Cambridge Healthtech Institute’s 5th Annual

Target Identification & Phenotypic Screening

Leveraging Functional Genomics, Cellular Assays and Computational Tools

June 19-20, 2019

Identifying novel, druggable targets for therapeutic intervention or probing existing drug targets for new therapeutic indications is a crucial part of the early discovery process. Target-based and phenotypic screening are most commonly used approaches for finding and validating drug targets. How well do these approaches work? What new technologies are being developed? How do you evaluate and decide on which technique or assay to use? Are there ways to screen “hard-to-find” targets? Cambridge Healthtech Institute’s conference on Target Identification & Phenotypic Screening brings together experts from pharma/biotech and academia to address some of these questions and more. It provides a unique networking opportunity for people to interact, share ideas and discuss new strategies and technologies helping target discovery.

Final Agenda

Wednesday, June 19

12:00 pm Registration Open

12:00 Enjoy Lunch on Your Own

12:30 Transition to Plenary


2:20 Booth Crawl and Dessert Break in the Exhibit Hall with Poster Viewing

2:25 Meet the Plenary Keynotes

Harborview 3

3:05 Chairperson’s Remarks

Yuan Wang, PhD, Investigator III, Data Science, Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research

3:10 Hit Triage and Validation for Phenotypic Screening: Considerations and Strategies

Fabien_VincentFabien 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 is 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.

3:40 CASE STUDY: Phenotypic Screen for Alzheimer’s Disease: From Compounds to Novel Pathways

Nava Krishnan, PhD, Senior Scientist, Molecular Screening and Characterization, AbbVie Inc.

At AbbVie, several assay platforms have been established for phenotypic screening using physiologically relevant disease models for diverse indications. This presentation will highlight the workflow performed to screen and evaluate therapeutic candidates for Alzheimer’s disease (AD). Hits from a screen utilizing a focused library of annotated compounds are being further characterized in disease specific models and prioritized for target identification.

4:10 Frequent Hitters in Phenotypic Screens and Where to Find Them

Wang_YuanYuan Wang, PhD, Investigator III, Data Science, Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research

Phenotypic screens are increasingly employed in drug discovery both for lead and tool compound finding. The use of potent and selective chemical tools (probes) in phenotypic screens can help understand underlying biological processes. For this purpose, we have designed the Novartis MOA box and used it to deconvolute targets. Furthermore, we have also computationally identified promiscuous compounds and promiscuous targets in internal and external phenotypic screens.

LipoType 4:40 Shotgun Lipidomics: Gateway to Drug Discovery and Design

Klose_ChristianChristian Klose, PhD, Head of Research and Development, Lipotype GmbH

Quantitative shotgun lipidomics offers unique capacities for drug discovery, mode-of-action studies, target validation, biomarker identification and clinical screenings. We explain the mass spectrometry-based technology and feature scientific novelties in lipidomics and lipidomics-associated multiomics of 2019 to highlight current impacts and future implications.

5:10 4th of July Celebration in the Exhibit Hall with Poster Viewing

5:30-5:45 Speed Networking: Oncology

6:05 Close of Day

5:45 Dinner Short Course Registration

6:15 Dinner Short Course*

*Separate registration required.

Thursday, June 20

7:15 am Registration Open

7:15 Breakout Discussion Groups with Continental Breakfast

Harborview 3

8:10 Chairperson’s Remarks

John Doench, PhD, Associate Director, Genetic Perturbation Platform, Broad Institute of Harvard and MIT

8:15 Application of CRISPR Technology to in vivo Models of Cancer Immunotherapy

Doench_JohnJohn Doench, PhD, Associate Director, Genetic Perturbation Platform, Broad Institute of Harvard and MIT

CRISPR screens have become the method of choice for large-scale assessment of gene function, but implementation in complex model systems remains a significant challenge. Here I will present the optimization of mouse models to discover modulators of tumor immunotherapy. Combinatorial screens present similar challenges and will also be discussed.

