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Phenotypic and Biomarker-Based Drug Discovery

Phenotypic and Biomarker-Based Drug Discovery

Tuesday, October 27, 2015

The New York Academy of Sciences

Presented By


Phenotypic screening programs were the mainstay of target-based drug discovery and development until the 1980s. While over half of the compounds approved by the FDA between 1999 and 2008 were derived from phenotypic screening programs, recent challenges have shown the limitations of target- or pathway-based drug discovery, and this method of drug discovery struggles to gain acceptance. Many investigators are now revisiting the strategy of finding effective compounds using unbiased disease models, then using these effectors to identify a relevant drug target.

This symposium aims to deepen the level of scientific understanding behind phenotypic drug discovery and to foster the exchange of ideas between industry and academic research scientists. In this symposium, we will explore current strategies enabling phenotypic drug discovery to become more mainstream. We will discuss the ability of stem cell-based and -omics technologies to create highly relevant disease model systems in vitro. We will also discuss successful approaches to effectively identify specific targets to the effectors discovered using this strategy. Specific case studies will highlight notable successes in this approach.

*Reception to follow.

This event will also be broadcast as a webinar.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City when possible.

Registration and Webinar Pricing

Student / Postdoc Member$15
Nonmember (Academia)$65
Nonmember (Corporate)$85
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$45

The Biochemical Pharmacology Discussion Group is proudly supported by

  • Boehringer Ingelheim
  • Pfizer

American Chemical Society


* Presentation times are subject to change.

Tuesday, October 27, 2015

8:00 AM

Registration and Continental Breakfast

8:45 AM

Introductory Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Marco Prunotto, PhD, F. Hoffmann-La Roche, Ltd.

9:00 AM

Phenotypic Drug Discovery: Take Two
Jonathan A. Lee, PhD, Eli Lilly

9:10 AM

Identifying Subtype-selective Vulnerabilities in Non-small Cell Lung Cancer Using Phenotypic Screening
Bruce A. Posner, PhD, University of Texas, Southwestern Medical Center
(* The 9:10 am slides will not be broadcast as part of the live webinar.)

9:40 AM

Using the Library of Integrated Network-based Cellular Signatures (LINCS) to Characterize the Mechanism of Action of Small-molecule Therapeutics
Aravind Subramanian, PhD, Broad Institute

10:10 AM

Networking Coffee Break

10:40 AM

Phenotypic Drug Discovery at AstraZeneca
Martin Main, PhD, AstraZeneca

11:10 AM

Target Hypothesis Generation and Validation for PTS Hits Using Target Space Annotations
Andras J. Bauer, PhD, PharmD, Boehringer Ingelheim USA

Young Investigator and Data Blitz Presentations

Moderator: Jonathan A. Lee, PhD, Eli Lilly

11:40 AM

Systematic, Master-Regulator-Based Assessment of Compound Activity in Human Malignancies
Yao Shen, PhD, Columbia University

12:00 PM

Identification of GPR31 as a Novel Mediator of Kras Membrane-Association and Kras-Driven Oncogenesis
Nicole Fehrenbacher, PhD, New York University School of Medicine

12:05 PM

Direct Targets Identification of a Bioactive Compound Using Chemical Biology
Petra Tafelmeyer, Hybrigenics Corporation

12:10 PM

Phenotypic Screening Assays for the Discovery of SREBP Activation Inhibitors
Muhua (Grace) Yang, PhD, Genesis Biotechnology Group
(* The 12:10 PM slides will not be broadcast as part of the live webinar.)

12:15 PM

Networking Lunch and Poster Session

1:30 PM

High-Content, Full Genome siRNA Screen for Regulators of Oncogenic H-Ras Driven Macropinocytosis
Myles Fennell, PhD, Memorial Sloan-Kettering Cancer Center

2:00 PM

High-power Phenotyping and Target Deconvolution by Pharmacoscopy and Thermal Shiftome
Giulio Superti-Furga, PhD, Austrian Academy of Sciences
(* The 2:00 pm slides will not be broadcast as part of the live webinar.)

2:30 PM

High Content Screening of Patient Derived Cells: Balancing Biological Relevance with Throughput
Michael R. Jackson, PhD, Sanford Burnham Prebys Medical Discovery Institute

3:00 PM

Networking Coffee Break

3:20 PM

Phenotypic Drug Discovery in Spinal Muscular Atrophy Disease: Parallel Efforts in Preclinical Development and Target Identification
Susanne Swalley, PhD, Novartis Institutes for BioMedical Research

3:40 PM

Spinal Muscular Atrophy: Screening for Molecular Phenotypes to Identify a Disease-Modifying Therapy
Friedrich Metzger, PhD, F. Hoffmann-La Roche Ltd.
(* The 3:40 pm slides will not be broadcast as part of the live webinar.)

