Pre-Conference Workshop Day

PRE-CONFERENCE WORKSHOP DAY - OCTOBER 13, 2020

Our workshops are streamed so you are able to attend 3 out of 9 workshops. You can choose A, B or C followed by D, E or F, followed by G, H or I. Do you want to attend all of our workshops? Check out our group booking discounts so you can bring your colleagues!

Workshop A - 8:30 - 10:30

Workshop B - 8:30 - 10:30

Workshop C - 8:30 - 10:30

Mathematical Understanding of the Target Engagement or Ternary Complex Formation by PROTAC or Molecular Glue Compounds

The target engagement for these molecules is a ternary complex (TC) formation among the target protein, the small molecule, and an E3 ubiquitin ligase protein. Unlike the traditional drugs where the target engagement can be described by a simple bimolecular equilibrium equation, there is currently no mathematical tools that can properly describe such complex multi-body interactions, which substantially increases the challenge in developing drugs of this mechanism. This workshop will provide multiple mathematical tools to address kinetics and equilibrium binding properties of the ternary complex formation, and practical implications will be discussed based on theoretical understanding of the system.

Join this interactive session to discuss:

  • What are the practical implications of the “hook effect”?
  • What are the equivalent concepts in PROTAC world for Kd, EC50, Bmax, effective concentrations, etc.?
  • What determines efficacy of different PROTAC molecules?
  • Why do my PROTAC molecules fail to degrade the target protein?
  • How to design PROTAC molecules to maximise efficacy and minimise toxicity?
  • How to design toxicology studies given the complex nature of the system?

Expanding PROTAC Applications by Identifying Cell- & Disease Specific E3 Ligases

PROTAC technology has the potential to overcome the on-target drug toxicities of some existing drugs and drug candidates by targeting a protein of interest (POI) to an E3 ligase that is differentially expressed in different tissues and tumors. The workshop will cover how to identify cell-, tissue-, or disease- (such as cancer) specific/selective E3 ligases; the challenges associated with developing ligands for cell-, tissue-, or disease- (such as cancer) specific/selective E3 ligases, and will discuss examples of known tissue-selective PROTACs that are capable of overcoming the on-target toxicities of small molecular inhibitors.

Join this interactive session to discuss:

  • Are E3 ligases differentially expressed in different types of cells and tissues?
  • How to identify cell- and tissue-specific/selective E3 ligases?
  • Do tumors express unique E3 ligases?
  • How to develop ligands for cell-, tissue-, or disease- (such as cancer) specific/selective E3 ligases
  • How to design tissue- and/or tumor-specific/selective PROTACs to overcome on-target toxicity of small molecular inhibitors

Rational Design of Bioactive Small Molecules Targeting RNA

Our programmatic focus over the past 15 years has been on developing technologies to decipher which cellular RNAs are “druggable” targets for small molecules and which small molecules can target them. Here I will describe my laboratory’s advances in the area of Small Molecules Interacting with RNA (SMIRNAs), including: compounds as both advancers of lead medicines and as chemical probes to understand previously unknown RNA biology; a sequence-based small molecule rational design tool dubbed Inforna; and approaches allowing for targeted degradation of RNAs in cells and animals by using SMIRNAs. Although RNA has been thought to not be broadly targetable with organic ligands, these advances generated in my laboratory imply a necessary reassessment, and as such we believe the future for SMIRNAs to deliver precision medicines is bright.

Join this interactive session to discuss:

  • How to find small molecules that bind an RNA
  • What are the factors that affect biological activity?
  • How do you validate that a small molecule binds to a specific RNA in cells and animals?
  • How to cause RNAs to be recognized by quality control machinery by using small molecules
  • What is next to do?

Workshop Leader:

Bomie Han, Research Advisor, Eli Lilly

Bomie-Han

Workshop Leaders:

Daohong Zhou, Professor of Pharmacodynamics & Associate Director for Translation & Drug Development, University of Florida

 

Daohong Zhou

Guangrong Zheng, Associate Professor of Medicinal Chemistry, University of Florida

Guangrong Zheng

Shaomeng Wang, Warner-Lambert/Parke-Davis Professor in Medicine; Director of Michigan Center for Therapeutic Innovation, University of Michigan

Shaomeng Wang

Workshop Leader:

Matthew Disney, Professor of Chemistry & Neuroscience, Scripps Research

Matt Disney

Workshop D - 11:30 - 13:00

Workshop E - 11:30 - 13:00

Workshop F - 11:30 - 13:00

Harnessing the Power of PROTACs as Tools for Biological Discovery

Technological advances often lead to major biological discoveries, which in turn drive new technology development. Beyond serving as potential drugs, PROTACs provide unique tools for the study of protein function, combining the advantages of small molecules with those of other gene silencing/editing techniques. Perhaps most importantly, they enable the study of acute protein loss rather than the gradual selection of cells that survive without a given protein, thus avoiding issues arising from compensatory pathways/reprogramming. Using examples, we will discuss opportunities for PROTACs in biological research where they may prove advantageous over other approaches.

Join this interactive session to discuss:

  • Advantages of PROTACs for Biological Research
  • Disadvantages of PROTACs for Biological Research
  • Comparison of PROTACs to other approaches
  • What can we do to improve use of PROTACs in the biological community?
  • Other applications of PROTACs beyond drug discovery

Leveraging Targeted Protein Degradation in Antibacterial Drug Discovery

The application of targeted protein degradation as an approach in drug discovery has so far been limited to human cells. Recently, we discovered that an antibacterial drug, the tuberculosis antibiotic pyrazinamide, functions as a promotor of degradation of its target aspartate decarboxylase. Efforts are under way to exploit this mechanism for the discovery of next generation pyrazinamide. The objective of this workshop is to discuss whether targeted protein degradation as an approach to antibacterial drug discovery can be generalized, similar to what has been achieved in the area of drug discovery for human diseases. What are issues and gaps, and what and possible strategies?

