Cambridge Healthtech Institute’s Inaugural

Target Identification and Validation - Part 1

Proteomics-Based Target Discovery

September 16 - 17, 2020 ALL TIMES EDT

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 in identifying and validating targets that will yield viable drugs. How are genomics and proteomics helping overcome some of the challenges in target discovery today? What new tools and strategies are being employed and how well are they working? What’s being done to adequately validate the targets once they are identified? What efforts are being taken to go after difficult or “undruggable” targets? Cambridge Healthtech Institute’s conference on Target Identification and Validation will bring together leading experts to discuss some of these critical issues. This is a unique opportunity to meet and network with biologists and screening groups from around the world to share ideas and best practices. Besides target identification, target deconvolution and validation are also equally challenging and remain important bottlenecks in drug discovery. Chemical biology, particularly chemoproteomics and other mass spectrometry-based tools and assays are playing an important role in identifying, evaluating, and prioritizing new drug targets. The first part of the Target Identification and Validation conference focuses on Proteomics-Based Target Discovery that leverages these new chemical probes, assays, and screening tools being developed.

Wednesday, September 16

ADVANCES IN CHEMICAL PROTEOMICS

9:30 am

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.

9:50 am

Design of Photoaffinity and Electrophilic Probes for Target Identification and Validation

Christopher am Ende, PhD, Associate Research Fellow, Internal Medicine Medicinal Chemistry, 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.

10:10 am

Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development

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. 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 targets.

10:30 am Session Break
11:10 am Coffee Break - View Our Virtual Exhibit Hall
11:25 am

In-Cell Cysteine Chemoproteomics with Tunable Electrophiles

Brent Martin, PhD, Director, Chemical Biology, Scorpion Therapeutics

Current methods for proteome-wide cysteine profiling rely on iodoacetamide-linked probes. Progess will be presented evaluating diverse heteroaromatic sulfides with different oxidation states, heteroatom substitutions, and a series of electron donating and electron-withdrawing substituents. Select substitutions profoundly influence reactivity and stability compared to conventional cysteine conjugation reagents, increasing the reaction rate by >3-orders of magnitude. Direct addition of desthiobiotin-functionalized probes to cultured cells simplified enrichment and elution to enable mass spectrometry discovery of unique thiols labeled in their native cellular environments in a fraction of the standard analysis time. These probes offer advantages over existing cysteine alkylation reagents, including accelerated reaction rates, improved stability, and robust ionization for mass spectrometry applications. Overall, heteroaromatic sulfones provide modular tunability, shifted chromatographic elution times, and superior in-cell cysteine profiling for in-depth proteome-wide analysis and covalent ligand discovery.

11:45 am

Re-Imagining Fragment-Based Multiplexed Chemical Proteomics for Cell-Based Screening of Large Electrophile Libraries

Steve Gygi, PhD, Professor, Department of Cell Biology, Harvard Medical School

We have redesigned the entire workflow for activity-based protein profiling (ABPP) of reactive cysteine residues towards electrophilic compounds with an eye towards screening large libraries containing hundreds to thousands of compounds directly in cells. Altogether, a 42-fold improvement in sample throughput was achieved corresponding to profiling library members at a depth of >8,000 reactive cysteine sites using only 18 min per compound. We applied the method to screen hundreds of electrophiles directly in cells.

12:05 pm Session Break
12:25 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Doug Johnson, PhD, Senior Director, Chemical Biology & Proteomics, Biogen
Panelists:
Christopher am Ende, PhD, Associate Research Fellow, Internal Medicine Medicinal Chemistry, Pfizer Inc.
Katherine Donovan, PhD, Scientist, Laboratory of Dr. Eric Fischer, Cancer Biology, Dana-Farber Cancer Institute/Harvard Medical School
Brent Martin, PhD, Director, Chemical Biology, Scorpion Therapeutics
Steve Gygi, PhD, Professor, Department of Cell Biology, Harvard Medical School
12:45 pm Lunch Break - View Our Virtual Exhibit Hall
Daniel Nomura, PhD, Professor of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California Berkeley

Our research group is advancing and applying chemoproteomic platforms to discover and pharmacologically target unique and novel druggable hotspots for disease therapy. We currently have three major research directions. Our first major focus is on developing and applying chemoproteomics-enabled covalent ligand discovery approaches to rapidly discover small-molecule therapeutic leads that target unique and novel druggable hotspots for undruggable protein targets and pathways. Our second research area focuses on discovering and exploiting unique druggable modalities accessed by natural products. Our third research area focuses on using chemoproteomics-enabled covalent ligand discovery platforms to expand the scope of targeted protein degradation and to discover new induced proximity-based therapeutic modalities. Collectively, our lab is focused on developing next-generation transformative medicines through pioneering innovative chemical technologies to overcome challenges in drug discovery.

1:55 pm

Integration of Chemical and Phosphoproteomics for Dissecting Network Pharmacology

Uwe Rix, PhD, Associate Member, Department of Drug Discovery, Moffitt Cancer Center

Many cancers are driven by complex signaling networks. It is therefore attractive to target more than one disease-relevant pathway or target. Optimal design of multi-targeted strategies requires detailed knowledge of drug targets and how drugs engage oncogenic signaling networks. Here, we will present examples of how the integration of chemical and phosphoproteomics approaches can dissect drug mechanisms of action within complex signaling networks and inform the rational design of novel drug combination approaches.