4:00 PM

Pathway Reporter Genes Define Molecular Phenotypes of Human Cells—Application to Compound Screening and Prioritization
Jitao David Zhang, PhD, F. Hoffmann-La Roche Ltd.

4:20 PM


4:50 PM

Poster Prize Awards and Closing Remarks
John Moffat, PhD, Genentech

5:00 PM

Networking Reception



Michael Foley, PhD

Tri-Institutional Therapeutics Discovery Institute

Dr. Foley is an accomplished chemist and entrepreneur with more than 25 years of industry and academic experience. He has been scientific co-founder of four companies and one academic institute and has placed twelve single agent or combination drugs into clinical development. He was most recently the Director of the Chemical Biology Platform at the Broad Institute of Harvard and MIT, which successfully established over 150 high throughput screening development collaborations under his leadership. Dr. Foley previously worked at Bristol-Myers Squibb and GlaxoSmithKline, and obtained his PhD in chemistry at Harvard.

Ralph Garippa, PhD

Memorial Sloan Kettering Cancer Center

Ralph J. Garippa is the Director of the RNAi and Gene Editing Core Facility at MSKCC and interim Head of the HTS/HCS Core. His RNAi group develops protocols in the design and execution of loss-of-function screens, provides consultation in the areas of RNAi library design, vector construction, CRISPR Cas9 knockout protocols, and data management. The HTS Core curates a collection of ~350,000 small molecules and performs screens using 384/1536 well formats via plate readers and high content microscopy. Dr. Garippa is the former Head of Cell-Based High Throughput Screening (HTS) and Microscopic Imaging-based High Content Screening (HCS) at Hoffmann-La Roche’s Nutley NJ facility from 1998-2008. Additionally, he was central member of a task force which explored the rollout of the Research-Based Stem Cells at Roche, with academic and industrial partners including Harvard University, Massachusetts General Hospital, and The Hebrew University in Israel. He also participated in the Therapeutic Stem Cell Task Force, investigating corporate opportunities with allogeneic and autologous mesenchymal stem cells (MSCs). From 1982 to 1998, he served in various positions at Roche, including pre-clinical Project Manager in Metabolic Diseases (1994-1998) and Laboratory Leader in Bronchopulmonary Pharmacology (1986-1992).  He was also involved with the NIH’s Small Molecule Repository (SMR) probe screening effort, as an ad hoc scientific advisor, since the project’s inception. Dr. Garippa holds a PhD in Pharmacology from Columbia University in New York City (where he studied with Drs. Fred Maxfield and Tim McGraw) and a BA degree in Biology from Fairleigh Dickinson University in New Jersey (where he studied developmental biology in the axolotl, Ambystoma mexicanum with Dr Gervasia Schreckenberg).

David Mark, PhD

F. Hoffmann-La Roche, Ltd.

David joined Hoffmann-La Roche at Nutley, New Jersey in 1999 as Head of Assay Development and High Throughput Screening. He was the Deputy Site Head of Discovery Technologies at the Nutley site until its closure in 2013. During his tenure in Nutley, he introduced high content cell imaging technology to Roche and established a group to apply this technology in high throughput phenotypic screening of small molecule libraries. David had ten additional years of assay development and screening experience at Merck & Co. where he was responsible for a major portion of the Natural Products Discovery Program, including the Assay Development group in Rahway, New Jersey and the Natural Product Screening group in Madrid, Spain. David also had ten years of drug discovery experience at Cetus Corporation, where he participated in the discovery and development of two protein therapeutics: Betaseron and Proleukin. David received his PhD in Biochemistry from Harvard University in 1977, and was a postdoctoral fellow at Stanford University Medical Center, Department of Biochemistry in the laboratory of Dr. Paul Berg (1977-79). David has published over 30 papers and holds 19 patents and is the recipient of several awards.

