Target identification leading to novel, druggable targets for therapeutic intervention remains a top priority for the pharma/biotech industry when it comes to building a robust drug discovery pipeline. It also remains a formidable challenge and companies continue to invest a lot of resources in finding and validating good drug targets. Where are the challenges when it comes to identifying and validating targets? What tools and strategies are being used and how well are they working? What’s being done once targets are validated that will lead to better and safer therapies? Cambridge Healthtech Institute’s Inaugural conference on Target Identification Strategies will bring together leading experts to highlight the key developments in this field. This conference will help attendees network with experts and peers from around the world to share ideas and hear about new approaches for target identification that they can implement in their labs.

Final Agenda

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Wednesday, September 27

11:50 am Conference Registration Open

12:35 pm Plenary Keynote Program

(click here for details)

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

Using CRISPR and RNAi Screens for Target Identification & Validation

2:45 Welcome Remarks

Tanuja Koppal, Ph.D., Conference Director, Cambridge Healthtech Institute

2:50 Chairperson’s Opening Remarks

John Feder, Ph.D., Associate Director of Genome Biology and Emerging Technologies, Department of Genetically Defined Diseases and Genomics, Bristol-Myers Squibb

2:55 Development and Optimization of CRISPR Gene Editing for Drug Discovery Applications

John Feder, Ph.D., Associate Director of Genome Biology and Emerging Technologies, Department of Genetically Defined Diseases and Genomics, Bristol-Myers Squibb

The integration of CRISPR genome engineering into the drug discovery process is well underway. Examples will be presented as to how CRISPR is being used to address many of the issues that have traditionally stymied drug development. Data and learnings will also be shared from our recent efforts to improve the methods for CRISPR-based homology directed repair gene editing.

3:25 High-Throughput CRISPR-Based Approaches to Cancer Target Identification

Stephanie Mohr, Ph.D., Lecturer, Genetics & Director, Drosophila RNAi Screening Center at Harvard Medical School

Drosophila research has pioneered advances in cancer-related research, including identification of hedgehog and hippo signaling pathways. A new generation of fly studies seamlessly moves from work in the fly to mammalian systems. We use CRISPR knockout and activation to model cancers and identify new therapeutic strategies. Through this work, we are able to identify synthetic lethal interactions that can be recapitulated in mammalian cancer cells.

3:55 Ultra-Sensitive Targeted RNA Expression Profiling: DriverMap Human Genome-Wide Gene Expression Profiling Assay

Paul Diehl, Ph.D., COO, Cellecta

The DriverMap assay’s unparalleled specificity and sensitivity results in greatly enhanced detection of low- and medium- abundance mRNA transcripts as well as an improved cost-effectiveness for high-throughput research applications.

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

5:00 Combinatorial Omics: Leveraging Genomic-Phenomic Modulation for the Interpretation of Large Scale Screens

Arvind Rao, Ph.D., Assistant Professor, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center

In this talk, we will draw on studies from drug screening and RNAi to describe data mining workflows to go from phenotypic measurements to biological insight. The availability of modern bioinformatics tools and multiple public databases make for very interesting investigations in multimodal data integration. Our goal will be to present a view of what’s possible, using case studies from RNAi screening in triple negative breast cancer, and drug screening in glioblastoma.

5:30 CRISPR vs. RNA Interference for the Discovery of Cancer Genetic Dependencies

Jason Sheltzer, Ph.D., Principal Investigator, Cold Spring Harbor Laboratory

To date, many genetic dependencies in cancer have been discovered using RNAi. While RNAi is modular, reversible, and generally insensitive to gene copy number, it is also susceptible to off-target interactions. In several instances, CRISPR/Cas9-mutagenesis fails to recapitulate genetic dependencies previously discovered using RNAi. For example, MELK a putative breast cancer dependency identified via RNAi screening can be mutated with CRISPR without any apparent fitness defect. We discuss the advantages and disadvantages of both in the light of these results.

6:00 RNAi Screens for Identifying Kinases That Mediate Tumor Resistance to T Cell Attack

Tillmann Michels, Ph.D., Head of Research Group Immune Checkpoint Inhibitors, Laboratory of Prof. Philipp Beckhove, Regensburg Center for Interventional Immunology

Effector molecules of T cell attack against tumors not only fail to induce tumor death at low concentrations (or effector-to-target ratios) but induce tumor proliferation. Using high throughput RNAi screens, we identified kinases that shift effector molecule induced signaling form apoptosis to survival. These kinases are optimal targets to increase the clinical benefits of immunotherapy.