8:45 Large Scale Proteomics Approaches to Accelerate Degrader Development

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

Targeted protein degradation utilizing the Ubiquitin Proteasome System has emerged as a promising strategy for drug discovery. Small molecules like molecular glues and PROTACs can hijack E3 ligases to induce ubiquitin-mediated degradation of neo-substrates. To aid discovery and development of novel degraders, effective tools for proteome-wide monitoring of degrader targets and off-targets are necessary. We will present strategies for target identification and mode-of-action deconvolution centered on multiplexed shotgun proteomics.

9:15 From Co-Culture with Non-Cancerous Cells to the Production of Macrotumors: New Horizons for the Targeted Development of Anti-Cancer Therapy

lelievre_sophieSophie Lelievre, DVM, PhD, LLM, Professor, Cancer Pharmacology, Purdue University College of Veterinary Medicine

In vitro production of tumors is paramount to improve target identification and drug testing compared to classical monolayer culture. However, the microenvironment ought to be considered to best recapitulate conditions promoting tumor progression and resistance to treatment. Tumor size also matters to reproduce intermittent oxygenation and the proper ratio of tumor and stromal cells. I will present how 3D cell culture might be used for the identification of targets to fight anti-cancer drug resistance.

9:45 ZeGenesis: CRISPR/Cas9 Innovative Zebrafish Platforms for Disease Modelling and Target Validation

De-Santis_FlaviaFlavia De Santis, R&D, Scientist, Scientific department, ZeClinics

Zebrafish is rapidly imposing itself as a powerful model to understand human disease. Recently, the implementation of CRISPR/Cas9-based techniques for targeted gene manipulation enhanced the use of this animal in pharmaceutical research.We have developed ZeGenesis, a platform for the phenotypic characterization of candidate genes potentially involved in a pathological conditions. We present how the use of the zebrafish in the drug-discovery process, can reinforce preclinical studies, allowing reliable disease modeling and fast target validation.

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

10:45 Poster Winner Announced


10:55 Chairperson’s Remarks

Dan Anderson, PhD, Vice President, Biology, Recursion Pharma

11:00 AI and ML approaches to Target Validation

Shruthi Bharadwaj, PhD, Senior Scientist, Novartis Oncology Precision Medicine

Artificial Intelligence (AI) and Machine Learning (ML) tools have been shown to have an increasing influence on how we understand and interpret clinical and genomic data, especially in target validation.  Understanding the limitations as well as the plethora of applications of these approaches is of utmost importance.  I will provide a brief overview of the current AI/ML approaches to target validation, their caveats and future perspectives.

11:15 Targeting the Morphological Impact of Disease: Case Studies from Rare Disease and Mental Disorders

Marzieh Haghighi, PhD, Post-Doctoral Associate, Imaging Platform (Carpenter Lab), Broad Institute of Harvard and MIT

We present a framework for detecting phenotypic changes of cell states using morphological measurements. We explore how to use machine learning (ML) methods to prioritize potential drugs for reverting the changes in morphological phenotypes due to a condition. We show the application on detection of impactful rare disease mutants and on mitochondrial abnormalities in skin cells of a few categories of patients with mental disorders. For both problems, we explore the potential drugs which can reverse the target phenotypes using ML.

11:30 In silico Identification and Validation of Targets through Integrative Analytical Approaches for Different Indications

Johannes M. Freudenberg, Senior Scientific Investigator, Computational Biology, GSK R&D

A plethora of data sources are currently available that provide diverse types of evidence (e.g., genetic association, gene expression, literature mining, animal models, molecular pathways, etc.) which support target-disease associations on a genome-wide scale. Integrating these data sources can facilitate identification and prioritization of potential therapeutic drug targets to treat human diseases. We discuss several use cases and describe our approaches to data integration and hypothesis prioritization and validation.

12:00 Leveraging Phenomics to Accelerate Drug Discovery and Understand Compound Mechanism

Dan Anderson, PhD, Vice President, Biology, Recursion Pharma

The Phenomics platform developed at Recursion provides high dimensional data across a wide array of disease indications. We are leveraging this platform to screen for new therapies in diseases where there is high unmet need. Additionally, we are applying machine learning to our data sets to infer compound mechanism and pharmacology properties. Combined, these predictive methods will accelerate drug discovery and development by de-risking molecules and providing insight into target deconvolution and pathway biology.

