASES Neglected diseases are a group of tropical infections that are especially endemic in the nearby developing regions of Asia, as well as Africa and the Americas, and which together cause more than one million deaths annually. Thus, chemical biologists 24

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working on neglected disease organisms can have a critical impact on global health. Tanya Parish (Infectious Disease Research Institute, USA) related work she and her colleagues have done to develop a novel azole series active against Mycobacterium tuberculosis. Current tuberculosis (TB) treatment requires long-term, large daily treatment doses, and with an increasing occurrence of resistance there is an urgent need for new therapeutics. A series of azoles were originally identified from a 2000 compound screen as having both TB growth inhibitory and cidal activity. Parish’s group performed SAR with the aminothiazoles and found that high frequency resistance was linked to targets in the Type VII secretion system. Similarly, imidazole was linked to mycobacterial membrane proteins (MmpL/MmpS). Overall, a major challenge with the azole series appears to be efflux, possibly meditated through these MmpL systems MmpL3/MmpL5, although they had major effects on cells via carbon metabolism and cell wall perturbations.32 Threading the medicinal chemistry needle, Lars Hammarström (Chemical Biology Consortium Sweden, Karolinska Institutet, Sweden) described work focused on Human African Trypanosomiasis (HAT), a vector-borne parasitic disease caused by the flagellate protozoan parasite Typanosoma brucei and endemic to sub-Saharan Africa. Cordycepin was identified in a phenotypic viability screen of >2000 nucleoside analogues on T. brucei and acts as an adenosine mimic. T. brucei, which lacks the ability to biosynthesize this nucleoside itself, actively scavenges cordycepin from host plasma via high affinity transporters and incorporates the drug into growing RNA chains.33,34 Cordycepin is, however, rapidly degraded by adenosine deaminase (ADA) in host plasma, limiting its bioavailability in vivo. Hammarström and co-workers performed “delicate” SAR studies based on structural information of the cordycepin−ADA interaction and discovered 2-fluorocordycepin, which is a substrate for the T. brucei transporter but not for the ADA enzymes. However, despite resistance to ADAmediated degradation, 2-fluorocordycepin does not exhibit significantly extended oral or IP exposure.35 Other presenters in this session included Babak Javid (Tsinghua University, China), who also presented work on Mycobacterium tuberculosis, focusing on a finding that mycobacterial mistranslation is both necessary and sufficient for rifampicin drug resistance. Frequent mistranslation creates a heterogeneous collection of proteins throughout the cell, at least some of which result in increased resistance to antituberculosis drugs. Screening for compounds able to “help” the bacteria, Javid and colleagues developed a novel in vivo gain-offunction reporter assay using a mutated highly potent nanoluciferase screen to test for improved translation fidelity. Preliminary screening efforts have revealed several promising compounds, including kg1, which improves translation fidelity and modulates Rif phenotypic resistance. Parasuraman Jaisankar (CSIR-Indian Institute of Chemical Biology, India) was the final presenter in this session, describing work focused on the parasitic protozoa responsible for leishmania, Leishmania donovani. Jaisankar described the effects of 3,3′-diindolylmethane (DIM), the metabolic product of natural product indole-3-carbinol, on the leishmania DNA topoisomerase I and its generation of random mutations in the topoisomerase subunits.36

