Cambridge Healthtech Instituteの第5回年次
Protein Degraders and Molecular Glues - Part 1
Registration and Morning Coffee7:00 am
Welcome Remarks7:55 am
COVALENT CHEMISTRIES & INDUCED PROXIMITY
Structural and Biochemical Characterization of a BTK-cIAP1 Covalent Complex
Targeted protein degradation (TPD) using heterobifunctional chimeras holds the potential to expand target space and grow the ‘druggable proteome.' Most acutely, this provides an opportunity to target proteins that lack enzymatic activity or have otherwise proven intractable to small molecule inhibition. Bridging covalent ligand discovery with chimeric degrader design has emerged as a potential mechanism to advance both fields. Here, the authors, employ a set of biochemical and cellular tools to deconvolute the role of covalent modification in TPD using Bruton’s tyrosine kinase. Results reveals that covalent target modification is fundamentally compatible with the protein degrader mechanism of action.
Leveraging Higher Throughput Targeted Proteomic Technologies to Impact PROTAC Portfolio
Mass spectrometry-based targeted proteomics approaches have emerged as a promising technology to monitor absolute abundance of therapeutic target proteins that cannot be achieved via traditional protein detection technologies. We developed and applied these high-throughput strategies to address key MoA questions on PROTACs projects, including target protein and E3 abundance, protein turnover rates, and also for compound profiling. Case studies will be shown to demonstrate the technology and the impact on several PROTAC projects.
Discovery of Covalent Ligands Targeting CRL4DCAF2/DTL E3 Ligase for Targeted Protein Degradation
Using our proprietary chemoproteomics platform, we identified site-selective covalent ligands for the CRL4DCAF2 E3 ligase. DCAF2 is a substrate receptor upregulated in specific cancers. A ligand was developed into hetero-bifunctional degraders that exhibited robust cellular DCAF2-dependent BRD2/4 degradation. Our work validates DCAF2 as a novel E3 ligase substrate receptor amenable to targeted protein degradation and demonstrates the utility of the Frontier Platform to discover novel ligands enabling proximity-inducing therapeutics.
Networking Coffee Break9:35 am
Natural Recognition Motifs for the E3 Ligase Adapter Cereblon
Thalidomide and its derivatives, known as immunomodulatory drugs (IMiDs), bind to the E3 ligase substrate adapter cereblon (CRBN), resulting in lifesaving anti-cancer treatments or horrific teratogenicity. E3 ligase complexes recognize degrons, specific amino acid sequences sufficient to promote ubiquitination and degradation when embedded in a protein. I will discuss chemical approaches to finding a degron for the thalidomide-binding domain of CRBN and its implications for CRBN's physiological function and therapeutic engagement.
Using Novel E3s in Targeted Protein Degradation Therapies
Pin Therapeutics has created PinGLUE, a multifaceted discovery platform that integrates two primary components. The first is a novel degron display assay for screening of potential substrates against reconstituted cellular degradation machinery. The second is a streamlined E3 ligand discovery effort that extends current knowledge of heterobifunctional molecules with the intention of creating new therapeutic heterobifunctional molecules or uncovering new possible starting points for the degron display assay. We will discuss the challenges faced while building this platform and share some of our successful outcomes from these efforts.
Discovery of Novel E3 Ligands for Targeted Protein Degradation
Target protein degradation (TPD) technology provides promising therapeutic strategies for the treatment of human diseases. However, almost all of the advanced degraders recruit the same cereblon E3 ligase. Discovery of new E3 ligase ligands will help to realize the full potential of the TPD technology. In my talk, I will discuss our rationale and efforts in discovering novel E3 ligands for TPD.
Structure-based drug design (SBDD) is a powerful approach in therapeutic discovery, enabling researchers to target diseases with precision and efficacy. Cryo-electron microscopy (cryoEM), has revolutionized the field with high-resolution insights of three-dimensional structures. This presentation highlights the significant role of cryoEM in expediting SBDD and its impact on accelerating drug discovery.
Real-world case studies will be presented on the successful application of cryoEM, including PROTAC, ion channels, ABC transporters, GPCR, etc.
Transition to Lunch12:05 pm
Session Break12:40 pm
NOVEL DEGRADATION APPROACHES
Applying Targeted Protein Degradation Strategies for Drug Discovery
PROTACs are becoming an important therapeutic modality and a great tool for target validation. However, making a target-specific PROTAC can be challenging. To overcome this problem we use genetic engineering to modify target proteins in order to enable potent, selective, and reversible protein degradation with generic, degron-specific PROTACs. This presentation will focus on genetic and chemical tools for targeted protein degradation with a highlight on novel opportunities from our perspective.
