PRE-CONFERENCE DAY
Monday, October 28 2024
New Frontiers in TPD & Induced Proximity Research Day
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
Rationalising Degrader Design to Create Clear Approaches to Starting a Program
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 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
10:30 am Morning Break & Speed Networking
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
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
4:00 pm Detecting & Rewiring Cellular Interactomes
Synopsis
- Detecting proteostasis modulators and molecular glues with sensitivity in high throughput at scale is a challenge
- Multiplexed genetic circuits can bypass limitations in screening and mechanistic discovery
- Rational rewiring of subcellular transport can lead to gain-of-function pharmacology
4:00 pm Chair’s Closing Remarks
4:45 pm End of New Frontiers in TPD & Induced Proximity Day
TPD Assay Development & Screening Focus Day
8:00 am Check-in & Morning Coffee
8:45 am Chair’s Opening Remarks
Novel Assay Design & High Throughput Screening Approaches to Accelerate Degrader Discovery
9:00 am Discovering & Characterizing Latent E3 Ligase Protein-Protein Interactions Against 150 Therapeutic Targets
Synopsis
- Over 100 protein-protein interactions were identified between therapeutically relevant targets and a diverse set of ligases
- A subset of these interactions was further characterized using site-directed mutagenesis to define the interface and explore the ability to modulate the interaction
- These protein-protein interactions were used to prioritize small molecule discovery campaigns aimed at identifying molecular glues
9:30 am MicDrop – Phenotypic DEL Screen in Droplets for TPD
Synopsis
- Introduction to the concept of directed serendipity, a small-molecule equivalent of directed evolution enabled by DNA-encoded molecular glue library
- Overview of MicDrop, a phenotypic DEL platform enabled by droplet microfluidics and DNA-encoded one-bead one-compound library technology
- Walk-through of POI degradation screen data demonstrating the robustness of the platform with bead replicates and discovery of new glue degrader hits
10:00 am Predicting & Optimizing the Selectivity Profiles of Novel CELMoD Compounds
Synopsis
- Unlike achieving potency and selectivity for traditional small molecule inhibitors, reducing degradation of neosubstrate off-targets is complicated by the ternary nature of the complex formed between the POI, CRBN, and the CELMoD agent
- Herein we disclose an analysis of our glutarimide CELMoD library using a simple algorithm to identify the interpretable chemical features correlated with selectivity profiles and general cytotoxicity
- We also disclose simple multiparameter optimization (MPO) functions for each neosubstrate using two to three parameters to predict whether new molecules will likely have undesired off-target degradation activity
10:30 am Morning Break & Networking
11:30 am Deep Proteomics Screening Enables the Discovery of Novel Molecular Glue Targets
Synopsis
- High throughput proteomics screening of Cereblon-focused molecular glue library
- Identification of potent and selective molecular glue degrader for novel target
- Mechanistic profiling highlighting ubiquitinomics and mutational studies
12:00 pm Identify Novel E3 Ligases via Rapid Screening of DNA-Encoded Libraries
Synopsis
- DNA-encoded library technology enabled the identification of novel binders for buckets of E3 ligases in a cost-efficient way
- Examples of potent binders for both ubiquitous E3 and tissue specific E3 Ligases directly from DEL
- Refined workflow towards ligase binder and PROTAc discovery at GSK
12:30 pm Networking Lunch Break
Unearthing New Opportunities in Indications & Modalities with Tailored Assay & Screening Design to Create New Avenues for Your Candidate
1:30 pm Optimising Proteolysis Targeting Chimeras (PROTACs) for Oral Drug Delivery
Synopsis
- Outlining our approach towards target selection.
- Defining the key principles that govern oral absorption for bRo5 compounds.
- Extrapolating trends and conclusions drawn from the data analysis of AZ compounds.
2:00 pm A Novel Protein Degradation Modality to Address Multiple Diseases
Synopsis
- Screening and discovery of new small molecules to promote protein degradation
- Unique protein degradation modulation that holds promise as a new therapeutic approach
- Proof-of-concept data in an animal disease model
2:30 pm Afternoon Break & Networking
Advancing New Ligase & New Ligand Understanding with Novel In Vitro & In Vivo Assay Design to Expand the Therapeutic Potential
3:00 pm Discovery of Novel E3 Ligands for Targeted Protein Degradation
Synopsis
- Uncovering the catalytic mechanism to achieve higher efficacy, the ability to target previously undruggable proteins and the potential to deliver drug activity to selective tissues in TPD
- Demonstrating how E3 ligands hold the key to realize the full potential of TPD but are currently limited
- Discussing our rationale and efforts in discovering novel E3 ligands for targeted protein degradation
3:30 pm Robust Cullin-RING Ligases Employ Geometrically Optimized Catalytic Partners for Substrate Targeting
Synopsis
- Cullin-RING ligases collaborate with multiple distinct E2s and the ARIH1 ubiquitin ligase to efficiently target thousands of protein substrate for ubiquitylation
- What in vitro assays demonstrate high predictive value towards degrader drug efficacy? How can this be optimized?
- Does in vitro ubiquitin ligase efficiency correlate with cellular neo-substrate degradation?