Lorenz Mayr, PhD

Astra Zeneca

Lorenz is working since September 2012 as Vice President, Reagents & Assay Development with global responsibility for generation of biological reagents and assay development activities at AstraZeneca. This includes generation of proteins and cell lines for hit finding, hit-to-lead and lead optimisation activities including structure & biophysics activities across all therapeutic areas, the generation of tool antibodies, transgenic animals, stem cells and primary cells as tools for target validation studies and lead optimisation programmes. His department in the UK and Sweden is responsible for assay development activities for biochemical, cell-based and phenotypic assays for all therapeutic areas at AstraZeneca. Before that, he has been working as Executive Director at Novartis Pharma in Basel/Switzerland, at Bayer Pharma Research in Wuppertal/Germany, at Bayer Central Research in Leverkusen/ Germany and at the M.I.T./Whitehead Institute in Cambridge/Massachusetts (U.S.A.). He has published more than 50 papers in peer-reviewed journals and serves on several editorial and scientific advisory boards, including two terms at the Board of Directors for the Society of Biomolecular Sciences (2004-2011) and working as the Conference Chair of the MipTec Drug Discovery Conference, Europe’s largest drug discovery event, held in Basel/Switzerland.

John Moffat, PhD


Marco Prunotto, PhD

F. Hoffmann-La Roche Ltd.

Sonya Dougal, PhD

The New York Academy of Sciences


Andras J. Bauer, PhD, PharmD

Boehringer Ingelheim USA

Andras Bauer received his PharmD in 2003 from Semmelweis University and in 2004 started working in the laboratory of Dr. Brent Stockwell at Columbia University where he focused on rational drug design directed against protein-protein interactions and characterizing the mechanism of action of the genotype-selective lethal compound erastin. Upon being awarded his PhD in Biology in 2011 he became a presidential post-doctoral fellow at the Novartis Institute for Biomedical Research in Cambridge Massachusetts, where he worked on developing a platform for label-free target identification of bioactive small molecules. He is currently a Senior Scientist, Immunology and Respiratory at Boehringer Ingelheim involved in drug concept discovery and leveraging chemical biology approaches for early drug concept validation and target identification of phenotypic screening hits.

Myles Fennell, PhD

Memorial Sloan-Kettering Cancer Center

Myles Fennell has been a Senior Research Scientist at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY since 2013. He is currently responsible for developing and running RNAi, CRISPR and small molecule screens in both arrayed and pooled formats using a variety of technologies including high-content screening, FACS and next-generation sequencing. After receiving his PhD from the University of Edinburgh he went on to hold positions at Wyeth Neuroscience, Bristol Myers-Squibb and Gigacyte. His experience in high-content screening has been pivotal in developing novel image based screens for researchers at MSKCC and other institutions. Areas of impact include the development of HCS synaptogenesis and neurodegeneration assays, tumor organoid 3D models, as well as cellular physiology and signaling.

Michael R. Jackson, PhD

Sanford Burnham Prebys Medical Discovery Institute

Dr. Jackson is responsible for the operations of the Prebys Center, a multidisciplinary Drug Discovery enterprise focused on identifying and developing transformational new drugs to address unmet medical needs. The overall mission of the Center is to generate a pipeline of first-in-class drugs based on breakthrough research conducted by investigators at the Sanford Burnham Prebys Medical Discovery Institute (SBP) as well as external collaborators. Prior to joining SBP in 2009, Dr. Jackson spent 15 years at Johnson & Johnson developing a track record of managing large research and development organizations. Under his leadership many novel drugs were advanced to the clinic, and several drug delivery products successfully gained regulatory approval. He received his PhD from the Department of Biochemistry at the University of Dundee in Scotland and completed his post-doctoral training at The Scripps Research Institute.

Jonathan A. Lee, PhD

Eli Lilly

Dr. Lee is scientific leader in the pharmaceutical industry with a history of identifying/enabling innovative technologies/strategies and integrating them into the drug discovery process. Scientific background includes targeted and phenotypic drug discovery, high content cellular imaging, functional genomics, primary and stem cell-based assay development and screening, project management, and early discovery portfolio review. Dr. Lee was scientific initiator of the PD2 Initiative, a collaborative Lilly venture where compounds from academic and biotech institutes are tested in Lilly’s phenotypic assay platform in a manner where external collaborators receive test results free of charge and retain intellectual property. Jonathan is a recognized thought leader in phenotypic drug discovery and has networked with the global research community through creation of a LinkedIn discussion group, organizing/editing (with Ellen Berg) special issues, and through multiple invited lectures on phenotypic drug discovery.

