Solute Carrier Proteins: Unlocking the Gene-Family for Effective Therapies

Solute Carrier Proteins: Unlocking the Gene-Family for Effective Therapies

Tuesday, April 26, 2016

The New York Academy of Sciences

Metabolic homeostasis within living cells requires strict control over the import and export of ions, metabolites and nutrients across membranes. These polar chemical species require highly regulated transport proteins to control their movement. The solute carrier (SLC) family is the largest class of membrane transporters, playing a vital role across all tissues. Genetic databases show that >50% of SLC SNPs are associated with diverse human phenotype ranging from diabetes (SLC30A8 and SLC16A11) to autism (SLC9A9), compared to a rate of ~20% for the broader human genome. Dysregulation of SLCs also appears to be a common feature in many tumors, thus SLCs appear to be a highly disease relevant target class.

Importantly, while the family is also generally small molecule druggable, only ~2% of known SLCs are current drug targets, suggesting it may be an untapped resource. Remarkably, while intracellular metabolism has been the subject of decades of detailed investigation, until recently, membrane transporters have received relatively little attention. Technical barriers appear to have hindered their study; SLCs are complex, multi-spanning integral membrane proteins (IMPs) making them difficult to produce, characterize and research. Generating cell lines with functionally competent SLC proteins can also be challenging and accurately defining endogenous substrate preferences for SLCs has been another hurdle. Recent breakthroughs in IMP structural biology, cellular engineering and metabolomics hold the promise of "unlocking" this gene-family. This symposium aims to catalyze this process by bringing together world leaders in the field at the New York Academy of Sciences.

* Reception to follow.

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Nonmember (Academia)$65
Nonmember (Corporate)$85
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Agenda

* Presentation times are subject to change.


Tuesday, April 26, 2016

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Opening Remarks
Sonya Dougal, PhD, The New York Academy of Sciences

9:15 AM

Introduction
David Hepworth, DPhil, Pfizer Inc

Session I

9:30 AM

Fundamentals of Solute Carrier Proteins and New Perspectives for Drug Discovery
Matthias A. Hediger, PhD, University of Bern

10:05 AM

Genetic Variants in Membrane Transporters: Implications for Human Disease and Drug Response
Kathleen M. Giacomini, PhD, University of California, San Francisco

10:40 AM

Networking Coffee Break

11:10 AM

Sodium-Coupled Citrate Transporter (NaCT or SLC13A5) Inhibitors for the Treatment of Metabolic Diseases
Kim Huard, Pfizer

11:45 AM

Applications of the XRpro X-Ray Fluorescence Platform for the Development of Solute Transporter Assays
Aaron Gerlach, PhD, Icagen Inc.

12:00 PM

Structural Characterization of Substrate Transport Selectivity of the SLC13 Family of Na+/Dicarboxylate Cotransporters
Claire Colas, PhD, Icahn School of Medicine at Mount Sinai

12:15 PM

Networking Lunch and Poster Session

Session II

1:45 PM

Mechanism of Substrate Binding and Translocation in Sodium-dependent Bile Acid Transporters
Ming Zhou, PhD, Baylor College of Medicine

2:20 PM

Structure-based Ligand Discovery for Nutrient Transporters
Avner Schlessinger, PhD, Icahn School of Medicine at Mount Sinai

2:55 PM

Networking Coffee Break

3:30 PM

Development of Therapeutic ZnT8 Inhibitors
Dax Fu, PhD, John Hopkins School of Medicine

4:05 PM

Solute Carriers, Metabolism and Drug Response: a Magic Triangle
Giulio Superti-Furga, PhD, Austrian Academy of Sciences

4:40 PM

Poster Prize Awards and Closing Remarks
Claire M. Steppan, PhD, Pfizer Worldwide R&D

4:55 PM

Networking Reception

6:00 PM

Adjourn

Organizers

Mercedes Beyna, MS

Biogen

Mercedes Beyna, a researcher at Biogen, focuses on Drug Development mainly in the area of neurodegeneration. Captivated by neuroscience, she has worked in the field for over a decade, in both academic and industrial laboratory settings. Mercedes earned her undergraduate degree in Biology at Binghamton University and Master's Degree in Biology from New York University. As an active member of the Biochemical Pharmacology Discussion Group since 2010, she enjoys developing interesting and educational symposia.