6:30 Close of Day

6:30 Dinner Short Course Registration

Click here for details on short courses offered.

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Thursday, September 28

7:30 am Registration Open

8:00 Interactive Breakout Discussion Groups with Continental Breakfast

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 below. Please click here for full details on all breakouts.

Exploiting the Complementarity of CRISPR and RNAi

Moderator: Stephanie Mohr, Ph.D., Lecturer, Genetics & Director of the Drosophila RNAi Screening Center, Harvard Medical School

• Use of CRISPR v/s RNAi
• Understanding inherent limitations and need for using complementary techniques for validation
• Examples of how both techniques have been put to good use

Advances in Chemical Biology and Phenotypic Screening for Target Discovery

Moderators: Jeff Piotrowski, Ph.D., Principal Scientist, Target Identification, Yumanity Therapeutics 

Jaimeen Majmudar, Ph.D., Senior Scientist, Chemical Biology, Pfizer Inc.

• What is covered and what is missing when accessing available target space?
• Latest breakthroughs in on- and off-target identification
• Avoiding potential pitfalls in target identification
• Chemoproteomics and its utility in target ID/validation
• CETSA-Proteomics: Leveraging the power of thermal melting for target ID
• Latest advances in MS-proteomics applicable to drug-discovery
   

Phenotypic Screening & Chemical Biology Tools

9:00 Chairperson’s Remarks

Gregory A. Michaud, Ph.D., Chemical Biology and Therapeutics (CBT), Novartis Institutes for BioMedical Research, Inc.

9:05 Target Identification Using Chemogenomic and Reactivity-Based Screening

Lyn Jones, Ph.D., Vice President, Chemical Biology, Jnana Therapeutics

Target identification continues to be a resource intensive endeavor that often fails. The value of chemogenomic screening as a technology that can expedite the discovery of therapeutically relevant targets from phenotypic assays will be presented. New developments in protein labeling chemistry with applications to chemoproteomic profiling and molecular pathology studies will also be described.

9:35 A Small Molecule Inhibitor of C5 Complement Protein

Gregory A. Michaud, Ph.D., Chemical Biology and Therapeutics (CBT), Novartis Institutes for BioMedical Research, Inc.

The complement pathway is an important part of the immune system, and uncontrolled activation is implicated in many diseases. The human complement component 5 protein (C5) is a validated drug target within the complement pathway, as an anti-C5 antibody (Soliris) is an approved therapy for paroxysmal nocturnal hemoglobinuria (PNH). Compound 7l (Zhang et al, ACS Med. Chem. Lett., 2012), was recently reported as an inhibitor of the complement pathway, but its molecular target was not identified. Here we report that human C5 is the target for Compound 7I.

10:05 Whole-Genome siRNA Screen Identifying Novel Targets of the TGFβ Pathway

Chris Kitson, Ph.D., Principal Scientist, Fibrosis Biology Discovery, Bristol-Myers Squibb

Transfection of a genome-wide siRNA library into normal human lung fibroblasts enabled identification of novel targets from the TGFβ pathway, using high-content analysis to measure the degree of cellular differentiation. Hits were retested in multiple donors, with additional reagents, and triaged through a series of filters. Targets from the screen are supporting our early fibrosis portfolio.

10:35 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

11:20 Functional Annotation of Biological Processes Targeted by Chemical Libraries

Jeff Piotrowski, Ph.D., Principal Scientist, Target Identification, Yumanity Therapeutics

To characterize the functional diversity of large compound libraries, we developed a highly parallel and unbiased yeast chemical-genetic screening system and screened 7 diverse compound libraries. Our analysis shows that we can visualize the functional diversity of each library, prioritize subsets of compounds that target specific biological processes, globally validate targeted processes, and identify compounds targeting multiple processes. With spontaneous mutant analysis, we can link compounds to targets in yeast, and translate to mammalian orthologs.

