Cambridge Healthtech Institute’s 6th Annual

Accelerating Target Discovery

Advanced Genomics, Chemical Biology & Targeted Degradation Technologies

June 2-4, 2020


Finding novel, druggable targets for therapeutic intervention remains a top priority for the pharma/biotech industry. It also remains a formidable challenge, and companies continue to invest a lot of time and resources into identifying and validating targets that will yield viable drugs. What are the current challenges? What new tools and strategies are being developed to address those challenges and how well are they working? What’s being done to adequately deconvolute, validate and prioritize the targets once they are identified? What’s being done to go after difficult or “undruggable” targets? Cambridge Healthtech Institute’s conference on Accelerating Target Discovery will bring together leading experts to discuss some of these critical questions. This is a unique opportunity for biologists and screening experts to come together to share ideas and best practices, and find a way to populate the drug pipeline with novel, well-characterized drug targets.

Final Agenda

Recommended Short Course*

SC5: Chemoproteomics Enabling Drug Discovery

*Separate registration required.

Tuesday, June 2

10:00 am Main Conference Registration Open

EXPLORING GENETICS-BASED TARGET DISCOVERY

11:15 Chairperson’s Remarks

Jason Sheltzer, PhD, Principal Investigator, Cold Spring Harbor Laboratory

11:25 FEATURED PRESENTATION: CRISPR Screening for Target and Off-Target Identification

Jason Sheltzer, PhD, Principal Investigator, Cold Spring Harbor Laboratory

We have recently discovered that many anticancer drugs function through off-target interactions. By deploying a variety of spontaneous and directed mutagenesis approaches, we can identify resistance-granting mutations, and thereby uncover their true targets. Using these techniques, we have recently discovered the first potent and specific inhibitor of the cyclin-dependent kinase, CDK11.

11:55 CASE STUDIES: Using Targeted and Genome-Wide CRISPR Screens for Drug Target and Pathway Analysis

Michael Bassik, PhD, Assistant Professor, Department of Genetics, Stanford University

Studies highlighting the use of both genome-wide, as well as targeted CRISPR screens, for identifying novel potential therapeutic targets in cancer and neurodegenerative diseases will be presented.

12:25 pm Multiscale Network Biology Approach to Identify Novel Targets of Parkinson’s Disease

Bin Zhang, PhD, Professor, Department of Genetics & Genomic Sciences; Director, Mount Sinai Center for Transformative Disease Modeling, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai

Molecular mechanisms underlying idiopathic PD, which account for 80% of the PD cases, remain elusive. We performed multiscale gene network analysis of a large gene expression dataset in the substantia nigra from 83 PD cases and 70 controls and systematically identified and prioritized co-expressed gene modules and key regulators in PD. This study lays down a foundation for developing a comprehensive signaling map and novel therapeutics for PD.

12:55 Transition to Lunch

1:00 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:30 Session Break

CRISPR-BASED TARGET SCREENING

2:00 Chairperson’s Remarks

John Doench, PhD, Director R&D, Genetic Perturbation Platform, Broad Institute of Harvard and MIT

2:05 Deeper, Finer, and Wider with CRISPR Screens for Gene Function

John Doench, PhD, Director R&D, Genetic Perturbation Platform, Broad Institute of Harvard and MIT

Genome-wide CRISPR screens have revitalized functional genomics. Large-scale data sets enable rapid hypothesis generation, and focused screening efforts can provide detailed mechanistic insights into the function of any gene of interest. Here I will discuss how CRISPR screens are being employed in gene function discovery projects, with an emphasis on the latest technological advances.

2:35 In vivo T Cell CRISPR Screen for Immunotherapy Target Discovery

Sidi Chen, PhD, Assistant Professor, Department of Genetics and Systems Biology Institute, Yale University; Member, Yale Cancer Center and the Yale Stem Cell Center

In vivo CRISPR screen is a powerful means for discovering therapeutic targets in physiologically relevant settings. Here we describe recent advancements in in vivo T cell CRISPR screen for immunotherapy target discovery and characterization of example targets.