David Hepworth, DPhil

Pfizer Inc.

Dr. David Hepworth is Senior Director in Pfizer's Worldwide Medicinal Chemistry organization based in Cambridge MA. He completed undergraduate and graduate degrees at the University of Oxford then 2 years post-doctoral research at The Scripps Research Institute, La Jolla before joining Pfizer in 1999. Currently David supports the Inflammation and Immunology Research Unit, but has previously worked in a number of therapeutic areas across several Pfizer sites in the US and UK. David has built up a strong interest in SLCs having worked on several projects through his career that have targeted members of this protein class for reasons of pharmacology or pharmacokinetics.

Devyn Smith, PhD

Pfizer Inc.

Dr. Devyn Smith is Head of Strategy in Pfizer's Pharmatherapeutics Division of Research and Development. He received a BS in Zoology from Brigham Young University and a PhD in Genetics from Harvard Medical School. He worked as a strategy consultant for The Frankel Group for several years before joining Pfizer in 2009. He currently supports the Pharmatherapeutics division of Pfizer in developing and implementing strategies that further enable drug discovery and innovation. His interest in SLCs is driven by the importance of this gene family for drug discovery and the need to create platforms to enable the discovery of new drugs targeting the SLC family.

Claire M. Steppan, PhD

Pfizer Worldwide R&D

Dr. Claire Steppan is an Associate Research Fellow in the Primary Pharmacology group within Pfizer's Pharmacodynamics and Metabolism Department based in Groton, CT. She received BS in Biochemistry from Lehigh University and PhD in Biochemistry at Boston University School of Medicine. Prior to joining Pfizer in 2004, Claire was an assistant research professor at University of Pennsylvania School of Medicine in the Division of Diabetes, Endocrinology and Metabolism. Currently, Claire supports the Neuroscience and Pain Research unit, but has previously worked in diabetes and obesity groups within Pfizer. Claire has a long standing research interest in glucose transporters including GLUTs and Pfizer's SGLT2 inhibitor. More recent interests have been focused on functional expression and technologies for assessing function for other SLC transporters.

Sonya Dougal, PhD

The New York Academy of Sciences

Caitlin McOmish, PhD

The New York Academy fo Sciences

Speakers

Dax Fu, PhD

Johns Hopkins School of Medicine

Dax Fu is an associate professor in department of physiology, Johns Hopkins School of Medicine. His research is focusing on zinc transporters using a multidisciplinary approach of membrane biochemistry, structural biology and cell biology. He is a founding member of International Society for Zinc Biology, a member of the editorial board of Journal of Biological Chemistry, and served a dozen of reviewing/advisory panels for NIH, NSF and DOE. He received a National Research Service Award in 1998 from National Institutes of Health and tenured in 2007 by Brookhaven Science Associates.

Kathleen M. Giacomini, PhD

University of California, San Francisco

Kathleen M. Giacomini, PhD, Professor in the Department of Bioengineering and Therapeutic Sciences and Co-Director of the UCSF-Stanford Center of Excellence in Regulatory Sciences and Innovation, is a well-renowned pharmacologist. Dr. Giacomini is considered a pioneer in the field of pharmacogenomic studies of membrane transporters. She led the discovery of genetic variants in membrane transporters that play a role in drug response in ethnically diverse populations and has been involved in the inception and leadership of the International Transporter Consortium. Dr. Giacomini has co-authored over 200 manuscripts and has received many honors and awards, most recently the Honorary Doctorate Degree from Uppsala University in 2016. Dedicated to mentoring scientists, Kathy Giacomini has also received many internal awards from UCSF, including the UCSF Martin Luther King, Jr. Award for the Advancement of Minorities, and most recently, the Outstanding Mentor Award from the UCSF Postdoctoral Scholars Association in 2009.

