Finding novel, druggable targets for therapeutic intervention remains a top priority for the pharma/biotech industry, especially when it comes to building a robust drug discovery pipeline. It also remains a formidable challenge and companies continue to invest a lot of time and resources in identifying and validating good drug targets to pursue. What are the challenges in target discovery? What tools and strategies are being used and how well are they working? What’s being done to ensure that validated targets lead to better and safer therapies? Cambridge Healthtech Institute’s conference on Target Identification and Validation will bring together leading experts to discuss some of these critical questions. The conference will help attendees meet and interact with experts and peers from around the world to share ideas and hear about new strategies and technologies helping target discovery.

Part 2: Focus on Chemical Biology and Phenotypic Screening

This part of the Target Identification and Validation conference will describe how phenotypic screening and chemical biology can be used to find new drug targets, validate existing targets for new indications, and better understand how inhibiting or activating these targets could impact other cellular pathways.

Final Agenda


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Thursday, September 27

11:50 am Conference Registration Open


12:20 pm Plenary Keynote Program

2:00 Refreshment Break in the Exhibit Hall with Poster Viewing

Exploring Various Assays & Platforms For High-Throughput Screening

2:45 Welcome Remarks

Tanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute

2:50 Chairperson’s Opening Remarks

James Inglese, PhD, Head, Assay Development & Screening Technologies, National Center for Advancing Translational Sciences, NIH

2:55 Strategies for the Development of Quantitative HTS Assays Targeting Rare Diseases

James Inglese, PhD, Head, Assay Development & Screening Technologies, National Center for Advancing Translational Sciences, NIH

Phenotypic assays enabled by genome editing in combination with novel reporter gene and high content imaging technology were integrated to create quantitative HTS assays. The assays were designed to target pathophysiology arising from gene duplication, haploinsufficiency, defective organelle biogenesis or genes with implied protective properties, associated with CMT, Dravet syndrome, Parkinson’s and more. Our goal was to identify transcriptional and post-translationally active pharmacological agents acting by a variety of mechanisms, including chromatin co-regulators accessible by our assay.

3:25 Comprehensive Proteomics Characterization of a Selective Cyclin-Dependent Kinase Inhibitor

J. Adam Hendricks, PhD, Associate Principal Scientist, Discovery Biology, Discovery Sciences, IMED Biotech Unit, AstraZeneca

We describe a comprehensive characterization of a cyclin-dependent kinase inhibitor using a combination of affinity enrichment-based chemoproteomics and thermal proteome profiling strategies. Application of these orthogonal approaches enabled “static and dynamic” proteome characterization of a CDK9 inhibitor. This case study highlights the advantages and limitations of different proteomics readouts and their applications in drug discovery toward understanding the mechanism of action of clinical candidates.

3:55 Presentation to be Announced


4:10 ZeCardio: A Zebrafish-Based Screening Platform for Genetic Association Studies in Cardiovascular Disease

Vincenzo Di Donato, PhD, Project Manager, Genome Editing Platform, ZeClinics

The advent of CRISPR/Cas9 methodologies has greatly expanded the possibilities of in vivo target identification and validation. However, the generation of knockout animal models is a low-throughput and time-consuming process. Here, we will present a zebrafish-based mutagenesis platform allowing high-throughput phenotypical validation of candidate genes readily in the F0 generation.

4:25 Refreshment Break in the Exhibit Hall with Poster Viewing

Building Physiologically Relevant Models

5:00 Development of a Biologically Intelligent High-Throughput Assay Platform for Phenotypic Screening - Redefining the Screening Toolbox

Madhu Lal-Nag, PhD, Team Leader, RNAi Screening, National Center for Advancing Translational Sciences, National Institutes of Health

Developing physiologically relevant assays with predictive, measurable phenotypic end points has been the pain point for high-throughput screening in drug discovery. Here we describe the development of a platform of physiologically relevant screenable phenotypes and biologically intuitive analysis algorithms that capture and define these phenotypes in a physiologically relevant context. This also encompasses the development of a biologist’s toolbox designed to target a majority of diverse biological phenotypes.

5:30 Patient-Derived Xenograft-Derived ex vivo (PDXEx) Model for Evaluation of Tumor-Specific Therapies

Geoffrey Bartholomeusz, PhD, Associate Professor and Director, Target Identification and Validation Program, Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center

We have developed a PDXEx model that closely replicates the tissue architecture of the original tumor and has a gene expression profile showing a high degree of correlation to that of the original tumor. Our model has great application as a screening platform exhibiting a high predictive value in identifying effective tumor-specific therapies in a resource-, time-, and cost-efficient manner.

6:00 Building Precision in vivo Models Using CRISPR-Based Editing

Lukas Dow, PhD, Assistant Professor of Biochemistry in Medicine, Department of Medicine, Hematology and Medical Oncology, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine

The development of animal models that precisely reflect the genetic changes that occur in human tumors is a key step in developing immunocompetent preclinical models. I will discuss our efforts using CRISPR to engineer both large chromosomal rearrangements and single nucleotide variants (SNVs) in animal models, to understand the impact of defined genetic changes on tumor initiation, progression and therapy response.

6:30 Dinner Short Course Registration

9:30 Close of Day

Friday, September 28

7:00 am Registration Open

7:30 Interactive Breakfast Breakout Discussion Groups

Grab a cup of coffee and join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are available on the conference website.