Martin Main, PhD


Martin Main leads the Reagents & Assay Development UK department at AstraZeneca, which operates out of Alderley Park and Cambridge. An ion channel electrophysiologist by training, Martin has worked in the pharmaceutical industry for 20 years, at Merck, GlaxoSmithKline and AstraZeneca. The remit of Martin’s department is to generate the reagents & tools that drive innovative drug discovery projects: proteins, cells, antibodies, biochemical & cellular assays and experimental data-sets are developed in close collaboration with project teams, with a focus on Oncology and Neuroscience targets.

Friedrich Metzger, PhD

F. Hoffmann-La Roche Ltd.

Friedrich Metzger is Head of Discovery in Rare Diseases at Roche, where he is responsible for developing and leading a portfolio of discovery projects that aim to treat rare genetic disorders with high unmet medical need. He has studied Biology at the Universities of Freiburg and Tübingen, Germany, where he received a PhD degree in pharmacology in 1996. After Post-Docs in Würzburg and Freiburg, Germany, where he did research in the field of rare neuromuscular disorders Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA) as well as in neuronal plasticity, he became Associate Professor at the University in Groningen, Netherlands, continuing his research on ALS. In 2002, he joined Roche, where he initiated and coordinated several drug development programs for treatment of Alzheimer’s Disease, Parkinson’s Disease, ALS, Duchenne Muscular Dystrophy (DMD) and myotonic dystrophy I (DM1). Currently, he is coordinating all preclinical aspects in the SMA program in collaboration with PTC Therapeutics and the SMA Foundation, which is in patient trials. He has his specific scientific expertise and a strong track record in rare genetic neuromuscular and neurodevelopmental disorders. In 2011, Friedrich has been appointed adjunct professor in Neurobiology at the University of Freiburg, Germany, where he teaches in neurobiology, synaptic plasticity and neurological diseases.

Bruce A. Posner, PhD

University of Texas, Southwestern Medical Center

Dr. Posner received his PhD in biochemistry with Professor Stephen Benkovic at Penn State University in 1994 and then carried out an NIH-sponsored post-doctoral fellowship with Professor Alfred G. Gilman at the University of Texas’ Southwestern Medical Center (UTSMC). Subsequently, he joined Pfizer, Inc as a Principal Scientist in the High Throughput Screening Center of Emphasis. During his 9 year tenure there, he led over 60 HTS campaigns and identified more than 20 hit-to-lead starts for early drug discovery programs. Two of these chemical series were submitted to first-in-human clinical trials. His efforts resulted in his recognition with Pfizer’s Discovery Recognition Award 2004 and subsequent promotion to Senior Principal Scientist. In 2009, he joined the biochemistry faculty at UTSMC as an associate professor and the director of the High Throughput Screening (HTS) Core. In this capacity, he leads the core facility efforts to aid in the discovery and the early stage, pre-clinical development of new small molecule therapeutics. He has co-authored over 18 publications (papers and patents) since joining UT Southwestern in 2009. His efforts at UT Southwestern have contributed to the licensing of 4 candidate small molecules to 3 pharmaceutical companies.

Yao Shen, PhD

Columbia University

Yao Shen received her PhD in Chemistry and MSc in Computer Science in 2011 from University of Notre Dame. Her PhD thesis focused on applying structural-based drug discovery techniques to predict hits for essential genes in pathogens identified using metabolic network analysis. After that, she joined the laboratory of Dr. Andrea Califano at Columbia University as a postdoc scientist, where she worked on projects involving inferring compound mode-of-action, predicting synergistic compound combinations, and reversing drug resistance using systems biology approaches.

Aravind Subramanian, PhD

Broad Institute

Aravind Subramanian is Director of Computational R&D at the Broad Institute of MIT and Harvard. He is also co-PI of the NIH-funded Center for Transcriptomics at the Broad which is part of the Library of Integrated Network-based Cellular Signatures (LINCS) program and the Big Data to Knowledge (BD2K) initiative.
As a graduate student at the Whitehead Institute for Genome Research, Dr. Subramanian helped develop  Gene Set Enrichment Analysis (GSEA) - a widely cited algorithm for the interpretation of high-dimensionality genomic datasets. Dr. Subramanian extended this approach to the analysis of genome-scale pooled genetic screens for the identification of essential genes in cancer cells (RIGER).
In postdoctoral work, Dr. Subramanian collaborated with Broad Institute scientists to invent a novel approach to gene expression profiling that combines highly automated laboratory workflow with a computational framework that selects a representative subset of the transcriptome for measurement. This platform, called L1000, is now in routine use at the Broad for the Connectivity Map project and is increasingly used by the pharmaceutical industry as part of their drug discovery process.
In his current work, Dr. Subramanian leads a group of molecular biologists, software engineers and computational analysts whose efforts are directed towards developing new technologies for perturbational profiling and in using these data with pattern recognition approaches to discover relationships between genes, drugs and diseases. The group has three goals a) to construct a comprehensive reference dataset of perturbational signatures b) to develop algorithms and software to make these data and results accessible to the biomedical community and c) to engage in collaborative efforts - within academic and with industry - that leverage these resources to make biological and therapeutic discoveries.