Matthias A. Hediger, PhD

University of Bern

Matthias A. Hediger received his PhD degree in Biochemistry at the Swiss Federal Institute of Technology, Zürich, Switzerland, in 1982. As a post-doctoral trainee at the University of California Los Angeles, he developed the expression cloning technique for membrane transport proteins (Hediger et al., Nature 1987 330:379–81). Between 1989 and 2005 he was Assistant Professor and later on Associate Professor at Harvard Medical School. As of May 2005, he became Professor and Director of the Institute of Biochemistry and Molecular Medicine, University of Bern, Switzerland. His research focusses on medically relevant solute carriers (SLCs) and ion channels that facilitate the transport of iron, zinc, calcium, amino acid, vitamins, uric acid and peptides across cell membranes. Major human diseases are often linked to the dysfunction of such transport proteins. Matthias Hediger has published more than 200 papers in his field and obtained patent protection on commercially relevant transporters. In recognition of his work, he received the 2004 Rank Prize in Nutritional Sciences (Surrey, UK) and the 2009 Japanese Society for the Study of Xenobiotics Award (Kyoto, Japan). To advance pharmaceutical applications in the transporter field, he established in 2009 the Swiss National Center of Competence in Research, NCCR TransCure (www.nccr-transcure.ch). Early in 2013, he released a series of reviews entitled "The ABCs of Membrane Transporters in Health and Disease (SLC series)" in the Journal Molecular Aspects of Medicine. He serves as Special Advisor on Solute Carriers (SLCs) to the HUGO Gene Nomenclature Committee (HGNC) and established a web-based genomic resource of all HUGO-approved SLC families (www.bioparadigms.org).

Kim Huard, PhD

Pfizer Inc.

Dr. Kim Huard is a senior principal scientist at Pfizer where she leads chemistry teams on various drug discovery programs in the cardiovascular and metabolic diseases research unit located in Cambridge, Massachusetts. Kim graduated from the University of Montreal with a BSc in chemistry and a PhD in organic chemistry where she developed a rhodium-catalyzed carbon-hydrogen bond nitrene insertion methodology. Following her graduate studies, Kim contributed to the total synthesis of the structurally complex natural product daphnipaxinin as a FQRNT postdoctoral fellow at the University of California, Irvine. In her medicinal chemistry role at Pfizer, Kim works on modulating different types of targets such as enzymes, GPCRs, and transporters as well as targeting specific compound disposition such as liver selective or brain penetrant agents. Kim's work focuses on identifying hits and developing them into leads using approaches such as high throughput screening, fragments, and structure-based drug design, which led to the discovery of three clinical candidates since she joined Pfizer in 2010.

Avner Schlessinger, PhD

Icahn School of Medicine at Mount Sinai

Dr. Schlessinger is an Assistant Professor in the Department of Pharmacology and Systems Therapeutics, and is a member of the Tisch Cancer Institute, at the Icahn School of Medicine at Mount Sinai in New York City. The overall goal of Dr. Schlessinger's laboratory is to improve and automate the structure-based discovery process by developing and applying novel computational approaches, and to collaborate with experimental labs to characterize pharmacologically important proteins, with a long-term goal of developing cancer drugs. His lab publishes in the areas of structural biology, bioinformatics, and drug discovery, as well as in personalized medicine and systems pharmacology. Dr. Schlessinger graduated from Tel Aviv University with a BSc in Chemistry and Biology, and completed his PhD from Columbia University in the Department of Biochemistry and Molecular Biophysics. Following his graduate studies, Dr. Schlessinger was an NIH NRSA postdoctoral fellow at the Department of Bioengineering and Therapeutic Sciences, University of California San Francisco (UCSF), where he developed methods for protein structure prediction and structure-based drug design. Dr. Schlessinger is an Associate Editor of PLOS Computational Biology. Dr. Schlessinger joined the faculty at the Icahn School of Medicine at Mount Sinai in January, 2013.

