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Advances in the development of high-quality chemical probes, bio-orthogonal techniques, proteomics and quantitative mass spectrometry, in conjunction with improved structural biology and in silico studies, are accelerating target identification, localization and engagement. Yet deconvolution of a molecular entity’s mode of action still represents a significant challenge even starting from the most sophisticated of phenotypic screens. This difficult task can be compounded by interaction with a lesser known and studied target, that falls outside of well characterized gene families. Cambridge Healthtech Institute’s Phenotypic Screening and Chemical Biology conference will bring together drug discovery leaders to discuss these emerging tools and techniques, along with how best to approach the elucidation of drug-target-phenotype relationships even for novel targets.


Final Agenda

Tuesday, June 19

7:30 am Registration Open (America Foyer) and Morning Coffee (Foyer)

ADVANCES IN CHEMOPROTEOMICS
Independence

8:15 Chairperson’s Opening Remarks

Ivan Cornella Taracido, PhD, Vice-President of Chemical Biology and Proteomics, Cedilla Therapeutics

8:20 Application of Clickable Chemical Biology Probes in Drug Discovery

Doug_JohnsonDoug Johnson, PhD, Director, Chemical Biology & Proteomics, Biogen

This talk will describe how we used clickable chemical biology probes for target identification and selectivity profiling for multiple projects in neuroscience drug discovery. For example, we generated clickable probes of covalent inhibitors to evaluate their proteome-wide selectivity. In another example, we used clickable 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. We also generated a clickable photoprobe of a BACE1 inhibitor.

8:50 Chemical Biology Strategies Applied to Drug Discovery: A Case Study on MCT4 Inhibition

Ronald_TomlinsonRonald Tomlinson, Associate Principal Scientist, Discovery Sciences – Chemical Biology, AstraZeneca

Monocarboxylate transporter 4 (MCT4) is a hypoxia regulated lactate transporter, which is upregulated across a range of solid tumors. Inhibition of MCT4 is predicted to result in glycolic shut down and thus MCT4 inhibitors are potential therapeutic agents for the treatment of cancers. We would like to share our discovery of potent inhibitors of MCT4 and the use of chemical biology techniques to confirm target engagement of MCT4.

9:20 New Druggable Targets from Chemoproteomic Space Exploration

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

Advances being made in the development of the chemical biology toolkit to enable the study of previously unchartered areas of chemoproteomic space will be presented. Opportunities to improve chemogenomic coverage using chemical probes will be described.

9:50 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing (America Ballroom)

10:35 Redefining Druggability Using Chemoproteomic Platforms

Daniel_NomuraDaniel K. Nomura, PhD, Professor of Chemistry, University of California, Berkeley

One of the greatest challenges that we face in discovering new disease therapies is that most proteins are considered “undruggable” or difficult to target with small-molecules. Our research group addresses this challenge by applying chemoproteomic platforms to discover and pharmacologically target unique and novel therapeutic druggable hotspots for disease therapy. The talk will provide examples of how we have used these approaches to discover new therapeutic targets and agents for cancer.

11:05 Profiling Structurally Diverse Chemical Matter to Map Proteome-Wide Interactions

Francisco_J_GarciaFrancisco Garcia, PhD, Associate Scientist/Postdoctoral Research Fellow, Chemical Biology and Proteomics, Merck Research Laboratories

Affinity-based chemoproteomics utilizes small molecules as bait, high resolution mass spectrometry, and informatics to establish compound-protein target relationships. Chemoproteomics is routinely applied to characterize drug-target engagement and selectivity for discrete project specific biosamples, though a comprehensive and systematic evaluation of the whole proteome is typically overlooked. We therefore aim to analyze proteome-wide interactions for hundreds of compounds against physiologically relevant human cells and tissue.

11:35 Proteomics as a Biological Assay

Steven GygiSteven Gygi, PhD, Professor of Cell Biology, Harvard Medical School

Mass spectrometry-based proteomics is a powerful tool to study protein function. In this presentation, I will provide an update on sample multiplexing where 11 experiments can be combined and analyzed simultaneously. This allows for complex experimental designs comparing protein expression with replicates from different drug doses or time points. I will also present the latest BioPlex network of protein-protein interactions, spanning more than 2/3 of all human genes.

12:05 Enjoy Lunch on Your Own

DECONVOLUTION OF NOVEL TARGETS
Independence

1:15 Chairperson’s Remarks

Ivan Cornella Taracido, PhD, Vice-President of Chemical Biology and Proteomics, Cedilla Therapeutics

1:20 Selective Stalling of the Human Ribosome by Small-Molecule Engagement of the Ribosome Nascent Chain

Nathanael LintnerNathanael Lintner, PhD, Senior Scientist, Discovery Network Group, Pfizer Inc

A phenotypic screen for small molecule PCSK9 anti secretagogues revealed a class of compounds that bind the ribosome nascent chain complex and selectively inhibit translation of PCSK9. These molecules bind in the ribosome exit tunnel and cause the ribosome to stall during translation of PCSK9. We developed a ribosome profiling computational pipeline to profile the proteome-wide activities of this compound family.