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.

Susanne Swalley, PhD

Novartis Institutes for BioMedical Research

Susanne Swalley, PhD, is an Investigator in the Developmental and Molecular Pathways department at the Novartis Institutes for Biomedical Research. Trained as a chemist, her current research focuses on biochemical and biophysical approaches to target identification. Prior to Novartis, she was a scientist at Vertex Pharmaceuticals where she contributed to a wide variety of project teams on the evaluation and screening of new targets. Susanne graduated from Amherst College with bachelor’s degrees in chemistry and music, and obtained a PhD in chemistry from the California Institute of Technology with Dr. Peter Dervan. She completed her postdoctoral training at Harvard University in the laboratories of Dr. Don Wiley and Dr. Stephen Harrison with fellowships from the Damon Runyon-Walter Winchell Cancer Research Fund and the Charles A. King Trust.

Jitao David Zhang, PhD

F. Hoffmann-La Roche Ltd.

Jitao David Zhang studied biology in Peking University, received an MSc in bioinformatics in University of Heidelberg and a PhD in computational biology and biostatistics in German Cancer Research Center, Germany. Dr. Zhang’s research focuses on modelling and integrative analysis of signaling and transcriptional networks for disease understanding and drug development.


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The Biochemical Pharmacology Discussion Group is proudly supported by

  • Boehringer Ingelheim
  • Pfizer

American Chemical Society


Phenotypic Drug Discovery: Take Two
Jonathan A. Lee, PhD, Eli Lilly

Most practicing biologists and chemists have been trained in an era where many molecular drug targets have been identified and are readily accessible on a genome-wide scale. This molecular framework to biology is very appealing from an intellectual and innovative science perspective and is foundational to most academic research. Similarly molecular centric drug discovery approaches were enticing because it utilized ground-breaking technologies and promised to provide systematic research and business processes to the pharmaceutical industry. The development of this Molecular Mindset in life science and drug discovery research was inevitable and promised to revolutionize the pharmaceutical industry. However, in contrast to the expected dominance of molecular targeted drug discovery strategies, more first-in-class small molecule FDA approved drugs were derived from functional/empirical lead generation approaches reminiscent of pre-genomics pharmacology. Moreover, innovation and productivity in pharmaceutical drug discovery remains below expectations. These observations have started discussion/debate within the drug discovery community. Should modern empirical/functional lead drug discovery strategies be reconsidered? When should molecular hypothesis driven vs empirical drug discovery approaches be utilized? What are the best practices to integrate TDD and PDD strategies? We are challenging our reliance on target centric approaches and re-establishing a biology-first, neoclassic drug discovery paradigm in which the Molecular Mindset is integrated with, but is positioned in service to phenotype and function. The pendulum of drug discovery that swung from physiology-based systems of the pre-molecular era to the promise of a genomics revolution in the early 1990s is now positioned for a return.

Identifying Subtype-selective Vulnerabilities in Non-small Cell Lung Cancer Using Phenotypic Screening
Bruce A. Posner, PhD, University of Texas Southwestern Medical Center, Dallas, Texas, United States

Lung cancer is the leading cause of cancer-related deaths with more than 1.3 MM people dying of this disease each year. Drs. John Minna and Adi Gazdar have collected over 100 lung cancer tumor samples and created corresponding cell lines that they have characterized by molecular and biological methods. From these studies and others, we postulated that lung cancer can be characterized as a collection of diseases, each distinguished by unique genetic dependencies and chemical vulnerabilities. Following this hypothesis, we carried out high throughput, phenotypic screens of 12 representative lung cancer cell lines from our panel against the UT Southwestern chemical library (~230,000 compounds). In follow up studies, we identified ~180 small molecule toxins representing over 30 chemical series that are toxic to subsets of the extended lung cancer cell panel but not to immortalized human bronchial epithelial cells (HBEC’s). Two chemical series were found to be selectively toxic to ~ 5% of the lung cancer panel. Using optimized analogs of the original hits, we were able to uncover an unexpected mechanism of action in which these compounds are metabolized in sensitive cell lines to a reactive metabolite that irreversibly inhibits stearoyl CoA desaturase (SCD) and causes cell death. Cell lines (lung cancer and normal) lacking the required metabolic enzymes are resistant to our compounds. This indicates a viable therapeutic window not previously observed with other SCD inhibitors. Importantly, these in vitro results are recapitulated in vivo in xenograft models of sensitive and resistant lung cancer cell lines.
Coauthors: Panayotis C. Theodoropoulos, BS, Stephen S. Gonzales, PhD, Sarah E. Winterton, BS, Carlos Rodriguez-Navas, PhD, Michael G. Roth, PhD, John D. Minna, MD, Michael A. White, PhD, Hamid Mirzaei, PhD, Noelle S. Williams, PhD, Joseph M. Ready, PhD, Deepak Nijhawan, PhD
University of Texas Southwestern Medical Center, Dallas, Texas, United States