2:15 pm Refresh Break - View Our Virtual Exhibit Hall
3:00 pm Interactive Breakout Discussions - View Our Virtual Exhibit Hall

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. Discussion topics and moderators will be listed on the website.

BREAKOUT: How Can Chemoproteomics Technologies and Assays be Exploited for Target ID and Validation?

Daniel Nomura, PhD, Professor of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California Berkeley
Uwe Rix, PhD, Associate Member, Department of Drug Discovery, Moffitt Cancer Center
  • What are persistent chemoproteomics bottlenecks and how can we overcome them?
  • What makes chemoproteomics approaches complementary to other technologies (e.g. functional genomics) and what can it provide that these don’t?
3:35 pm Close of Day

Thursday, September 17

STRATEGIES FOR TARGET ENGAGEMENT & DECONVOLUTION

10:15 am

Utilization of Chemical Probes for Kinase Target Engagement and Selectivity Profiling

Bekim Bajrami, PhD, Senior Scientist, Chemical Biology and Proteomics, Biogen Inc.

Probe-based chemical proteomics technologies play an integral role in target identification and validation of the biological target(s) through which the drug is proposed to exert its mechanistic effects. A suite of chemical probes was evaluated for selectivity profiling and measuring target engagement for several kinase inhibitors. A sulfonyl fluoride XO-44 probe was used for target identification and selectivity profiling of kinase drug candidates under physiological conditions and Ibrutinib-based probes were utilized to measure BTK target occupancy both in vitro and in vivo.

10:35 am

Identification of Novel Target and Biology from Human Macrophage Repolarization Screen

Sreemanti Basu, Senior Scientist, Drug Discovery Science & Technology, AbbVie

Phenotypic screening is a powerful approach for identification of novel disease-relevant targets and pathways for drug discovery. Here, I present a case study to identify targets, involved in pro-inflammatory to anti-inflammatory macrophage repolarization, that can be utilized for autoimmune drug discovery.­­ Using a small-molecule phenotypic screening approach, we were able to identify known, as well as novel, targets that facilitated induction of anti-inflammatory phenotype in LPS/IFNγ-activated, human monocyte-derived macrophages by distinct mechanisms. The targets were validated using tool compounds, target-to-phenotype correlation, profiling approaches, followed by target knock down and in vivo POC studies. Together, our phenotypic screening platform allowed discovery of novel targets and mechanisms to support development of macrophage-targeted therapeutics for autoimmune disorders.

10:55 am

Chemoproteomic Approaches to Profile RNA Binding and Modifying Proteins

Ralph Kleiner, PhD, Assistant Professor, Department of Chemistry, Princeton University

The properties of eukaryotic messenger RNA can be modulated by dynamic chemical modifications that occur post-transcriptionally (known as the “epitranscriptome”). We are developing chemical proteomic strategies based upon metabolic RNA labeling with artificial nucleosides and synthetic oligonucleotide probes to discover and characterize RNA modification writers, erasers, and readers, and understand their biological roles. This should provide powerful and general strategies for interrogating fundamental RNA regulatory mechanisms and lead to new insights for targeting epitranscriptomic protein factors for therapeutic benefit.

11:15 am Session Break
11:35 am LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Bekim Bajrami, PhD, Senior Scientist, Chemical Biology and Proteomics, Biogen Inc.
Panelists:
Sreemanti Basu, Senior Scientist, Drug Discovery Science & Technology, AbbVie
Ralph Kleiner, PhD, Assistant Professor, Department of Chemistry, Princeton University
11:55 am Coffee Break - View Our Virtual Exhibit Hall

PLENARY KEYNOTE PROGRAM

12:20 pm

PLENARY KEYNOTE: Tackling Undruggable Oncoproteins: Lessons from the VHL Tumor Suppressor Protein

William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics

VHL tumor suppressor protein (pVHL) inactivation is common in kidney cancer and upregulates the HIF2 transcription factor. PT2977/MK-6482 is an allosteric HIF2 inhibitor now in Phase 3 testing. Thalidomide-like drugs (IMiDs) bind to cereblon which, like pVHL, is the substrate-binding unit of a ubiquitin ligase. IMiDs redirect cereblon to destroy the myeloma oncoproteins, IKZF1 and IKZF3. We have developed new assays for identifying drugs that can destabilize oncoproteins of interest.

12:45 pm LIVE Q&A:

Plenary Keynote Discussion

Panel Moderator:
Stewart Fisher, PhD, CSO, C4 Therapeutics, Inc.
Panelist:
William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics
12:55 pm LIVE PANEL AND Q&A:

Plenary Keynote Discussion: De-Risking Early Drug Discovery

Panel Moderator:
Nadeem Sarwar, PhD, Founder & President, Eisai Center for Genetics Guided Dementia Discovery, Eisai, Inc.
  • Data Sciences
  • ​Novel Chemical Modalities
  • Investment and Partnering Models
  • COVID-19 Progress as Examples of Successful Partnerships
Panelists:
Anthony A. Philippakis, PhD, Chief Data Officer, Data Sciences & Data Engineering, Broad Institute; Venture Partner, GV
Stephen A. Hitchcock, PhD, Head, Research, Takeda Pharmaceuticals, Inc.
1:35 pm Lunch Break - View Our Virtual Exhibit Hall
2:05 pm Close of Target Identification and Validation - Part 1 Conference

Please click here to continue to the agenda for Target Identification and Validation - Part 2






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