8:30 am Morning Coffee & Virtual Networking

8:55 am Chair’s Opening Remarks

Advancing the Horizon & Impact of PROTAC-Based Targeted Degradation

9:00 am Selecting Targets to Harness the Therapeutic Opportunities Afforded by PROTAC-Mediated Protein Degradation

  • John Harling Senior Scientific Director of Medicinal Chemistry, GlaxoSmithKline

Synopsis

  • With a significant proportion of the intracellular proteome likely being amenable to PROTAC-mediated degradation, considerable focus needs to be placed on identifying the best therapeutic opportunities for this technology
  • This presentation will share some experiences at GSK assessing different targets and the consideration of whether a PROTAC approach represented the modality of choice
  • Data will be presented highlighting how factors such as protein synthesis rates, the relationship between the extent of degradation and functional response as well as additional pharmacology that cannot be accessed via an inhibitor can impact this assessment

9:20 am New Approaches to Degradation – Beyond the Usual Suspects

  • Ian Churcher Chief Scientific Officer , Amphista Therapeutics

Synopsis

  • Amphista Therapeutics uses a completely novel range of mechanisms to degrade a wide range of disease-relevant proteins
  • Mechanisms go beyond the usual E3 ligases utilized by most in the field and instead use other UPS proteins which offer new opportunities to expand the scope and utility of TPD strategies
  • We will discuss how novel mechanisms have the potential to overcome current limitations with TPD strategies

9:40 am PROTAC-Mediated Degradation Reveals a Non-Catalytic Function of AURORA-A Kinase

Synopsis

  • Aurora-A kinase interacts with the MYC oncoprotein and is an established cancer target
  • Kinase inhibitors have not been clinically successful, maybe because Aurora-A has non-catalytic functions
  • We developed PROTACs which rapidly and specifically degrade Aurora-A in Cancer cells and present a novel pharmaceutical anti-cancer strategy

10:00 am Building a PROTACs Toolbox for Contract Research

  • Tom Coulter Director of Integrated Drug Discovery , Selvita

Synopsis

  • Meeting our clients’ needs on PROTAC projects
  • Developing a proprietary approach to PROTAC discovery
  • Creating valuable PROTAC assets

10:10 am Discussion/Q&A

  • John Harling Senior Scientific Director of Medicinal Chemistry, GlaxoSmithKline
  • Ian Churcher Chief Scientific Officer , Amphista Therapeutics
  • Elmar Wolf Professor , University of Würzburg
  • Tom Coulter Director of Integrated Drug Discovery , Selvita

10:40 am Virtual Speed Networking

Delving into Target Intrinsic Approaches & Degrader Design to Induce Selective Protein Degradation

11:30 am Teaching an Old Dog New Tricks – Traditional Small Molecule Drug Discovery & Targeted Protein Degradation

Synopsis

  • Setting up a screening cascade in an industrial environment
  • Selected highlights from in-house projects
  • Turning a traditional inhibitor into a degrader to introduce new biology

11:50 am 0 Enhancing Applicability, Specificity & Effectivity: Leveraging the Potential of a Protein Aggregation Based Platform to Transform Drug Discovery

Synopsis

  • Aelin’s protein-aggregation based platform allows the targeting of previously undruggable target, since no requirement such as a specific binding- or active sites are anymore necessary to start drug discovery
  • Through harnessing this new technology, we can overcome challenges surrounding discovery of new molecules for exciting but still “undruggable” oncology targets
  • Outline of the technology and potential of the protein aggregation platform
  • Aelin’s platform as an alternative in the space of PROTACs

12:10 pm Computational Workflows for Bifunctional Degrader Design

Synopsis

  • Presenting three computational workflows to address different design challenges of bifunctional degraders
  • The workflows include the conformational sampling of the isolated bifunctional degrader, the determination of the degrader exit vector and the prediction of the target-degrader-ligase ternary complexes
  • Preliminary method validation using available public crystal structures and highlights of their limitations

12:30 pm Discussion/Q&A

12:50 pm Lunch Break

Harnessing Alternative Next-Generation Platforms for Inducing Protein Degradation

1:50 pm Mass Photometry – a Novel Method for Protein Analysis

Synopsis

  • Introduction to mass photometry as a technology
  • Sharing specific examples including for the study of PROTACs and other
    multicomponent complexes

2:05 pm Deubiquitylating (DUB) Enzyme Targeting for Treatment of Human Disease

Synopsis

  • DUBs antagonise action of ubiquitin ligases – inhibiting the inhibitor
  • DUB specificity/localization informs target/indication selection – USP30 as an example
  • DUB/substrate/ligase partnership data mining for new opportunities
  • DUB inhibition opportunities exist in neurodegenerative disease

2:25 pm Next-Generation PROTAC Discovery with a Systematic Screening Engine

Synopsis

  • Small molecule PROTAC development is hampered by a low complexity matrix of E3 recruitment modules, and hindered by a high degree of substrate specificity
  • PhoreMost have developed SITESEEKER, an ultra-high throughput pooled phenotypic screening platform, exploiting high-diversity programmable drug mimetics
  • Systematic application of the SITESEEKER tools to PROTAC discovery has yielded a substantial cache of novel E3 ligase ligands and peptide-based PROTACs which have been deployed to degrade key therapeutic targets

2:45 pm Involvement of the Deubiquitinase USP13 in Cancer

Synopsis

  • Introduction to DUBs and to USP13 roles in cancer pathways
  • Characterisation of two novel substrates of USP13 linked to cancer
  • Discussion on inhibition of USP13 by small molecules

3:05 pm Discussion/Q&A

3:30 pm Chair’s Closing Remarks & End of TPD Europe Summit