Using the Library of Integrated Network-based Cellular Signatures (LINCS) to Characterize the Mechanism of Action of Small-Molecule Therapeutics
Aravind Subramanian, PhD, Broad Institute

The Library of Integrated Network-based Cellular Signatures (LINCS) is an NIH program that aims to create a network-based understanding of biology by cataloging changes in gene expression and other cellular processes that occur when cells are exposed to a variety of perturbing agents (e.g., chemicals and shRNAs). As part of the LINCS program the Broad Institute has generated ~2.0M gene-expression profiles from the effect of 4,000 small-molecule compounds and 3,000 genes on a diversity of cancer cell lines and primary cells. These reference signatures provide a systematic, unbiased approach to relate novel compounds to established pharmacological classes, gene targets and mechanisms of toxicity.
This talk will describe the LINCS resource (data and analytical tools) and demonstrate how they are being used to characterize query signatures. Importantly, as the number of signatures has grown dramatically, it has become vital to use readouts from complementary assays including phenotypic measurements to prioritize hypothesis for laboratory testing. Analytical approaches to data integration will be described as well as a cloud-based informatics platform that allows analysis within web-browser based user interfaces and programmatic access via APIs. Finally, example applications of these resources for identification of putative gene targets by integrating readouts from small-molecules, shRNAs and CRISPRs will be described.

Systematic, Master-Regulator-Based Assessment of Compound Activity in Human Malignancies
Yao Shen, PhD1

Large-scale genomic studies have provided a comprehensive repertoire of genetic alterations in human cancers. Yet, the majority of human cancers present with a much more complex mutational landscape that is becoming increasingly harder to decipher in terms of potential therapeutic targets. As a result, less than 25% of all cancer patients present with potentially actionable mutations for targeted therapy. Rather than focusing on the mutated genes, we have shown the ability to identify master regulator (MR) proteins that integrate the effect of a large and heterogeneous repertoire of genetic alterations in tumor subtypes. We have shown that many of these MRs represent essential or syntethic lethal dependencies in these tumors. As such, they represent novel, valuable drug targets. Despite these successes, we have not yet systematically tested the hypothesis that cancer cell MRs are enriched in bona fide dependencies and that pharmacological targeting of MRs abrogates tumor cell viability. The recently published genome wide pooled-shRNA screening and the large-scale drug screening data in cell lines enabled us to perform such analysis. Here, we show that MRs of tumor cell state, identified based on gene signatures using context-specific regulatory networks, are significantly more likely to represent tumor dependencies. We also show that MRs activated in drug resistant but not in sensitive cells are conserved in independent data sets, including cell line and patient samples and thus represent candidate biomarkers. Moreover, tumor MRs are significantly more efficient than gene expressions in predicting drug sensitivity in both cell lines and patient cohorts.
Coauthors: Mariano J. Alvarez, PhD1, Andrea Califano, PhD1,2,3,4,5,6
1 Department of Systems Biology, Columbia University, New York, New York
2 JP Sulzberger Columbia Genome Center, Columbia University, New york, New York
3 Department of Biomedical Informatics, Columbia University, New york, New York
4 Department of Biochemistry & Molecular Biophysics, Columbia University, New york, New York
5 Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
6 Motor Neuron Center and Columbia Initiative in Stem Cells, Columbia University, New York, New York

Phenotypic Drug Discovery at AstraZeneca
Martin Main, PhD, AstraZeneca

The application of phenotypic assays and screening to the early phase of drug discovery offers the potential to address two of the greatest challenges in the pharmaceutical industry; namely high attrition rates due to lack of efficacy and a shortage of novel target ideas. In AstraZeneca, we believe that phenotypic drug discovery is critically dependent on three factors – use of the most physiologically relevant cellular system; development of the most appropriate phenotypic read-outs; and application of the best screening libraries. In this presentation, we will describe development of phenotypic assays in the cardiac biology and diabetes research areas, and the screening and de-convolution of annotated compound sets in these assays. Finally, we will outline our plans to expand phenotypic discovery beyond the use of small molecule libraries.

