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Phenotypic screening (aka classical pharmacology) has been historically used in drug discovery. While technological developments have made the prevalence of target-based screening more popular, statistical analysis shows that a disproportionate number of first-in-class drugs with novel mechanisms of action come from phenotypic screening. Cambridge Healthtech Institute’s Inaugural Phenotypic Drug Discovery meeting will address the advantages of phenotypic screening vs. target-based screening, and focus on assay development, selection of physiologically-relevant models and subsequent target identification.

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Monday, October 28

7:30 am Main Conference Registration and Morning Coffee


Advantage of Phenotypic Drug Discovery 

8:15 Chairperson’s Opening Remarks

8:30 The Contribution of Mechanistic Understanding to Phenotypic Screening for First-in-Class Medicines

David C. Swinney, Ph.D., CEO, Institute for Rare and Neglected Diseases Drug Discovery (iRND3)

The level of mechanistic understanding required for drug discovery is a central feature of most strategies. Paradoxically, an understanding of mechanism is not required for regulatory approval. Recent analysis of how medicines were discovered showed that some mechanistic understanding was used to select starting points in the majority of successful phenotypic drug discovery programs. It was concluded that mechanism takes on different connotations depending on context and perspective, and that a target need not be the exclusive definition of mechanism.

8:55 Integrating Novel Technologies to Identify Small Molecules that Drive Translational Research and Therapeutics

Michelle Palmer, Ph.D., Director, Discovery and Preclinical Research,
Broad Institute

9:20 Systematic Repositioning of Drugs Using Phenotypic Screening Data

Mark Hurle, Ph.D., Senior Investigator, Bioinformatics and Computational Biology, GlaxoSmithKline

Computational analysis of phenotypic screening data is often geared toward analysis of results from a single screen, identifying targets via annotation of the compounds hit. Hits are also commonly defined via change in a single measurable. By utilizing large numbers of screens and/or measurables, commonalities between targets and phenotypes can be detected. Two examples will be discussed: Connectivity Map, which utilizes genome-wide expression data, and CRUSH (Compound Repositioning Using Screening Hits), which analyzes high-throughput and focused screening data. These pipelines lead to repositioning of compounds and targets against additional diseases.

9:45 Coffee Break


High-Content Analysis 

10:15 The Role of HCA in Quantitative Systems Pharmacology

Dr TaylorD. Lansing Taylor, Ph.D., Director, University of Pittsburgh Drug Discovery Institute & Allegheny Foundation Professor, Computational and Systems Biology, University of Pittsburgh

We are implementing quantitative systems pharmacology (QSP) as a novel approach to drug discovery and development when combined with phenotypic methods using high-content analysis. We are implementing QSP for understanding the heterogeneity of response within tumors and then developing optimal therapeutics to address this biological complexity. In addition, QSP is being applied to the development and implementation of a 3-D, human biomimetic liver acinus model to be used as an early safety assessment platform to optimize the development of lead compounds.

10:40 High-Content and High-Definition Screenings Identified Stem Cell Regulators

Sheng Ding, Ph.D., William K. Bowes, Jr. Distinguished Investigator, Gladstone Institutes; Professor, Pharmaceutical Chemistry, UCSF

Recent advances in stem cell biology may make possible new approaches for treatment of a number of diseases. A better understanding of molecular mechanisms that control stem cell fate/function as well as an improved ability to manipulate them is required. Toward these goals, we have developed and implemented high-content and high-definition cell-based screens of chemical libraries to identify and further characterize small molecules that can control stem cell fate in various systems. This talk will provide latest examples of discovery efforts in my lab that have advanced our ability and understanding toward controlling stem cell fate.

11:05 A One-Step High-Content Imaging Assay to Monitor Apoptosis and Cell Cycle State in Mammalian Cells

Caroline Shamu, Ph.D., Lecturer, Systems Biology and Director, ICCB-Longwood, Harvard Medical School

We have developed a rapid and convenient high-content cell-imaging assay that measures multiple physiological changes in cells responding to anti-mitotic small-molecule drugs. The no-wash assay uses three dyes to stain living cells and is much more accurate for scoring weakly adherent mitotic and apoptotic cells than conventional antibody-based assays. This assay can help distinguish between alternative mechanisms for drug resistance that are not discriminated by conventional cell survival assays.

11:30 Sponsored Presentations (Opportunities Available. Contact Ilana Quigley at 781-972-5457 or iquigley@healthtech.com.)

