Targeted Protein Degradation Europe Summit Day 1 Agenda
8:50 am Chair’s Opening Remarks
Uncovering New Technologies to Expand Undruggable Targets
9:00 am New Approaches to Degradation – Beyond the Usual Suspects
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 utilised 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
9:30 am Targeted Protein Degradation Using Biologics & PROTAC Derivatives for Hard to Drug Targets
Synopsis
- Intracellular antibodies and other biologics can be engineered for highly specific targeted protein degradation
- Agnostic targeted protein degradation can be engineered with biologics
- Intracellular antibodies and other biologics can be used to guide development of compounds and PROTACs
10:00 am Degradation of Lipid Droplets by Chimeric Attecs
Synopsis
- The concept of autophagosome-tethering compounds (ATTECs) and the rationale of using them to target both proteaceous and non-proteaceous targets
- The design and functional tests of chimeric ATTECs targeting lipid droplets
- The MoA study of ATTECs targeting lipid droplets
10:30 am Structured Networking
Advancing Discovery & Development
Unravelling The Next Wave of E3 Ligases
11:30 am Discovery of a Novel Functional E3 Binder Through PROTEINi-Enabled Screening
Synopsis
- The development of novel degraders with appropriate drug development properties requires a systematic functional deconvolution of the E3 ligase space
- The PROTEINi screening developed by PhoreMost has been used to uncover novel phenotypically active peptide ligands from which to build drug discovery pipelines
- In this seminar, we will show how we have used to thisto find both novel lead functional small molecule E3 binders, and fully active heterobifunctional peptide degraders
12:00 pm A Strategy to Assess the Cellular Activity of E3 Ligase Components against Neo-Substrates Using Electrophilic Probes
Synopsis
- COFFEE (Covalent Functionalization Followed by E3 Electroporation) tests neo-substrate degradation by chemically modified E3 ligase components
- Recombinant E3s are labelled with maleimide functionalized neo-substrate ligands, and then electroporated into cells
- Proof-of-concept degradation by electroporated JQ1- or dasatinib-labeled VHL. Discovery that SPSB2 and SKP1 can be redirected to degrade tyrosine kinases
Optimising Pre-Clinical Validation & Translation
Addressing Safety Concerns of PROTACs
11:30 am PROTAC Safety Perspective, Consideration For Oncology/Non-Oncology Indications
Synopsis
- What are the potential PROTAC safety liabilities?
- Can we optimise the safety profile?
- What is an acceptable safety profile of non-oncology targets?
12:00 pm Round Table Discussion: How to Maximise the Safety Profile to Achieve Efficient Degradation
Synopsis
- What are the current strategies to effectively scale up material for toxicity studies?
- How to optimise the safety profile to progress into the clinic
12:30 pm Networking Lunch
Reviewing Target Validation Strategies from Hit to Lead Optimisation
2:00 pm Challenges & Lessons-Learned of Degrader Lead Identification
Synopsis
Details to be revealed
2:30 pm Cellular Parameters of PROTAC Selectivity
Synopsis
- Aurora kinase A (AURKA) is a cellular target that exists in functionally distinct subcellular pools
- Cereblon-directed PROTACs bring about targeted protein degradation (TPD) of AURKA but the different subcellular pools of the target are not equally degraded
- Our experiments aim to identify the cellular parameters influencing target selection and degradation
3:00 pm HaloProtac as Degradation Tool for Target Validation
Synopsis
Details to be revealed
Addressing Translational Challenges of invivo Pharmacology, Species Difference & Selectivity
2:00 pm Targeted Protein Degradation to Treat Leukaemia: By Accident & By Design
Synopsis
- The potential and mechanism of action of existing protein degraders in the treatment of leukaemia
- The development of new model systems to test these drugs
- The design of new therapies to degrade key leukemia targets
2:30 pm Revealing PKPD & Dosing Regimens to Advance into the Clinic
Synopsis
- Understanding PK/PD-efficacy relationship of targeted protein degraders is essential to translating degradation kinetics from preclinical to clinic
- Mechanistic models of the data enable us to predict degradation and efficacious dosing regimens and effectively reduce clinical development timelines
3:00 pm Strategies & Challenges to Achieve SMARCA2 Degradation Potency & Selectivity
Synopsis
- Correlation between cell-free biochemical assays and cellular degradation potency and selectivity
- Identification of poly-ubiquitinated Lys residues may reveal degraders’ potency and selectivity MoA
- Validation of degradation potency/selectivity in different species for pre-clinical in-vivo studies and ADME/toxicology studies
3:30 pm Afternoon Break & Refreshments
Utilizing Targeted Protein Degradation Strategies to Address the Antimicrobial Crisis
4:00 pm Hijacking Protein Degradation in Bacteria
Synopsis
- Outline of a simple ubiquitin-proteasome like degradation pathway in bacteria
- Reprogramming bacterial Clp proteases by small molecules (BacPROTACs)
- Applications of BacPROTACs in antibiotic development and basic research
4:30 pm Chimeric Peptide Degraders for Protein Knockdowns in Gram Negative Bacteria
Synopsis
- Targeted protein degradation in Gram negative bacteria must use direct protease recruitment due to the absence of proteolysis-targeting posttranslational
modifications - The unfoldase ClpX is a conserved component in proteolytic machinery of most bacteria that may be used to anchor bacterial degraders
- Chimeric peptides recruiting ClpX to degrade essential proteins show antimicrobial activity in Escherichia coli correlated with depletion of the target proteins