4:00 pm Discovery & Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease
Synopsis
- A phenotypic screen identified inducers of fetal hemoglobin to treat SCD
- Subsequent target elucidation identified CRBN dependent degradation of the transcription factor WIZ as driver of HbF induction
- Med chem optimization resulted in molecules with improved WIZ degradation selectivity and in vivo PK/PD and efficacy and candidates for development
4:30 pm Chair’s Closing Remarks
4:45 pm End of TPD Assay Development & Screening Focus Day
TPD & Induced Proximity 101 Bootcamp Day
7:00 am Check-in & Morning Coffee
8:15 am Chair’s Opening Remarks
Introducing the Fundamental Principles Underpinning Targeted Protein Degradation & Induced Proximity to Jump-Start Your Degrader Program
9:00 am Harnessing Protein Degradation to Drug the Undruggable: The History & Promise of Targeted Protein Degradation
Synopsis
- The field of targeted protein degradation has rapidly expanded to offer the potential to drug targets that were previously considered undruggable
- PROTACs, MoDEs, and molecular glues have led the way into clinical trials and have shown promise for durable, effective therapeutics in cancer and other indications
- Multiple new targeted protein degradation modalities have been developed in the preclinical space that may allow targeting signaling pathways, cell types and tissues that were previously thought to be difficult to drug
9:30 am Structure & Regulation of the Proteasome
Synopsis
- The proteasome degrades ubiquitinated proteins by unfolding them and translocating them into a proteolytic chamber
- The proteasome is regulated by numerous cofactors, among them substrate delivery factors, inhibitors, deubiquitinating enzymes, protein kinases, ubiquitin ligases, and assembly chaperones
- Whether a ubiquitinated protein is a good proteasome substrate depends on multiple features, a major one being the presence of an “initiation element” that is is critical for effective unfolding
10:00 am Next Generation of Induced-Proximity Modalities
Synopsis
- Overview of concepts and mechanisms of induced proximity-driven strategies
- Exploring diverse technologies and rapidly growing effector-target space
- Highlighting case studies and challenges/opportunities
10:30 am Morning Break & Networking
Meet the E3 Ligase Family: Understanding this Protein’s Role in Protein Degradation & Development into Therapeutics
11:30 am Novel E3 Ligase-Based Targeted Protein Degradation: Potential Applications Within & Beyond Cancer Therapy
Synopsis
- Somatic mutation of some E3 ligases create novel E3 ligase that are not exist in normal tissues
- Targeted protein degradation using the mutated E3 ligases are very specific and only happen with the presence of the mutated E3 ligase
- Novel E3-based TPD and potential applications are discussed with an example
12:00 pm Gluing the Pieces Together, to Break it All Down: Harnessing Novel E3 Ligases for Molecular Glue Degraders
Synopsis
- The TPD field currently lacks rational chemical design principles for converting protein-targeting ligands into molecular glues
- Using known protein binders, we sought to identify transposable motifs which would convert these ligands into protein degraders
- RNF126, a previously unliganded RING E3 ligase, was determined to be an amenable ligase mediating a multitude of neo-substrate recognition events, leading to the discovery that it could be harnessed in a protein complex and act as an effective ubiquitinating and degrading chaperone
12:30 pm Networking Lunch Break
1:30 pm Roundtable Discussion: Crash Course on the E3 Ligase Family & How to Harness this Class for Drug Development
Synopsis
- Spotlighting the structures and fundamental biology of CRBN and VHL that has underpinned all targeted protein development thus far
- Cataloguing the modalities that have shown most promise in targeting these E3s
- Exploring how to begin characterizing novel E3 ligases to guide
2:00 pm Discovery & Development of Small-Molecule Glue Degraders of KRAS G12D as the First-in-Class Anticancer Drugs
Synopsis
- Cancer cell-based drug screening identified hit compounds that abide Lipinski rule and degrade active GTP KRAS G12D protein in KRAS G12D mutated cancer cells
- High-throughput technologies revealed a novel E3 ligase and mechanism of drug action in which degraders bind the E3 ligase and KRAS G12D and induce the KRAS degradation
- Protein structure-guided and AI-powered drug design speeded up hit to lead optimization for identification of preclinical candidates as the first-in-class anticancer drugs
2:15 pm End of TPD 101 Bootcamp Day 2024
Unleashing the Full Potential of Protein Degradation Machinery with New Applications
2:30 pm Afternoon Break & Networking
3:00 pm Molecular Glues for Target Protein Degradation
Synopsis
- Emerging themes in molecular glue degrader mechanisms
- How molecular glue degraders are advancing as therapeutics
- Moving from serendipitous discovery to rationale design
3:30 pm ASGPR vs M6PR: Common & Orthogonal Applications for Extracellular Protein Degradation
Synopsis
- Review of two endocytotic cell surface receptors, ASGPR and M6PR, and their uses for degrading soluble circulating and membrane proteins
- Novel proprietary ligands for ASGPR and M6PR as backbones for ATAC (ASGPR Targeting Chimeras) and MTAC (M6PR Targeting Chimeras) degraders
- In vitro and in vivo protein degradation studies comparing ATACs vs MTACs and therapeutic implications
4:00 pm Chair’s Closing Remarks
Novel Technologies to Accelerate TPD Discovery Workshop Day
Workshop A - 8.30am
Intergrating Structural Dynamics
Studies into Drug Discovery
Attend this workshop to:
- Overview of methods for observing ternary complex formation and their value for enabling SAR
- Focus on the unique advantages and challenges of cryo-EM and single particle analysis for leveraging conformational dynamics, specifically in the context of E3 ligases relevant to TP
- Discuss in depth time-resolved cryo-EM and its applications to merging quantitative biochemistry and structural biology for drug discovery
- Use high-purity FRET-active E2~Ub conjugates for monitoring degrader-mediated protein ubiquitylation in single-step FRET assays
Download the Full Event Guide for full details
Radoslav Enchev, Group Leader, The Francis Crick Institute
Dmitri Ivanov, Associate Professor, UT Health San Antonio
10:30am: Morning Break & Networking
Workshop B - 11.30am
Workshop C - 1.30am