DiscovRx12:00 pm Luncheon Presentation:
The BioMAP® Platform of Primary Human Cell Systems for Phenotypic Drug Discovery and Development – Lessons Learned

Ellen L. Berg, Ph.D., General Manager and Scientific Director, BioSeek, a division of DiscoveRx

The BioMAP® platform of primary human cell-based disease models has been used since 2004 by companies, academics and the government to profile small molecules, natural products and biologics. From this experience, we have developed guidelines and best practices for the use of these assays in phenotypic drug discovery. Key applications that will be presented include the use of this platform to identify compounds that are more likely to progress in development and for deconvolution of compound mechanisms of action.

Phenotypic Screening in Physiologically-Relevant Models 

1:30 Chairperson’s Opening Remarks

1:35 Phenotypic Screening and Profiling in Increasingly Physiologically-Relevant Contexts

Anne CarpenterAnne Carpenter, Ph.D., Director, Imaging Platform, Broad Institute

Shantanu Singh, Ph.D., Postdoctoral Researcher, Broad Institute

Our laboratory works with dozens of collaborators worldwide to design and execute large-scale microscopy-based experiments to identify causes and potential cures of disease. Physiologically-relevant model systems are increasingly being used in this work, including co-cultures of two different cell types to better mimic functional tissue and whole organisms such as Caenor habditis elegans to study entire organ systems. Machine-learning approaches, in some cases guided by biologists’ intuition, have been successfully used to measure subtle phenotypes in these complex model systems.

2:00 Expanding the Use of Primary Cell Systems in Hit Identification and Compound Profiling

Steve Ludbrook, Ph.D., Section Head, Screening and Compound Profiling, GlaxoSmithKline

The current focus on translationally-aligned drug discovery approaches, together with significant technology improvements, offers the potential to accelerate the uptake of primary cell screening systems in the drug discovery process. Examples of primary cell systems will be described, encompassing the increased usage of phenotypic assays in specific program critical path activities, but also primary screening activities for hit identification, with the aim of improving translation from the screening plate to the diseased patient.

2:25 Human Induced Pluripotent Stem Cells and Patient Specific Cell-Based Disease Models for Drug Discovery

Anne Bang, Ph.D., Director, Cell Biology, Sanford-Burnham Medical Research Institute

Patient-specific primary cells and human induced pluripotent stem cells (hiPSC) could aid in the development of clinically useful compounds. We used patient cells to develop a phenotypic assay for muscular dystrophy and conducted a high-content screen with the goals of identifying early treatment candidates. In addition, using hiPSC derived neurons, we performed a high-content screen for compounds that modulate neurite growth. We will discuss our high-content screening results and development of hiPSC based models.

2:50 Sponsored Presentation (Opportunity Available. Contact Ilana Quigley at 781-972-5457 or iquigley@healthtech.com.)

3:05 Refreshment Break in the Exhibit Hall with Poster Viewing

4:00 Identifying Cardioprotectants of an Ischemia-Reperfusion Model in iPSC-Derived Cardiomyocytes

Siobhan Malany, Ph.D. Chemical Biology Team Leader, Sanford-Burnham Medical Research Institute

Small molecules that protect cardiac cells from ischemia-reperfusion mediated death would potentially limit heart damage during heart attack. We have developed a 1536-well high-throughput phenotypic acute cell-based model of ischemia and reperfusion injury in human iPSC-derived cardiomyocytes (iCells). Hydrogen peroxide treatment simulates the oxidative stress of reperfusion and 2-deoxy-D-glucose simulates the metabolic stress of ischemia. We screened known drug collections for their ability to protect iCells against cell death in a viability assay to better understand pathways involved.

4:25 HCS to Discover RNA Therapeutics for Heart Failure

Mark MercolaMark Mercola, Ph.D., Professor, Bioengineering, UCSD; Professor and Director, Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute

There is an urgent need for therapies that reverse the course of ventricular dysfunction in heart failure, which is a leading cause of morbidity and mortality. Our research is focused on developing high-content screening assays and instrumentation to discover targets and screen for molecules active in cardiac regeneration and cardiomyocyte contractility. HCS that incorporates static and kinetic (live imaging) endpoints were used to develop a potential RNA therapeutic for heart failure that targets a clinically validated protein and shows efficacy in a mouse model.

5:00 Welcome Reception in the Exhibit Hall with Poster Viewing

6:00-9:00 Dinner Short Course*

SC3: Introduction to High-Content Phenotypic Screening

Instructor: Anthony M. Davies, Ph.D., Director, Irish National Center for High-Content Screening and Analysis (INCHSA)

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*Separate registration required

Day 1 | Day 2Short Courses | Download Brochure | Speaker Biographies