Target Hypothesis Generation and Validation for PTS Hits using Target Space Annotations
Andras J. Bauer PhD1

Binding of a small molecule to its target domain is a prerequisite of biological activity. By interrogating existing target-ligand pairs covering the known ligandable proteome, we can predict candidate target-ligand pairs for phenotypic screening hits. An alternative to this method is using purified protein libraries representing ligandable domains to screen for protein-target domain interactions in a label-free format. This talk will focus on implementation of both technologies for generating and validating target-ligand hypotheses for bioactive compounds emerging from phenotypic screens.
Coauthors: Qiang Zhang PhD2, Jonathan Hill MSc3, Jehrod Brenneman PhD2, Charles E. Whitehurst PhD1
1 Immunology and Respiratory Therapeutic Area, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, United States of America
2 Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, United States of America
3 Department of Computational Biology, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, United States of America


High-Content, Full Genome siRNA Screen for Regulators of Oncogenic H-Ras Driven Macropinocytosis
Myles Fennell1

Uptake of nutrients, such as glucose and amino acids, are critical to support cell growth, and is typically mediated by cell surface transporters. An alternative mechanism for the bulk-uptake of nutrients from the extracellular space is macropinocytosis, a non-clathrin, and non-receptor mediated endocytic process in which extracellular fluid is taken up into large intracellular vesicles called macropinosomes. Oncogenic transformation leads to the increased metabolic activity of tumor cells, and in Ras-driven tumors part of this enhanced activity is the stimulation of macropinocytosis.  To measure oncogene-dependent macropinocytosis, we used HeLa cells expressing oncogenic HRASG12D driven from a Tet-regulated promoter. Upon oncogenic HRAS expression, the cells undergo metabolic changes that include the elevation of macropinocytosis.  We detected macropinocytosis via the uptake of lysine-fixable, TMR-Dextran (70kDa) from the cell media into nascent intracellular macropinosomes.  These macropinosomes were quantified by image-based high-content analysis, with the size, intensity and position of macropinosomes measured.  Using this model system, we ran a full genome-wide siRNA screen (GE, siGenome™) in order to identify genes involved in controlling oncogenic HRAS-dependent macropinocytosis.  Hits from the primary screen were confirmed with siRNA reagents from a different library (GE, OTP), which allowed us to mitigate potential off-target effects.  Candidate genes from this screen include known regulators of macropinocytosis, as well as novel targets.
Coauthors: Cosimo Commisso2, Craig Ramirez3, Ralph Garippa1, Dafna Bar-Sagi3
1 RNAi & Gene Editing Core Facility, Memorial Sloan-Kettering Cancer Center, 417 East 68th Street, New York, NY 10065
2 NCI-Designated Cancer Center-Cell Death and Survival Networks Program Sanford-Burnham medical research institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037
3 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA

High-power Phenotyping and Target Deconvolution by Pharmacoscopy and Thermal Shiftome
Giulio Superti-Furga, PhD1,2

Phenotyping screens suffer from at least two problems: 1) the assays seldom recapitulate the genetic and tissue complexity of patients and 2) the route to target deconvolution is long and tortuous. We present two technological breakthroughs. The first one, that we call pharmacoscopy, is a procedure based on automated microscopy and single-cell image analysis in peripheral blood mononuclear cells (PBMCs) that allows to quantitatively measure spatially resolved drug-perturbation phenotypes over large cell populations at single cell level and high throughput. With a blood sample of an individual proband or patient one can screen thousands of compounds and predict therapeutic outcome. We are also able to monitor differential cell-cell interactions and found that we could classify drugs according to their ability to modulate the cellular interaction network following activation of immune cells. We plan to screen for drugs able to modulate these interactions specifically with cancer cells. But how to know what the drugs target? Thermal stabilization of proteins after ligand binding provides an efficient means to assess the binding of small molecules to proteins. We developed an approach that in combination with quantitative mass spectrometry, allows for the systematic survey of protein engagement by cellular metabolites and drugs. We profiled the targets of methotrexate and (S)-crizotinib and the metabolite 2′3′-cGAMP in intact cells and identified the 2′3′-cGAMP cognate transmembrane receptor STING, involved in immune signaling. Thus, without any modification, it is possible to have an unbiased survey, in intact cells, of the proteins engaged by a drug or a metabolite, greatly facilitating mechanism of action studies.
Coauthors: Snijder B, PhD1, Vladimer G, PhD1, Jeryczynski G3, Jäger, U, MD3, Gisslinger H, MD3, Rebsamen M, PhD1, César-Razquin A, MSc1, Lardeau C, MSc1,4, Colinge, J, PhD1, Bennett KL, PhD1, Kubicek S, PhD1,4, Huber KVM, PhD1
1 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
2 Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
3 Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria
4 Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives, Vienna, Austria