3:05 Use of in vivo Screening in Target Discovery

Danilo Maddalo, PhD, Lab Head, ONC Pharmacology, Novartis Institutes for BioMedical Research, Novartis Pharma AG

Identification of novel-cell and non-cell autonomous targets has proven challenging as tumor cells display crucial differences in a 2D culture as opposite to an in vivo, 3D setting. To overcome such limitation, the ability to perform in vivo screening is key. I will give a brief overview of the current approaches to perform target identification and validation in in vivo models, their caveats, and the future perspectives.

3:35 Sponsored Presentation (Opportunity Available)

4:05 Networking Refreshment Break and Transition to Keynote


PLENARY KEYNOTE SESSION

4:25 - 6:05 Driving Entrepreneurial Innovation to Accelerate Therapeutic Discoveries

The life sciences community has an unprecedented scientific arsenal to discovery, develop and implement treatments, cures and preventions that enhance human healthcare.

Moderator: Nadeem Sarwar, President, Eisai Center for Genetics Guided Dementia Discovery (G2D2), Eisai Inc.

Panelists: Anthony Philippakis, Chief Data Officer, Broad Institute; Venture Partner, GV

Barbara Sosnowski, Vice President and Global Head, Emerging Science & Innovation Leads, WWRDM, Pfizer

John Hallinan, Chief Business Officer, Massachusetts Biotechnology Council

6:05 Welcome Reception in the Exhibit Hall with Poster Viewing

7:10 Close of Day

Wednesday, June 3

7:30 am Registration Open and Morning Coffee

PROTEOMICS-BASED TARGET DISCOVERY

8:10 Chairperson’s Remarks

Doug Johnson, PhD, Senior Director, Chemical Biology & Proteomics, Biogen

8:15 Application of Chemical Biology Probes and Bioorthogonal Chemistry in Drug Discovery

Doug Johnson, PhD, Senior Director, Chemical Biology & Proteomics, Biogen

This talk will describe examples of how chemical biology probes and bioorthogonal chemistry were used for target identification and engagement, selectivity profiling (off-targets), and mechanism of action studies in drug discovery. Several different types of chemical biology probes were utilized including enzyme class-specific, activity-based probes, cysteine-specific reactivity-based probes, as well as target-specific clickable covalent inhibitor and photoaffinity probes. These probes proved to be invaluable for target discovery.

8:45 Design of Photoaffinity and Electrophilic Probes for Target Identification and Validation

Christopher am Ende, PhD, Senior Principal Scientist, Pfizer Inc.

Photoreactive and electrophilic probes are valuable tools in chemical biology to identify small-molecule/protein interactions. This presentation will compare and evaluate different photoreactive groups and electrophilic compounds in the context of drug discovery programs, with emphasis on target deconvolution, off-target identification, and activity-based protein profiling. Additional focus on the advancement of new sulfur (VI) fluoride probes, the development of a chemical biology toolbox, and synthetic chemistry advancements will also be discussed.

9:15 FEATURED PRESENTATION: Small-Molecule Phenotypic Screening: Biological Tools, Novel Targets or Leads?

Sujatha Gopalakrishnan, PhD, Head, Molecular Screening and Characterization, AbbVie

Phenotypic screens present a unique opportunity to uncover novel biology and discover druggable targets. At AbbVie, a combination of phenotypic and target-based screening strategies is in place to augment our early discovery pipeline. I will highlight recent phenotypic screens conducted using disease-relevant cellular models to identify and validate novel targets and mechanisms of action. Using an integrated approach of cell-based and target-based screening, we successfully progressed these targets to the next step in drug discovery.

9:45 Sponsored Presentation (Opportunity Available)

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

11:00 Uncovering Targets with Potential Cardiotoxicity

Eric Miele, PhD, Team Leader, Proteomics - Chemical Biology, AstraZeneca Pharmaceuticals

Janus Kinase 1 (JAK1) plays an important role in mediating signaling of cytokine family members resulting in downstream activation of STAT3 and STAT1, which have been shown to be oncogenic. A lead JAK1 inhibitor resulted in cardiotoxicity during a 28-day rat study. Using a combination of three label-free techniques, CETSA-MS, KiNativ and Digiwest, showed a convergence towards MAPK proteins. A putative mechanistic pathway has been identified and tested in cardiomyocytes and will be discussed.

