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.
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Thursday, September 27
11:50 am Conference Registration Open (Foyer)
12:20 pm Plenary Keynote Program (Constitution Ballroom)
2:00 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)
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
3:55Preclinical Strategies for Evaluating Treatment Efficacy to Prevent or Cure Auditory Disorders
Sylvie Cosnier-Pucheu, CSO, CILcare
No effective treatment exists to cure hearing loss (affecting 360 million persons worldwide) and tinnitus (which affects around 10–15% of the general population). This presentation provides an overview of current animal models of hearing disorders
and potential targets for new therapies.
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 (Grand Ballroom)
5:00 A Membranome cDNA Library for Biologics Discovery and Phenotypic Screening
Xi Ai, PhD, Associate Principal Scientist, Screening & Compound Profiling, Merck Research
About 20-30% of all proteins are membrane proteins, which accounts for over 50% of marketed drug targets. We have established a human membranome cDNA library consisting of 2900 membrane protein genes and developed a live-cell assay for screening. The
library will enable us to study novel cell surface receptor/ligand interaction for early target identification and cell surface receptor de-orphanization, as well as antibody specificity profiling.
5:30 Novel Targets and Compounds for Lung Fibrosis: Screening for Genes and Compounds that Control Fibroblast YAP/TAZ Activation
Daniela M. Santos, PhD, Postdoctoral Fellow, Division of Pulmonary and Critical Care Medicine, The Andrew M. Tager Fibrosis Research Center and Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital and
Harvard Medical School
Idiopathic Pulmonary Fibrosis is a lethal disease driven by pathological fibroblast accumulation and differentiation. Recent evidence indicates that transcription co-activators YAP and TAZ integrate the chemical and mechanical signals that activate fibroblasts.
We designed a small molecule and siRNA screen to identify YAP inhibitors and new pathways controlling YAP activation in human fibroblasts. The resulting hits may lead to the development of novel anti-fibrotic therapies.
6:00 Building Precision in vivo Models Using CRISPR-Based Editing
Maria Paz Zafra Martin, PhD, Postdoctoral Fellow, 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 (Foyer)
9:30 Close of Day
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Friday, September 28
7:00 am Registration Open (Foyer)
7:30 Interactive Breakfast Breakout Discussion Groups - View Details
Room: Constitution B
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.
Table 15: Chemical Biology Approaches for Target ID and Target Discovery
Moderators: Doug Johnson, PhD, Director, Chemical Biology & Proteomics, Biogen
Jaimeen Majmudar, PhD, Senior Scientist, Chemical Biology, Pfizer, Inc.
- Chemical biology approaches as an avenue for new targets
- Chemo-proteomics approaches to understand protein degradation
- Covalent fragment screening for the coupled discovery of targets and leads
- How can chemical biology approaches complement CRISPR-based technologies?
8:30 Chairperson’s Remarks
Fabien Vincent, PhD, Associate Research Fellow, Hit Discovery and Lead Profiling Group, Pfizer
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
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 (Grand Ballroom)
10:45 Phenotypic High-Content Approach to Identify Novel Targets of Autophagy
Stephen Walker, PhD, Senior Research Scientist III, High Throughput
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 Computational Methods to Help Find Chemical Matter to Uncover Novel Biology
Yuan Wang, PhD,
Investigator III, Data Science, Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research
To explore new targets and biology, phenotypic screens are increasingly utilized in drug discovery. Potent and selective chemical tool compounds against well-defined targets can be used as probes in diseaserelevant phenotypes. In Novartis we have
designed an evidence-based metric to systematically rank tool compounds and collected over 4000 compounds (“MOAbox”) to connect targets with novel biology. We are also exploring algorithms that can connect previously un-drugged targets
to known ones.
12:15 pm Session Break
12:25 Enjoy Lunch on Your Own
1:15 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)
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
The IL23/IL17 signaling axis plays a key role in the pathophysiology of psoriasis. We conducted a small molecule and a CRISPR screen in primary human keratinocytes to identify druggable targets in the IL17 signaling pathway. I will discuss functional
genomics approaches, technology platforms, and target validation strategies to confirm and prioritize screen hits. Examples of successful gene perturbation in primary cells with CRISPR RNPs and RNAi will be highlighted.
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
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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.