Join this interactive session to discuss:

  • Brief discussion on the discovery of the first antibacterial target degrader and its ongoing optimization
  • Can PROTAC-like approaches be applied for the discovery of antibacterials?
  • What are the possible strategies?

What are the key hurdles and knowledge/tools/gaps?

Exploiting Chemical Biology Approaches to Degrade Epigenetic Targets

Rapid advances in chemical biology and functional genomics have facilitated exploration of targeting epigenetic proteins, yielding effective strategies to target transcription while reducing toxicities to untransformed cells. Recent developments in conventional active site and allosteric inhibitors, peptidomimetics, and novel PROTAC technology expanded our biological understanding of these targets in cancers. This workshop will discuss using chemical biology approaches to targeting epigenetic proteins by comparing the options of inhibitors and degraders.

Join this interactive session to discuss:

  • What is the mechanistic insight degrader can bring to us?
  • Is the degrader better than inhibitor?
  • What is the key challenge to develop degrader into drug?
  • What is the new option for degrader development?
  • What is the best option for degrader development?

Workshop Leader:

George Burslem, Assistant Professor, University of Pennsylvania

George Burslem

Workshop Leaders:

Thomas Dick, Professor, Hackensack Meridian Health, Center for Discovery and Innovation

 

Thomas Dick

Courtney Aldrich, Professor, University of Minnesota

Courtney Aldrich

Workshop Leader:

Jun Qi, Assistant Professor of Medicine, Dana-Farber Cancer Institute

SONY DSC

Workshop G - 14:00 - 16:00

Workshop H - 14:00 - 16:00

Workshop I - 14:00 - 16:00

Developing Novel Mass Spectrometry Tools to Aid PROTAC Research & Development

Native mass spectrometry (nMS) is an effective technique to measure protein complex formation. Key advantages include the label-free measurement of protein complexes and its capability to report on multiple binding stoichiometries present in dynamic protein mixtures, including molecular species populated to a low extent. For these reasons, nMS is particularly applicable for the characterisation of PROTAC systems.

Join this interactive session to discuss:

  • An overview of a typical nMS experiment, including sample requirements?
  • How nMS can report on the formation of ternary complexes, and on-pathway intermediate binary complexes, in a single experiment?
  • How nMS can be used to delineate the binding specificity of a PROTAC to substrate proteins
  • Capability of multiplexing experiments to compare PROTAC specificity to multiple substrate proteins in a single measurement
  • Opportunities for further development, including screening techniques during the PROTAC development stage

Advancing PROTACs to Clinic: Considering the Important Aspects of Translational Biology

This workshop aims to provide an overview of some key considerations for advancing the preclinical studies employing the PROTAC modality and the progression of lead molecules into clinical studies. Topics covered will emphasize target selection, published PK and efficacy studies, route of delivery considerations and the excitement about measuring target protein level as a biomarker for MOA in clinical studies.

Join this interactive session to discuss:

  • Which proteins are exciting PROTAC targets for clinical development?
  • What are the important preclinical data that distinguish degraders from Standard of Care (SOC), even if target is the same for an inhibitor and degrader?
  • Incredible potency/selectivity of PROTACs and what that means for PD and efficacy
  • Route of delivery: it all depends on who you ask
  • Target protein level as a clinical biomarker: SERDs and PROTACs.
  • Considerations for raising awareness about a new drug modality in the research and clinical community. Do patients and clinicians care about your drug’s novel MOA?

Beyond Degraders: Developing Bifunctional Molecules for Phosphorylation or Glycosylation

Several new classes of small molecules are emerging that endow neo-functions to enzymes via proximity-mediated effects. This workshop will discuss design, activities, and utility of bifunctional molecules that can induce phosphorylation, dephosphorylation, or glycosylation, as well as phenotypic approaches to identify “linkerless” bifunctional molecules, including PROTACs.

Join this interactive session to discuss:

  • Biological applications of bifunctional molecules that can induce native- or neo-posttranslational modifications, including phosphorylation and glycosylation
  • How do we design such bifunctional molecules?
  • A phenotypic platform to discover linkerless bifunctional molecules

Workshop Leader:

Rebecca Beveridge, Chancellor’s Fellow & UKRI Future Leaders Fellow, University of Strathclyde

Rebecca Beveridge

Workshop Leader:

Taavi Neklesa, Vice President of Biology, Halda Therapeutics

 

Taavi Neklesa

Workshop Leaders: 

Amit Choudhary, Assistant Professor, Broad Institute, Harvard Medical School & Brigham and Women’s Hospital

Workshop Leaders:

Amit Choudhary
Assistant Professor
Broad Institute, Harvard Medical School & Brigham and Women’s Hospital

Amit Choudhary

Christina Woo, Assistant Professor, Harvard University

Christina Woo

Ashley Modell, Postdoctoral Associate, Broad Institute, Harvard Medical School & Brigham and Women’s Hospital

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Sachini Siriwardena, Postdoctoral Associate, Broad Institute, Harvard Medical School & Brigham and Women’s Hospital

Sachini Siriwardena