1:50 ADDENDUM Reimagining Drug Discovery through AI

Ron_AlfaRonald Alfa, MD, PhD, Vice President, Discovery & Product, Recursion Pharma

At Recursion, we are augmenting phenotypic screening with artificial intelligence to dramatically improve the power of screens, the pace of discovery, and the ability to prioritize hits in the discovery process. The foundation of our approach is an AI-enabled phenotypic screening platform through which we’ve generated over 700 TB of data to fuel predictive approaches to drug discovery. Here, I will describe applications of our platform across multiple therapeutic areas.

  Cyclica 2:20 Target Deconvolution by In Silico Proteome Screening 

Andrew HopeAndrew Hope, PhD, Vice President, Business Development, Cyclica Inc

Cyclica's new cloud-based and AI-augmented platform, Ligand Express allows a small molecule to be screened in silico against the structurally-characterized proteome to determine its polypharmacological profile. Moving beyond canonical binding sites it identifies known and novel binding sites, including allosteric sites. The talk will describe applications in deconvolution of phenotypic screens, such as guiding the repurposing of a retroviral drug to a rare automimmune disease.

2:50 Refreshment Break in the Exhibit Hall with Poster Viewing (America Ballroom)

3:30 Chemical Biology Approaches for Target Identification and Validation

Kilian_HuberKilian Huber, PhD, Principal Investigator, Structural Genomics Consortium (SGC), Target Discovery Institute, Nuffield Department of Medicine, University of Oxford

Drug target identification and validation represent paramount objectives for chemical biology. In this talk, I will focus on recent progress in the development of specific small molecule tool compounds, also referred to as chemical probes, for target validation and proteomic methods for target deconvolution and identification.

4:00 How Will Your Chemical Probes Data and Knowledge Outlive the Program?

Meir_GlickMeir Glick, PhD, Director, Informatics, Chemistry, Merck Research Laboratories

We will describe our efforts in the following areas: improving information capture with respect to compound design hypotheses, strategy, and chemical reactivity. Second, we will discuss making better use of all of our captured data through improving data access, data visualization, and application of machine learning methods.

4:30 Profiling Host and Gut Microbiome Xenometabolism in Mammalian Development and upon Chemical Exposures

Aaron_WrightAaron Wright, PhD, Principal Investigator and Group Leader, Chemical Biology & Exposure Sciences Group, Pacific Northwest National Laboratory

The expression and activity of drug metabolizing enzymes in the host are major determinants of the overall pharmacokinetic differences observed throughout human development. However, microbiome-mediated transformations of xenobiotics may also be a critical component of individual variability and susceptibility to toxicity, drug bioavailability, efficacy, and interactions. Using activity-based protein profiling, we are beginning to dissect the host-microbiome interplay involved in xenometabolism, and how external exposures and developmental stages alter metabolism.

5:00 Find Your Table and Meet Your Moderator

5:05 Interactive Breakout Discussion Groups

This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas and active networking.

Compound Collections for Phenotypic Screening and Chemical Biology

Francisco Garcia, PhD, Associate Scientist/Postdoctoral Research Fellow, Chemical Biology and Proteomics, Merck Research Laboratories

  • How many and how large such collections should be
  • Fit-for-phenotype and pathway sets, general MoA-annotated screening decks, diversity decks and the use of fragments and possibly other modalities (aptamers, etc.)
  • Screening modalities (fragments, small molecules, natural products, aptamers, peptides, proteins, RNAi and genome editing reagents)

Developments in Methodologies to Enable Target Identification

Ivan Cornella Taracido, PhD, Vice-President of Chemical Biology and Proteomics, Cedilla Therapeutics

  • What is new in chemical building blocks, reagents and reactions to enable omics and target ID?
  • Photo-affinity ligation and activity-based probe workflows
  • Advances in chemical genomics in mammalian haploid systems
  • In silico (off)-target prediction and other computational tools
  • Advances in analytical sciences (MS-based methods, imaging, bio-NMR,…)

5:45 Reception in the Exhibit Hall with Poster Viewing (America Ballroom)

7:00 Close of Day

Wednesday, June 20

7:45 am Registration Open (America Foyer) and Morning Coffee (Foyer)

COMPLEMENTARY TECHNOLOGIES TO CHEMICAL BIOLOGY
Independence

8:20 Chairperson’s Remarks

Ivan Cornella Taracido, PhD, Vice-President of Chemical Biology and Proteomics, Cedilla Therapeutics

8:30 ADDENDUM Advances in Compound MOA Prediction

Jeremy_JenkinsJeremy Jenkins, PhD, Executive Director, Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research

Phenotypic screening can yield many bioactive compound molecules, although laborious characterization of the compound targets or cellular mechanisms may be necessary. While target identification is often carried out for individual lead molecules, technologies to characterizing chemical libraries at scale are emerging, including high content imaging, well-based transcriptomics, and new methods for in silico target prediction.

