New Frontiers in TPD & Induced Proximity Research Day
Monday, October 28 2024
8:00 am Check-in & Morning Coffee
8:45 am Chair’s Opening Remarks
Advancing Induced Proximity & Molecular Glues to Propel Degrader Discovery
9:00 am Molecular Glues & Bifunctional Compounds: Therapeutic Modalities Based on Induced Proximity
Synopsis
- Exploiting similarity of molecular glues and bifunctional compounds to hot spots, missense mutations, and posttranslational modifications (PTMs)
- Coming full circle from natural product glues to simple synthetic compounds back to natural product-like glue compounds with high structural diversity
- Methods to discover cooperative molecular glues and bifunctionals for biomedical targets of interest
9:30 am Combining Structure & Large-Scale Proteomics Studies to Accelerate Degrader Discovery
Synopsis
- Large-scale proteomics have been transformative for the accelerated discovery of degraders
- Innovation in structural studies enable structure guided design principles
- Combining structural and large scale profiling data enabled predictive models
10:00 am A Novel & Differentiated Approach to Targeted Protein Degradation – Leveraging the Ubiquitin Conjugating Enzyme (E2) Family
Synopsis
- Ubiquitin Conjugating Enzymes are challenging to modulate pharmacologically using small molecules due to lack of druggable pockets
- Fragment Based Drug Design for the Modified (PTM) – E2 complex enabled discovery of first in class ligands
- Through E2 ligand extension and molecular design, efficacious bi-functional degraders have been developed for multiple proteins of interest
10:20 am Molecular Glues Targeting Parkinson’s & Alzheimer’s Disease-Relevant 14-3-3 PPIs
Synopsis
- 14-3-3 proteins modulate pathology-related activities of aSyn, Tau and LRRK2
- Molecular glues of these interactions might provide new avenues for therapeutic intervention
- X-ray crystallography and biophysics enable identification of molecular glue chemistry
10:50 am Morning Break & Speed Networking
Rationalising Degrader Design to Create Clear Approaches to Starting a Program
11:30 am Novel Technologies to Target Undruggable Proteins
Synopsis
- Bridged PROTAC, a novel approach to target undruggable proteins
- Harness the USP7 deubiquitinase for DUBTAC development using non-covalent inhibitors of USP7
- AceTAC, a novel technology and modality for inducing targeted protein acetylation
12:00 pm Chemical Biology Studies of the Thalidomide-Binding Domain of Cereblon
Synopsis
- Investigation of ligands for the thalidomide-binding domain of cereblon
- Update on chemistry of formation the C-terminal cyclic imide modification recognized by cereblon
- Mechanisms of regulating the thalidomide-binding domain of cereblon
12:30 pm Lunch Break
1:30 pm Panel Discussion: Looking Ahead: The Next Generation of Induced-Proximity-Based Therapeutic Discovery
Synopsis
Moderator: Ian Churcher, Consultant, Janus Drug Discovery
- Where is TPD field going next?
- What are the biggest unsolved challenges and how might they be addressed?
- Which induced-proximity modalities have the most potential to match success of PROTACs?
2:30 pm Afternoon Break & Networking
Advancing the Discovery & Deepening Understanding of Novel PROTACs & New Degraders
3:00 pm New Twists in Mechanisms & Rational Design of Protein Degraders
Synopsis
- Protein degraders (PROTACs, molecular glues) recruit a target protein to a ubiquitin E3 ligase, leading to the ubiquitination and subsequent proteasomal degradation of the target protein
- Degraders work via formation of a ternary complex target: degrader: ligase. Pioneering structural and biophysical studies have revealed molecular insights of degrader mechanism of action, and ushered their rational drug design
- This talk will highlight new twists in mechanisms (e.g. intramolecular bivalent glues); new approaches to degrader design (e.g. ternary complex-templated dynamic combinatorial chemistry); and new enabling tools to speed-up research in the community (e.g. CRBN-Midi and BromoTag)
3:30 pm Discovery & Targeting of an hRpn13 Product by PROTACs & Degraders
Synopsis
- The structure of hRpn13 with a small molecule binder was used to generate an hRpn13 PROTAC
- An hRpn13 PROTAC discovered hRpn13Pru which is generated by proteasomes with cell-type dependency
- A class of hRpn13Pru degraders was developed for preclinical application