11:30 Large-Scale Proteomics Approaches to Enable Degrader Development for Challenging Targets in Cancer

Katherine Donovan, PhD, Scientist, Laboratory of Dr. Eric Fischer, Cancer Biology, Dana-Farber Cancer Institute/Harvard Medical School

Small molecules that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. We and others have demonstrated that efficacious degradation of kinases and other targets can be achieved in vitro and in vivo, however, many targets remain recalcitrant to degradation. In this presentation, I will discuss the use of large-scale chemical proteomics approaches to accelerate the development of degraders as novel chemical probes for kinases and other disease targets.

12:00 pm Presentation to be Announced

12:30 Transition to Lunch

12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:05 Session Break


PLENARY KEYNOTE SESSION

1:45 - 3:15

Lgr5 Stem Cell-Based Organoids in Human Disease

Hans Clevers, MD, CSO, Director of Research, Princess Máxima Center for Pediatric Oncology, University Medical Center Utrecht; Principal Investigator, Hubrecht Institute for Developmental Biology and Stem Cell Research

Systematically Drugging Ras

Stephen Fesik, PhD, Professor of Biochemistry, Pharmacology, and

Chemistry, Orrin H. Ingram II Chair in Cancer Research, Vanderbilt

University School of Medicine

3:15 Refreshment Break in the Exhibit Hall with Poster Viewing

SINGLE-CELL TECHNOLOGIES FOR TARGET DISCOVERY

4:00 Chairperson’s Remarks

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

4:05 Pooled CRISPR Screens with Single-Cell Chromatin Accessibility Profiling

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

Forward genetic screens using CRISPR-associated nucleases are a powerful tool to pinpoint genes involved in disease. Recently, we have combined pooled CRISPR perturbations with single-cell measurements of chromatin accessibility to provide genome-wide, multidimensional phenotypes of altered chromatin. Using this new technology, we perturb chromatin modifiers commonly mutated in tumors and pinpoint specific promoters and enhancers with altered chromatin accessibility across many transcription factor binding sites.

4:35 The State of the Art in Highly Multiplexed Multi-in situ OMICs

Richie Kohman, PhD, Senior Research Scientist and Lead, Synthetic Biology Platform, Wyss Institute for Biologically Inspired Engineering, Harvard University

Biological tissues are immensely complex containing a huge diversity of chemical motifs in specific, three-dimensional locations. Most OMICs techniques, such as single-cell transcriptomics, do not retain the location of the targets they are analyzing. This talk will cover the state of the art in in situ OMICs, where molecules are analyzed within their endogenous environment, providing a crucial insight into the content of healthy and diseased tissues.

5:05 Find Your Table, Meet Your Moderator

5:10 Roundtable Breakout Discussions

TABLE: Leveraging Advanced Genomics Tools for Target Identification

Moderators: Neville Sanjana, PhD, Assistant Professor, Departments of Neuroscience and Physiology, New York University; Faculty, New York Genome Center

Richie Kohman, PhD, Senior Research Scientist and Lead, Synthetic Biology Platform, Wyss Institute for Biologically Inspired Engineering, Harvard University

TABLE: Impact of Chemical Biology and Phenotypic Screening on Drug Discovery

Moderators: Jaimeen Majmudar, PhD, Principal Scientist, Chemical Biology, Pfizer Inc.

Sujatha Gopalakrishnan, PhD, Head, Molecular Screening and Characterization, AbbVie

5:45 Reception in the Exhibit Hall with Poster Viewing

6:45 Close of Day

Thursday, June 4

8:00 am Registration Open and Morning Coffee


PLENARY KEYNOTE SESSION

8:30 - 9:40 Applications of Artificial Intelligence in Drug Discovery – Separating Hype from Utility

Patrick Walters, PhD, Senior Vice President, Computation, Relay Therapeutics

9:40 Coffee Break in the Exhibit Hall with Poster Viewing

EMERGING TOOLS FOR TARGET DECONVOLUTION

10:25 Chairperson’s Remarks

John Brognard, PhD, NIH Stadtman Investigator, Laboratory of Cell and Developmental Signaling, National Cancer Institute, National Institutes of Health

10:30 Quantum Mechanics-Based Deep Learning Drug-Repurpose Screening System

Wenjin Zhou, PhD, Assistant Professor, Department of Computer Science, University of Massachusetts Lowell

Current drug design practice either employs a “blind” drug search for all possible molecules or limits the search to proteins’ 3D structural shape. Using quantum mechanics, we dramatically reduce the search space by computing the electron structure of the protein so as to gain information on the active binding sites and atoms. We then provide a deep learning-based drug screening system that can repurpose existing Food and Drug Administration (FDA)-approved drugs. We will demonstrate our initial success.