Phenotypic Screening For Target Discovery And Mechanism-Of-Action Studies

8:30 Chairperson’s Remarks

Neville Sanjana, PhD, Assistant Professor, Departments of Biology, Neuroscience and Physiology, New York University; Core Faculty Member, New York Genome Center

8:35 Hit Triage and Validation for Phenotypic Screening: Considerations and Strategies

Fabien Vincent, PhD, Associate Research Fellow, Hit Discovery and Lead Profiling Group, Pfizer

Phenotypic screening is a validated approach to identify novel therapeutic targets. However, significant differences exist between target-based and phenotypic screening, prompting a need to re-assess our strategies and processes to most effectively prosecute phenotypic projects. The hit triage and validation process was critically re-evaluated in light of the unique characteristics of phenotypic screening. Key considerations and specific strategies will be shared and illustrated by in house and literature examples.

9:05 Understanding the Mechanism of Kinase Inhibitors

Lyn Jones, PhD, Vice President, Chemistry and Chemical Biology, Jnana Therapeutics

Advances in the development of chemoproteomic profiling technologies are enabling a deeper understanding of the selectivity and hence mechanism of action of small molecule kinase inhibitors. Additionally, many ATP-site binders have been found to degrade their cognate target kinases. The drug discovery impact of kinase profiling and MoA studies will be presented.

9:35 Chemo-Genomic Screening in AML: A New Approach to Identify Therapeutic Strategies

Anne Marinier, PhD, Principal Investigator and Director of Medicinal Chemistry, IRIC and Associate Professor, Department of Chemistry, Université de Montréal

Capitalizing on new leukemia stem cell culture conditions, we developed a chemo-genomic screening approach using genetically and clinically characterized acute myeloid leukemia (AML) specimens and a structurally diverse compound collection. Clustering of hits demonstrating similar specimen inhibition patterns generated CCCs (Compound Correlation Clusters) which reveal sensitized target pathways essential to tumor survival. The CCCs’ therapeutic relevance will be exemplified by the identification of a novel target for poor prognosis AML.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

10:45 Phenotypic High-Content Approach to Identify Novel Targets of Autophagy

Stephen Walker, PhD, Senior Research Scientist III, High Throughput Screening, AbbVie

We have established various phenotypic screening approaches and conducted small molecule screens for diverse indications using physiologically relevant disease models. This presentation will highlight the workflow performed for a screen combining autophagy specific cellular models with high content multi-parametric analysis to identify autophagic regulators for clearance of accumulated proteins. Hits from a screen utilizing a focused library of annotated compounds are being further characterized in disease-specific models and prioritized for target identification.

11:15 Identification of Essential Genes for Cancer Immunotherapy Using High-Throughput Genome Engineering

Neville Sanjana, PhD, Assistant Professor, Departments of Biology, Neuroscience and Physiology, New York University; Core Faculty Member, New York Genome Center

We have developed two-cell type whole-genome CRISPR screens to dissect the complex interactions between tumor cells and primary immune cells in cancer immunotherapy. Using primary human cytotoxic T cells, we identify loss-of-function mutations genome-wide that drive resistance to immunotherapy with transgenic TCR T cells and validate several novel immunotherapy resistance mechanisms across different melanomas, cancers, and antigens (in collaboration with N. Restifo’s, National Cancer Institute).

11:45 Sponsored Presentation (Opportunity Available)

12:15 pm Session Break

12:25 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

Case Studies On How To Deconvolute Existing Targets & Tackle Challenging Ones

1:55 Chairperson’s Remarks

Paul Brennan, PhD, Associate Professor, Medicinal Chemistry, University of Oxford; Principal Investigator, Target Discovery Institute, Structural Genomics Consortium

2:00 Chemical Probes in Target Discovery

Paul Brennan, PhD, Associate Professor, Medicinal Chemistry, University of Oxford; Principal Investigator, Target Discovery Institute, Structural Genomics Consortium

Chemical probes are selective small molecule inhibitors that can be used in cellular assays to induce a phenotype and link it to a small set of protein targets. Chemical probes have been developed for many bromodomains, the principal epigenetic readers of histone lysine acetylation, and been used to decipher the biology of bromodomains in cancer and inflammation. We are current developing chemical probes for new protein families.

2:30 Target Validation in the IL17 Signaling Pathway: Challenges and Opportunities

Alex Lipovsky, PhD, Senior Scientist, Foundational Immunology, AbbVie

3:00 Small Molecule Modulators of Conformationally Dynamic Protein Targets

Evripidis (Evris) Gavathiotis, PhD, Associate Professor, Department of Biochemistry and Medicine, Albert Einstein College of Medicine

My presentation will discuss approaches for targeting two conformationally dynamic protein targets that critically control cell death and cell survival pathways converging at the mitochondria. Validation of novel targets and mechanisms go hand-in-hand with the discovery of small molecules. Structure-based drug design, biochemical, cell-based and in vivo proof-of-concept studies provided lead compounds and insights on modulating dynamic protein targets.

3:30 Small Molecule Modulators of Inflammation

Sinu John, PhD, Staff Scientist, Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Recent studies have shown that a macrophage-driven inflammatory signature is common to a large majority of the diseases. We have developed a TNF reporter assay that can be used to identify small molecule modulators of the human macrophage inflammatory response. We have conducted a screen of biologically active small molecules and identified several compounds that have substantial modulatory effects on the TNF response. In validation studies, we find that these molecules can be grouped into classes with both negative and positive effects on the inflammatory response, with therapeutic potential.

4:00 Close of Conference

Come early to attend -

Part 1: Focus on Functional Genomics & Computational Screening

This part of the Target Identification & Validation conference will highlight some of the existing and emerging functional genomics, artificial intelligence and machine learning tools that are being used for generating novel drug targets. The use of such tools and screens for validating existing targets or associating them with new disease indications will also be discussed.