PsychoGenics 12:30 Using Machine Learning Approaches to Identify New Treatments for Psychiatric Disorders

Taleen Hanania, PhD, Senior Vice President, Behavioral Pharmacology, PsychoGenics Inc.

PsychoGenics’ has developed a target agnostic platform known as SmartCube® that has led to the discovery of numerous putative treatments for neuropsychiatric disorders including SEP-363856, a novel antipsychotic discovered in partnership with Sunovion, with robust effects across a range of disabling symptoms of schizophrenia.  The presentation will describe the SmartCube® platform, a high content, mouse behavioral/physiological phenotyping platform that offers unique opportunities to reinvigorate the drug discovery process by identifying promising candidate compounds.

1:00 Enjoy Lunch on Your Own

1:35 Dessert and Coffee Break in the Exhibit Hall with Poster Viewing

1:45-2:00 Speed Networking: Last Chance to Meet with Potential Partners and Collaborators!

Cityview 2

2:20 Chairperson’s Remarks

Davide Gianni, PhD, Associate Director, Discovery Sciences, AstraZeneca

2:25 KEYNOTE PRESENTATION: Constructing Tissue Atlases with Massively Multiplexed RNA Imaging

Moffit_JeffreyJeffrey Moffitt, PhD, Assistant Professor, Program in Cellular and Molecular Medicine, Boston Children’s Hospital and Department of Microbiology, Harvard Medical School

Image-based approaches to single-cell transcriptomics are emerging as powerful complements to single-cell RNA sequencing, in part, because these techniques preserve the native spatial context of RNAs within cells and tissues. I will describe multiplexed error robust single-molecule fluorescence in situ hybridization (MERFISH)—a technique capable of imaging thousands of different RNAs simultaneously in fixed cells—and its use for the discovery and mapping of cell types within intact tissues.

2:55 Genome Editing in Stem Cells for Generating Disease Relevant Cellular Models in Drug Discovery

Roudnicky_FilipFilip Roudnicky, PhD, Senior Scientist, pRED, F. Hoffmann-La Roche, Ltd.

Use of genome editing in human pluripotent stem cells (hPSCs) has revolutionized disease-modeling in vitro. However, differentiation to specialized cell types from hPSC in many cases is still not possible. I will show an example of genome editing in hPSCs to facilitate differentiation and also show how genome editing in hPSCs can allow modeling in vitro of severe metabolic genetic diseases (AKT2 loss-of-function or dominant active mutation).

3:25 Application of Genome-Wide Arrayed CRISPRn screening for Target Discovery

Gianni_DavideDavide Gianni, PhD, Associate Director, Discovery Sciences, AstraZeneca

CRISPR technology in an arrayed format holds great potential for rapidly identifying new targets. We have developed an end-to-end arrayed CRISPRn screening platform fully integrated with high content imaging and advanced imaging analytics for target discovery able to screen the whole genome in disease relevant models. Applications of this platform include target discovery, understanding compound mode of action, patient stratification and the identification of novel combination therapies. A number of case studies will be presented.

3:55 CASE STUDY: Identification of the Molecular Target of MTBL0036, a Promising Anti-NASH and Anti-Fibrotic Drug Candidate Selected by a Phenotypic Approach

Baverel_GabrielGabriel Baverel, DVM, PhD, President, Founder and CSO, Metabolys, Inc.

MTBL0036 is a small molecule, orally active with favorable PK characteristics, and safe. It is very efficacious in animal models of NASH and Fibrosis. Its mitochondrial molecular target has been recently identified by combining biochemical information pieces with carbon 13 Nuclear Magnetic Resonance and Bioluminescence Resonance Energy Transfer techniques.

4:25 Close of Conference

Arrive early to attend Tuesday, June 18 - Wednesday, June 19

Chemical Biology and Target Validation

Recommended Short Course

SC6: Targeted Protein Degradation Using PROTACs and Molecular Glues