11:00 Gating and Drug Modulation in 5-HT3A Receptor: Insights from Cryo-EM

Sandip Basak, PhD, Postdoctoral Fellow, Laboratory of Dr. Sudha Chakrapani, Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University

Serotonin receptor (5-HT3R) is a pentameric ligand gated ion channel and a common therapeutic target to manage nausea/vomiting during cancer therapies and for treating irritable bowel syndrome. To develop newer drugs, detailed molecular understanding of the gating mechanism and inhibition is important. We have solved the apo-, two serotonin-, and antagonists-bound structures of the full-length 5-HT3AR in distinct conformations using cryo-EM that reveal the mechanism underlying channel activation and inhibition.

11:30 Mining the Unexplored Cancer Kinome for Novel Therapeutic Targets in Squamous Cell Carcinomas

John Brognard, PhD, NIH Stadtman Investigator, Laboratory of Cell and Developmental Signaling, National Cancer Institute, National Institutes of Health

This presentation aims to identify new therapeutic targets for intervention in head and neck cancers and lung squamous cell carcinomas. The presentation will also include the synthesis of new molecules targeting novel activated drivers in squamous cell carcinomas.

12:00 pm Sponsored Presentation (Opportunity Available)

12:30 Transition to Lunch

12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:05 Dessert and Coffee Break in the Exhibit Hall with Poster Viewing

OPTIMIZING & ENGINEERING TARGETED DEGRADATION

2:00 Chairperson’s Remarks

Joe Patel, PhD, Director, Biochemistry, Biophysics & Crystallography, C4 Therapeutics, Inc.

2:05 Finding a Way Out of the Labyrinth: Degrader-Induced Ternary Complex Modelling

Joe Patel, PhD, Director, Biochemistry, Biophysics & Crystallography, C4 Therapeutics, Inc.

With targeted protein degraders come significant challenges in structural biology and computational modelling. Numerous examples now exist in the literature of the exquisite SAR possible through modifications in the “linker” regions of these molecules and this has driven a need to generate atomic-level ternary complex information to assist degrader design and elucidate mechanism of action. Here we will present our approach combining biophysical and computational methods to generate weighted models to support medicinal chemistry.

2:35 FEATURED PRESENTATION: Discovery of Novel Degraders Targeting Oncogenic Proteins

Jian Jin, PhD, Mount Sinai Endowed Professor in Therapeutics Discovery; Professor, Department of Pharmacological Sciences and Department of Oncological Sciences; Director, Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai

The Jian Jin Laboratory at Mount Sinai is a leader in developing novel small-molecule degraders targeting oncogenic proteins. Our recent progress in this area, including discovery of first-in-class EZH2 and MEK1/2 selective degraders, will be presented.

3:05 Immunotherapeutic Approaches for Degrading Tau Pathology in Alzheimer’s Disease

Gilbert Gallardo, PhD, Assistant Professor, Hope Center for Neurological Disorders, Washington University School of Medicine

Alzheimer’s disease is a tauopathy with no disease-modifying treatments currently available. However, an emerging therapeutic approach is anti-tau immunotherapies. While conventional immunotherapies are promising, they are limited to targeting extracellular proteins, whereas the majority of pathological tau remain in the cytosol of cells. Therefore, we have engineered anti-tau intrabodies for expression intracellularly that contain distinct tags to shuttle tau to either the proteasome or lysosome for degradation.

3:35 Close of Conference

* The program is subject to change without notice, due to unforeseen reason.

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June 2-4

Accelerating Target Discovery

Expanding Chemical & Druggable Space

New Small Molecule Drug Targets

Emerging Indications and Modalities

Immuno-Oncology Advances

Disease Modeling

Preclinical Strategies, Models & Tools in Oncology

Advances in Drug Metabolism & Safety Testing

Immuno-Oncology Biomarkers

Clinical and Translational Biomarkers

AI for Drug Discovery and Development

June 3-4

Drug Discovery Technologies