Giulio Superti-Furga, PhD

Austrian Academy of Sciences

Giulio Superti-Furga, PhD, is Scientific Director of the Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna (CeMM), Austria and Professor of Medical Systems Biology at the Medical University of Vienna. He is an Italian citizen. He performed studies in molecular biology at the University Zurich, while doing research also at Genentech, and the IMP/Vienna. Post-doctoral fellow and Team Leader at EMBL. He co-founded and was Scientific Director of Cellzome until 2005. He later founded Haplogen. Since 2005 he directs CeMM in the middle of the general hospital campus in Vienna, where, together with some 130 scientists/medical doctors, he is trying to bring the genomic and systems-views close to the clinical world to improve medical practice. Among his major achievements to date are the elucidation of basic regulatory mechanisms of tyrosine kinases in human cancers, the discovery of fundamental organization principles of the proteome and lipidome of higher organisms, the characterization of the molecular machinery involved in innate immunity and the development of integrated approach to understand the mechanism of action of drugs at the molecular level. His work on the organization of the eukaryotic proteome is among most highly cited in the field.

Ming Zhou, PhD

Baylor College of Medicine

Dr. Zhou received a Bachelor of Science in Biochemistry from Fudan University in Shanghai, China. He came to the U.S. to pursue a PhD at the State University of New York at Buffalo, where he studied the allosteric activation mechanism in acetylcholine receptor channels in the laboratory of Dr. Anthony Auerbach. After he obtained his doctorate in 1999, he joined Dr. Roderick MacKinnon's laboratory at the Rockefeller University to investigate structural mechanisms of inactivation gating and ion permeation in potassium ion channels. He became a faculty member in the Department of Physiology and Cellular Biophysics at Columbia University in 2004 and remained there until 2012, when he joined the Department of Biochemistry and Molecular Biology at Baylor College of Medicine. He is currently the Ruth McLean Bowman Bowers Professor of Biochemistry. Dr. Zhou's lab applies structural, biochemical, and functional approaches to understand basic chemical and physical principles in membrane transport proteins: How substrates are recognized; what structural changes are required for substrate translocation; and how the electrochemical gradient of one substrate drives the concentrative uptake of another substrate.

Abstracts

Fundamentals of Solute Carrier Proteins and New Perspectives for Drug Discovery
Matthias A. Hediger, PhD, University of Bern

Nearly 10% of the human genome is dedicated to membrane transport processes. SLCs or solute carrier proteins make up the largest class of transport proteins—far greater than ion channels, ABC transporters and ATPase pumps. Yet, very little is known about many of the SLC genes and thus this class of genes exemplifies one of the most disregarded and neglected group of human genes. SLC proteins transport "solutes", i.e. organic molecules like sugars, vitamins, waste products and drugs as well as inorganic ions and trace elements. SLCs may serve as direct pharmaceutical targets as is the case for the serotonin transporter SLC6A4 (targeted by the SSRIs, the most commonly prescribed class of antidepressants) or the glucose transporter SLC5A2/SGLT2 (targeted by the recently developed anti-diabetic drugs), or they can be utilized as drug delivery systems (i.e. the oligopeptide/drug transporter SLC15A1/PepT1). When exploiting SLCs therapeutically, one of the biggest challenges has been the large functional diversity that exists within the known 52 SLC families. Many SLC members have been proposed as potential candidate drug targets, but proof-of-concept studies are still scarce and our knowledge about their role in complex multigenic diseases like cancer, diabetes, hypertension or autoimmune diseases is incomplete. Extensive work is needed to leverage the therapeutic wealth represented by the SLCs. The establishment of international academia-industry hubs would help bundle know-how in the transporter, in order to ensure maximal benefit for human health.