High Content Screening of Patient Derived Cells: Balancing Biological Relevance with Throughput
Michael R. Jackson, PhD, Sanford Burnham Prebys Medical Discovery Institute

Development of technology platforms that can be used to perform compound screens against patient specific human induced pluripotent stem cells (hiPSC) derived cell types with relatively high throughput will be essential to realize the potential that these cells hold for disease modeling and drug discovery. Towards this goal, we have been working to develop a standardized battery of assays against which hiPSC-derived neurons can be screened for specific phenotypes. Our results demonstrate the feasibility of performing higher throughput drug screens on hiPSC-derived neurons and establishing disease relevant platforms for future screens using patient derived cells.

Phenotypic Drug Discovery in Spinal Muscular Atrophy Disease: Parallel Efforts in Preclinical Development and Target Identification
Susanne Swalley, PhD, Novartis Institutes for BioMedical Research

Historically, phenotypic drug discovery has been a mainstay of drug development, enabling the discovery of numerous therapeutic molecules. This approach is particularly attractive when there are no known targets for treating a particular indication but knowledge of the molecular pathology of the disease is high. A key challenge, however, has always been the determination of the efficacy target. A recent success story will be presented, where our team progressed a small-molecule preclinical candidate to treat Spinal Muscular Atrophy (SMA) while simultaneously elucidating the molecular mechanism of action. SMA is the most common genetic cause of pediatric mortality, caused by the loss of expression of the survival of motor neuron-1 (SMN1) gene. A duplicate copy of the gene (SMN2) is inefficiently spliced, producing a truncated and unstable protein. The molecules we discovered through phenotypic screening enhance SMN2 splicing in a sequence-selective manner, thereby elevating levels of full-length SMN protein and extending survival in a mouse model of severe SMA. The compounds act by stabilizing the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex. This novel mechanism validates the feasibility of small molecule-mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases.

SMA: Screening for Molecular Phenotypes to Identify a Disease-Modifying Therapy
Friedrich Metzger, PhD, F. Hoffmann-La Roche Ltd.

Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript, resulting in progressive neuromuscular degeneration and high rates of mortality. Through a chemical screen targeting the correction of dysfunctional SMN2 splicing and subsequent optimization, orally available small molecules were identified that shift the balance toward the production of full length SMN2 mRNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, protection of the neuromuscular circuit and eventually to extension of the life span of the mice. The presentation illustrates the development path from identifying molecules in a molecular phenotype screen towards the critical steps in translation and proof of mechanism in a Phase I study.

Pathway Reporter Genes Define Molecular Phenotypes of Human Cells - Application to Compound Screening and Prioritization
Jitao David Zhang, PhD, F. Hoffmann-La Roche Ltd.

The state of a living cell is characterized by its pattern of active signaling networks, giving rise to a “molecular phenotype” associated with gene expression profiles. We apply digital amplicon based sequencing to assess the activity of signaling networks based on a set of established key regulators and expression targets rather than the entire transcriptome. To this purpose we compiled and tested a panel of human pathway reporter genes, representing 154 human signaling and metabolic networks for integrated knowledge- and data-driven understanding of biological processes. The reporter genes are significantly enriched for regulators and effectors covering a wide range of biological processes, and faithfully capture gene-level and pathway-level changes in diverse cell systems. We apply the approach to a novel cellular model of diabetic cardiomyopathy using iPSC-derived cardiomyocytes to describe drug responses in molecular phenotypes. The reporter genes deliver an accurate pathway-centric view of the compounds’ effects. Molecular phenotyping reveals relevant signaling networks as potential targets, detects off-target and side effects of false positive hits, and identifies drugs that preserve cardiomyocyte phenotype in vitro during diabetic stress. We envision molecular phenotyping as a powerful tool for phenotypic drug discovery.

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