11:50 Interrogating the Plasma Membrane Proteome for New Targets

Shaun M. McLoughlin, Ph.D., Senior Research Scientist III, Target Identification and Validation Technologies, AbbVie

Surface proteins play an integral role in the progression of cellular pathology. Consequently, these proteins have been exploited for the development of pharmaceutical therapies. Despite its importance, the surface proteome has remained largely uncharacterized owing to significant analytical challenges, low protein copy number and rapid target degradation. This discussion will detail traditional and modern techniques for plasma membrane protein extraction and their application to models of cancer resistance.

12:20 pm How IBM Watson Health Helps Accelerate Life Sciences Research

Alix Lacoste, Ph.D., Lead Technical Solution Specialist, Watson Health for Life Sciences, IBM

IBM Watson's talk, entitled "How IBM Watson Health Helps Accelerate Life Sciences Research" will provide an overview of Watson Health, and demonstrate how Watson for Drug Discovery has helped researchers at Barrow Neurological Institute / ALS and Ontario Brain Institute / Parkinson's discover novel research targets. Watson for Drug Discovery can accelerate the drug discovery process by helping researchers uncover patterns and signals hidden in data to make non-obvious and orthogonal connections.

12:50 Session Break

1:00 New Approaches to Target Identification

Richard K. Harrison, Ph.D., CSO, Clarivate Analytics

Discovering new drugs and getting them to market is one of the most challenging endeavors in industrial R&D. Less than 1-in-10 compounds that enter clinical trials becomes a medicine. Target Identification is arguably the most important step in the drug discovery process. This talk will highlight the use of omic and pathway based analysis for identification of new targets and the use of new analytical tools to rapidly triage targets to identify the most promising.

1:50 Refreshment Break in the Exhibit Hall with Poster Viewing

Innovative Approaches for Finding Novel Targets

2:35 Chairperson’s Remarks

Doug Johnson, Ph.D., Research Fellow, Chemical Biology Group, Pfizer Worldwide Research & Development

2:40 Chemoproteomic Profiling with Clickable Photoaffinity Probes for Target ID and Mechanism of Action Studies

Doug Johnson, Ph.D., Research Fellow, Chemical Biology Group, Pfizer Worldwide Research & Development

This talk will describe how we used clickable photoaffinity probes for target identification/validation in live cells for two secretase projects relevant to Alzheimer’s Disease.  In the first example, we used γ-secretase modulator (GSM) and inhibitor (GSI) photoaffinity probes to determine the target and in one case the binding site within the γ-secretase complex.  In the second example, we generated a clickable photoprobe analog of a Pfizer BACE1 inhibitor that exhibited ocular toxicity in rats and found that the photoprobe labeled the off-target Cathepsin D in RPE cells.

3:10 Target Identification Strategies for Dermatological Indications

Deepak Kumar Rajpal, Ph.D., Director, Computational Biology, GlaxoSmithKline

We plan to share a framework for developing new therapeutic intervention strategies for psoriasis by computational approaches and utilizing publicly available clinical transcriptomics data sets. We share a proposed a psoriasis disease signature, present approaches to identify potential drug repurposing opportunities and outline a novel target selection methodology. We anticipate that methologies shared here or similar approaches will aid in target discovery in dermatological indication space, support biomarker discovery and the development of new drugs.

3:40 Session Break

3:55 A Genome Engineering Approach for Drug Target Identification in Malaria Parasites

 Sumanta Dey, Ph.D., Postdoctoral Associate, Laboratory of Dr. Jacquin C. Niles, Dept. of Biological Engineering, Massachusetts Institute of Technology 

A strategy for rapidly identifying targets for anti-malarial compounds using phenotypic assays is lacking. To address this, we developed a resource of Plasmodium falciparum lines, in which expression of individual target genes can be conditionally modulated. Through implementation of high throughput compound screens on these engineered parasites, we aim to identify novel inhibitors which specifically hit the target proteins to kill the parasites. 

4:25 Target Identification and Assay Validation for the Tox21 HTS Program

Menghang Xia, Ph.D., Leader, Systems Toxicology, Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, NIH

The toxicology in the 21st century (Tox21) program has developed and utilized a quantitative high throughput screening (qHTS) paradigm that has provided a more efficient and cost-effective alternative to traditional tests for profiling the toxicity of environmental chemicals. In this program, approximately 10K environmental chemicals including clinically used drugs have been screened against a panel of biologically relevant cell-based assays. This talk describes the Tox21 program, selection of qHTS-based assays and the various Tox21 screening assays.

4:55 Close of Conference

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