Genetic Variants in Membrane Transporters: Implications for Human Disease and Drug Response
Kathleen M. Giacomini, PhD, University of California, San Francisco

Human genetic studies have provided a wealth of information on the role of membrane transporters in human biology and pharmacology. For example, mutations in about 20% of Solute Carrier (SLC) transporters in the human genome have been associated with Mendelian disease. For common disease, genomewide studies have revealed associations between polymorphisms in a number of SLC proteins and human disease and drug response. Notable examples include SLC30A8, a pancreatic beta-cell specific zinc transporter, which has been associated with diabetes and SLCO1B1, an anion transporter, which has been associated with response to statins. In this presentation, following a brief review of genetic variants in SLC transporters that associate with human disease I will focus on genomewide association studies (GWAS) of drug response in my own laboratory. Two drugs will be discussed, the xanthine oxidase inhibitor allopurinol, a drug used in the treatment of gout, and metformin, a biguanide, used in the treatment of type 2 diabetes. These GWAS have revealed SLC transporters not previously associated with response to these drugs and have suggested new pharmacologic mechanisms for both drugs. The power of genomewide association studies to discover pharmacologic mechanism will be emphasized.

Sodium-Coupled Citrate Transporter (NaCT or SLC13A5) Inhibitors for the Treatment of Metabolic Diseases
Kim Huard, PhD, Pfizer Inc., Cambridge, Massachusetts

The sodium-coupled citrate transporter (NaCT or SLC13A5) transports citrate from the blood into the cell coupled to the transport of sodium ions. Inhibition of SLC13A5 has been proposed as a new therapeutic approach for prevention and treatment of metabolic disorders but only low affinity inhibitors have been reported. Here, we wish to describe the identification of a novel small dicarboxylate molecule capable of selectively and potently inhibiting citrate transport through SLC13A5, both in vitro and in vivo. The dicarboxylate was found to be both a substrate and an inhibitor of SLC13A5, and the detailed characterization of their molecular interaction will be described. Optimization of this series led to a more potent inhibitor with improved in vivo pharmacokinetic profile in rodent and was used to demonstrate dose-dependent inhibition of citrate uptake in liver and kidney, resulting in improvement of insulin responsiveness.
 
Coauthors: Derek M. Erion1, James R. Gosset1, Kentaro Futatsugi1, Janice Brown2, Shawn Cabral2, Daniel P. Uccello2, Justin I. Montgomery2, Matthew F. Gorgoglione1, and Julie Purkal1.
 
1. Pfizer Inc, Cambridge, Massachusetts.
2. Pfizer Inc, Groton, Connecticut.

Mechanism of Substrate Binding and Translocation in Sodium-dependent Bile Acid Transporters
Ming Zhou, PhD, Baylor College of Medicine

Bile acids (BAs) are synthesized in the liver, and after each meal, BAs are secreted into the small intestine to aid in the solubilization and absorption of fats and fat-soluble vitamins. It is estimated that more than 90% of the BAs are reabsorbed upon reaching the end of the digestive tract and returned to the liver via a process known as enterohepatic recirculation. A key secondary transporter involved in this process is the apical sodium-dependent BA transporter (ASBT) located in the terminal ileum and colon. ASBT is a sodium/BA symporter belonging to the Slc10A transporter family, and represents an important regulatory point for bile acid homeostasis. Inhibition of ASBT leads to loss of BAs and an increased demand for de novo synthesis. Because BAs are synthesized from cholesterol, small molecule inhibitors of ASBT are expected to increase consumption of cholesterol and could potentially be used for the treatment of hypercholesterolemia. ASBT is of pharmacological interest also because it can transport drugs conjugated to BAs and therefore increase drug absorption and oral bioavailability. To understand the mechanism of transport in ASBT, my lab solved structures of a bacterial homolog of human ASBT in two conformations, which suggest potential conformational changes that are required for substrate translocation. However, key mechanistic questions, such as how BAs bind to the protein and how BA transport is coupled to the sodium ion gradient, remain unanswered. Recent progress in our effort to address these questions will be presented.