Bifunctional Degrader Discovery with PROTEINi Screening
Small molecule degrader development is hampered by a low complexity matrix of E3 recruitment modules featuring a high degree of POI-specificity. High-throughput phenotypic screening using programmable PROTEINi exploits novel and unprecedented E3 ligases. Modular PROTEINi library design allows the discovery of bifunctional degraders scanning a vast diversity of new tissue- and POI-selective mechanisms. PROTEINi provide a phenotypically validated molecular inspiration as the foundation for degrader drug design and development.
Sponsored Presentation (Opportunity Available)2:20 pm
In-Person Group Discussions2:50 pm
Grand Opening Refreshment Break in the Exhibit Hall with Poster Viewing3:35 pm
Drugging Protein-Protein Interactions: Two Examples from the WD40 Repeat Protein Family
WD40 repeat proteins constitute one of the largest protein families, characterized by 44-60 amino acid repeats terminating in tryptophan and aspartate (WD). WD repeat proteins act as scaffolding proteins and play an important role in many cellular functions and as such have become an interesting family to drug. We will describe the discovery and optimization of small molecule binders to two members of this family (WDR5 and DCAF1).
FEATURED PRESENTATION: Discovering Tissue-Specific E3 Ligases and β-Catenin Degraders with Fragment-Based Approaches
The WNT pathway is a promising target in colon cancer that has been difficult to drug. Using fragment-based methods, we have discovered PROTACs that potently degrade b-catenin, inhibit the WNT pathway, and could be useful for treating colorectal tumors. We have also discovered PROTACs to degrade Bcl-xL, which is overexpressed in many tumors. These compounds created with ligands for tissue selective E3 ligases could exhibit less toxicity than Bcl-xL inhibitors.
Welcome Reception in the Exhibit Hall with Poster Viewing5:45 pm
Close of Day6:45 pm
Registration and Morning Coffee7:30 am
INNOVATIVE DEGRADER MODALITIES & MECHANISMS
Empirical Discovery of Functional Molecular Glues for Novel E3-Neosubstrate Pairs
SyntheX created empirical drug discovery platforms to identify protein interaction modulators. The ToRNeDO platform discovers molecular glues that can bridge a productive interaction between an E3 ubiquitin ligase and a neosubstrate of interest to achieve targeted protein degradation. Using genetically engineered circuits, the platforms rely on intracellular drug selection, bypassing many bottlenecks that exist with canonical in-vitro screening assays. This presents a novel approach to discover functional molecular glues from a first pass screen.
Sponsored Presentation (Opportunity Available)8:30 am
Targeted Plasma Protein Degradation Accelerates the Clearance of PCSK9 via the Asialoglycoprotein Receptor Mediated by Heterobifunctional Ligands
Circulating PCSK9 was degraded by various formats of heterobifunctional molecules that simultaneously bind to PCSK9 and the asialoglycoprotein receptor (ASGPR). Various formats, including bispecific antibodies, antibody-small molecule conjugates, and heterobifunctional small molecules demonstrate binding in vitro and accelerated PCSK9 clearance in vivo. These molecules showcase a new approach to PCSK9 inhibition, targeted plasma protein degradation (TPPD), and demonstrate the feasibility of heterobifunctional ligands to accelerate the clearance of circulating pathogenic proteins.
FEATURED PRESENTATION: Development of Self-Assembling and Ubiquitin-Independent Degraders
Traditional PROTACs have some limitations, including the existence of a hook effect, higher than ideal molecular weights, and the need for extensive "linkerology" to achieve high activity. This lecture discusses potential strategies to overcome these limitations through the reversible in celluo assembly of degraders from their component parts and the development of Ubiquitin-independent degraders that deliver the target protein directly to the proteasome.
Coffee Break in the Exhibit Hall with Poster Viewing10:00 am
PLENARY KEYNOTE PROGRAM
Plenary Keynote Introduction (Sponsorship Opportunity Available)10:45 am
PLENARY: The New Science of Therapeutics
I will share reflections on how new paradigms in the science of therapeutics are creating opportunities to approach historic challenges in medicine. Specifically, I will share approaches to targeting transcription factors and discuss how modularity is a paradigm for next-generation low-molecular weight and biological therapeutics. Finally, I will offer reflections on drug development and the fitness, opportunities, and challenges of the biomedical ecosystem.
PLENARY: Accelerating Drug Discovery Using Machine Learning and Cell Painting Images
Microscopy images can reveal whether a cell is diseased, is responding to a drug treatment, or whether a pathway has been disrupted by a genetic mutation. In a strategy called image-based profiling, often using the Cell Painting assay, we extract hundreds of features of cells from images. Just like transcriptional profiling, the similarities and differences in the patterns of extracted features reveal connections among diseases, drugs, and genes.
Close of Protein Degraders and Molecular Glues - Part 1 Conference12:25 pm