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RISING CHEMICAL BIOLOGISTS

The youth of today are going to be the leaders of tomorrow, a fact clearly embraced by ICBS with its many programmatic offerings for young chemical biologists. Offerings included the pre-meeting educational workshop given by well-known investigators in the field,6 a novel poster “flash” presentation session, young investigator presentations throughout the sessions, and a rising stars award and conference session that highlighted up and coming chemical biologists from around the world. A lively panel discussion, “Industry/Academic/Government Interaction in Drug Discovery”, chaired by Paul Bauer (Novartis, USA), gave rising chemical biologists the opportunity to hear the viewpoints of established scientists from different sectors and highlighted some of the similarities and differences in the roles and goals for academic and pharmaceutical research. Numerous topics were covered including the need for better target identification and validation research, the difference in viewpoints regarding “good” lead compounds, how to initiate academic/industrial partnerships, and the requirement for these partnerships to be based on reproducible and high quality data. The poster session was the largest yet at an ICBS meeting, with 70 presenters and a wide range of topics. A new program addition was the poster “flash” session allowing all poster submitters the opportunity to give a 1 minute, 1 slide overview of their research project. While the long line of presenters geared up to give a talk was daunting, the presentations ended up being one of the highlights of the meeting, providing the audience with a poster preview and providing young investigators with the experience of an oral platform presentation. The poster session wrapped up with awards, all three going to Japanese scientists and turning the spotlight on the quality of chemical biology research around the globe. Local student Mayumi Yoshida (Kyoto University, Japan) received the $500 first place poster award for her work on IKBKAP splicing modulators, while Yosuke Ota (Kyoto Prefectural University of Medicine, Japan) and Firman Jiang (University of Tokyo, Japan) received second and third place, respectively, for posters on HDAC3 inhibitors and light-activated nitric oxide carriers. Recognizing the key role young researchers play in the growth of the chemical biology field, young scientists were invited to present their research in nearly all of the scientific sessions. As examples, Wen Piao’s (University of Tokyo, Japan) work on devising fluorescent probes for subcellular regions of hypoxia was well-received, and Shimpei Iwaki (University of Tokyo, Japan) and Xin Ku (Technische Universität München, Germany) gave interesting talks on gadolinium-based MRI contrast agents and FGFR inhibitor profiling, respectively. In the natural products session, Kozo Yoneda (Kyoto University, Japan) dissected the molecular mechanisms behind the subnanomolar cytotoxicity of aplyronine A that occurs well below the micromolar actin depolarization activity, while Maho Morita (Keio University, Japan) detailed both the mode of action of the biselynbyasides class of marine natural products and the effect of the same on one of her colleagues after an accidental exposure. In the final scientific session of the conference, early career independent researchers Bradley Pentelute (Massachusetts Institute of Technology, USA), Christian Ottmann (Eindhoven University of Technology, Netherlands), and Xiaoguang Lei (National Institute of Biological Sciences, China) were selected 25

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as “Global Rising Stars of Chemical Biology.” Each gave a brief presentation on their recent work, collectively touching on topics discussed throughout the meeting. Bradley Pentelute presented the development of an innovative technique for transporting proteins and other macromolecules into cells in vitro, hijacking anthrax toxin’s ability to form a stable pore in the endosome following endocytosis. The anthrax toxin machinery unwinds proteins and pumps them into the cytoplasm, allowing them to refold on the other side. Translocation did not appear to be sequence specific, and a number of non-protein cargos were also able to enter the cell with this system. Meanwhile, Christian Ottmann discussed a new area in protein−protein interaction studies, small molecule stabilization of interactions rather than inhibition. He noted that such examples exist in nature, including rapamycin, forskolin, and brefeldin A. He discussed research projects in his lab focused on interaction stabilizers. One project involved Fusicoccin A, produced by the fungus Fusicoccum amygadaly, which is known to stabilize interactions between H+-ATPase and the highly conserved 14-3-3 adaptor proteins in plants, as well as exhibiting cytotoxic activity in human cancer cell lines. Building off these observed interactions, Ottmann and colleagues created an analogue, FC-THF, that selectively stabilizes interactions between 14-3-3 and the K+ channel protein TASK-3, increasing TASK-3 expression and thereby increasing passage of K+ across the cell membrane.37 Fusicoccin A and related compounds were found to affect interactions between 14-3-3 and both kinase C-Raf and the estrogen receptor, and it seems likely that analogues with selectivity against these targets are waiting to be discovered.38 Seeking novel chemical probes to dissect and modulate cell death pathways, Xiaoguang Lei and colleagues developed a robust high-throughput screening assay that they used to screen a 200,000 compound library to identify inhibitors of necrosis. Following SAR studies with positive hits, Lei and colleagues discovered necrosulfamide (NSA) as a potent inhibitor of necrosis. Mechanism of action studies with this compound revealed MLKL as the cellular target of NSA, and ultimately use of these novel probes allowed Lei and group to generate a model of functional necrosome formation.3

In Focus

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

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REFERENCES

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CONCLUSION Moving into its third year of existence, the International Chemical Biology Society is growing worldwide and bringing together chemical biology researchers from across the globe. During the meeting, the ICBS Board of Directors presented the ICBS Distinguished Service Award to John Watson (Promega, USA) in recognition of his critical contributions to this growth of the society. In addition, Haian Fu (Emory University, USA) passed the position of ICBS President to newly elected Masatoshi Hagiwara, who is also the current President of the JSCB, solidifying the global mission of the ICBS. It was announced that the next annual conference, ICBS2014, is scheduled for November 17−19 in San Francisco, CA (USA) with James Wells as the conference Chair. A plan is in place for this annual meeting to alternate locations between the USA and other global sites, with ICBS2015 to be located in Berlin, Germany. The theme of ICBS2014, “Driving Biology with Chemistry”, perhaps also captures the horizon ahead as the enthusiastic participants of ICBS2013 promise to drive ICBS and its impact on chemical biology research into the future. 26

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ACS Chemical Biology

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