Structure-based Ligand Discovery for Nutrient Transporters
Avner Schlessinger, PhD, Icahn School of Medicine at Mount Sinai

Alterations in cell metabolism support rapid growth and proliferation of cells and are key Hallmarks of Cancer. Solute Carrier (SLC) transporters are membrane proteins that transport solutes such as metabolites and drugs across membranes, and play a major role in mediating nutrient delivery in reprogrammed cancer metabolism networks. For example, the amino acid transporters LAT-1 (SLC7A5) and ASCT2 (SLC1A5) are upregulated in multiple cancer types such as Glioblastoma Multiforme, where they supply the growing tumor cells with essential amino acids that are used as nutrients to build biomass and signaling molecules to enhance proliferation. Here, we describe a structure-based discovery approach to identify small molecule modulators for ASCT2 and LAT-1, which function cooperatively in cancer metabolism and are highly expressed in the blood-brain-barrier (BBB). In particular, we use homology modeling, virtual screening, and experimental testing to identify ligands, including drugs, metabolites, and lead-like molecules for LAT-1 and ASCT2. Initial hits are then refined through iteration of computational modeling and experimental testing. Our results may explain some of the pharmacological effects (i.e., efficacy and/or side effects) of known drugs via polypharmacology, and rationalize the enhanced brain permeability of drug-like molecules. Finally, our top hits inhibited proliferation of various cancer cell lines via distinct molecular mechanisms, providing useful chemical tools to characterize reprogrammed metabolic networks, as well as a framework for developing efficacious lead compounds against these key targets and other SLC transporters.

Development of Therapeutic ZnT8 Inhibitors
Dax Fu, PhD, John Hopkins School of Medicine

ZnT8 (SLC30A) is a zinc transporter found exclusively in pancreatic islets. It is highly expressed in insulin secretory granules and responsible for vesicular zinc enrichment. Large-scale population genotyping analysis revealed that haploinsufficiency of human ZnT8 reduces the risk of type-2 diabetes (T2D) by 65%. The in vivo protective effects of loss-of-function mutations suggest ZnT8 a potential drug target for T2D prevention and treatments. In the past decade, our lab has developed an enabling toolset for structural and functional studies of zinc transporters. The crystal structure of a ZnT8 homolog (YiiP) revealed the molecular architecture of the protein while structural dynamics analysis uncovered the kinetic process of zinc transport. Functional reconstitution of purified human ZnT8 showed gain-of-function for an at-risk ZnT8 polymorphic variant, corroborating the in vivo protections by loss-of-function variants. I will discuss the mechanism of ZnT8 inhibition, biochemical assays for inhibitor screening and a cell biology platform for assessment of therapeutic efficacy of ZnT8 inhibitions at the cellular level.

Solute Carriers, Metabolism and Drug Response: a Magic Triangle
Giulio Superti-Furga, PhD, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna; Center for Physiology and Pharmacology, Medical University of Vienna

All biological organisms have genetic material that is kept apart from the environment by lipid-containing membranes. Management of exchange across membranes is critical to ensure access to nutrients, riddance of waste and to safeguard integrity and identity of the organism, by counteracting hostile pathogen invasion pathogen or intrusion of toxic matter. Dedicated proteins are thought to be involved in the import of most chemical matter. For energetic reasons, chemical safety and cellular homeostasis, transporters should be expressed only when/where required. It follows that expression of membrane transporters should reflect demand and offer rules, integrating the metabolic aspiration of the cell, with the availability in the environment. Solute carriers proteins (SLCs) represent the largest group of transporters in the human genome and most are poorly annotated. We reasoned that if we were to know the transport specificity and function of most SLCs, their dynamic expression pattern could act as proxy for the metabolic state of the associated cell/tissue. We have started to systematically map the genetic interaction among SLC genes, by mutating one and scoring for increase or decrease of fitness by genetic altering the expression of the others, across varying environmental conditions. We also score for mutations that confer resistance to cytotoxic drugs. Lastly, we limit nutrients and look for SLC that increase fitness upon overexpression. While we are only at the beginning of the process, we are confident that determining the genetic network of SLC as a function of metabolism could lead to the pharmacological exploitation of obligate dependencies.
 
Coauthors: Adrian Cesar-Razquin1, Manuele Rebsamen1, Konstantinos Papakostas1, Anna Moskovskich1, Berend Snijder1, and Enrico Girardi1.
 
1. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna.
2. Center for Physiology and Pharmacology, Medical University of Vienna.

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