9:00 Small Molecule and Pooled CRISPR Genomic Screens Targeting the IL-17 Pathway in Keratinocytes: Compare & Contrast Orthogonal Modes of Target Discovery

Eric_GoedkenEric Goedken, PhD, Principal Scientist, Foundational Immunology, AbbVie Bioresearch Center

My group has been working to study IL-17/TNF cytokine signaling in keratinocytes for applications in psoriasis and other dermatological diseases. We have performed screens using a CRISPR library as well as with small molecules. In this talk, I will outline this approach and compare/contrast the findings from these two orthogonal methods, and highlight a target with novel involvement in this pathway that we have identified in this manner.

LipoType  9:30 Shotgun Lipidomics Technology for High-Throughput Drug Discovery

Christian_KloseChristian Klose, PhD, Head, Research and Development, Lipotype GmbH

We present a comprehensive, absolutely quantitative shotgun lipidomics technology for biological samples on high-throughput scale. Its applications include drug discovery, mode-of-action studies, target validation, biomarker identification and clinical screenings. We explain the mass spectrometry-based technology and its explanatory data analysis power with examples.

9:45 Sponsored Presentation (Opportunity Available)  

10:00 Coffee Break in the Exhibit Hall with Poster Viewing (America Ballroom)

10:45 Functional Annotation of Natural Products via Integration of Gene Expression and High Content Imaging Approaches

John_MacMilanJohn MacMillan, PhD, Professor, Chemistry and Biochemistry, University of California, San Diego

Determination of the mechanism of action to botanicals, dietary supplements and natural products (mixtures and pure compounds) is a complex challenge that has limitations to their utility as supplements and therapeutics. To address this challenge, we have developed and integrated multiple phenotypic screening approaches to provide mechanistic hypothethes on a library scale. These platforms have been further integrated with metabolomics for a comprehensive chemical and biological evaluation of natural products.

11:15 Small Molecule Inhibitors Identified by Morphological Profile-Based Virtual Screening

Shantanu Singh, PhD, Senior Group Leader, Imaging Platform, Broad Institute

Images contain rich information about the state of cells, tissues, and organisms. We work with biomedical researchers around the world to extract quantitative information from images, particularly in high-content screening experiments involving physiologically relevant model systems. As the biological systems and phenotypes of interest become more complex, so are the computational approaches needed to properly extract the information of interest; we continue to bridge the gap between biologists’ needs and the latest in computational science (e.g., deep learning).

11:45 Enjoy Lunch on Your Own

12:20 pm Dessert and Coffee Break in the Exhibit Hall with Poster Viewing (America Ballroom)


1:00 PLENARY KEYNOTE SESSION
Essex South

Partnering for Sustainable Funding

The panel is designed to discuss partnering between various stake holders such as drug discovery startups, VC firms, large pharmaceutical companies and academic labs in order to advance new target discovery and preclinical research. VC companies, and pharma search & evaluation departments will be represented on the panel.

Jens Eckstein, PhD, President, SR One

Barbara K. Sosnowski, PhD, Vice President and Global Head, External R&D Innovation, Pharmatherapeutics and WRD External Partnerships, Pfizer, Inc.

Kevin Bitterman, PhD, Partner, Atlas Venture

Vivian Berlin, PhD, Director of Business Development, Life Sciences, Office of Technology Development, Harvard University

Ben Thorner, Senior Vice President and Head, MRL Business Development & Licensing, Merck

Plenary Technology Panel

Advancing Innovation in Drug Discovery and Translational Research

This year’s Plenary Technology Panel features a group of technical experts from life science technology and service companies, who share their perspectives on various trends and tools that will likely change the way in which we traditionally approach preclinical drug discovery and development. Attendees will have an opportunity to ask questions and understand the impact of recent technical advances.

Moderator: Leigh Zawel, PhD, Managing Director, MPM Capital

Ashley Rae Kark, MBS, Director, Corporate Relations, Scientist.com

Stefan Braam, PhD, Technical Director, Ncardia

Mark Paris, PhD, Director, Translational Applications, Mitra Biotech

Edgard Wood, PhD, Senior Research Director, Discovery, Charles River

2:30 Refreshment Break in the Exhibit Hall with Poster Viewing (America Ballroom)

3:10 Close of Conference