Cambridge Healthtech Institute’s 5th Annual

Protein Degraders and Molecular Glues – Part 1

Covalent Chemistries, New Ligases for Induced Proximity

September 26 - 27, 2023 EDT

A new generation of molecules are being developed to disrupt protein-protein interactions and to hijack the cell’s natural machinery for targeted protein degradation. Proteolysis-targeting chimeras (PROTACs), molecular glues, and other modalities are utilizing the ubiquitin-proteasome, lysosome, and autophagy systems to seek out previously “undruggable” targets for therapeutic intervention. Cambridge Healthtech Institute’s two-part conference on Protein Degraders and Molecular Glues brings together experts from industry and academia to discuss targeted protein degradation as a viable therapeutic approach. Part 1 focuses on emerging assays and screening strategies for new ligases and neosubstrates for targeted degradation. The use of covalent chemistry for inducing chemical proximity and use of AI/ML predictions and modeling to enable targeted protein degradation will also be discussed.

Tuesday, September 26

Registration and Morning Coffee7:00 am

Welcome Remarks7:55 am

COVALENT CHEMISTRIES & INDUCED PROXIMITY

8:00 am

Chairperson's Remarks

Daniel A. Erlanson, PhD, Senior Vice President, Innovation and Discovery, Frontier Medicines Corporation

8:05 am

Structural and Biochemical Characterization of a BTK-cIAP1 Covalent Complex

James Schiemer, PhD, Senior Scientist, Pfizer Inc.

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.

8:35 am

Leveraging Higher Throughput Targeted Proteomic Technologies to Impact PROTAC Portfolio

Uthpala Seneviratne, PhD, Associate Principal Scientist, AstraZeneca

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.

9:05 am

Discovery of Covalent Ligands Targeting CRL4DCAF2/DTL E3 Ligase for Targeted Protein Degradation

Kevin Webster, PhD, CSO, Frontier Medicines

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

10:05 am

Natural Recognition Motifs for the E3 Ligase Adapter Cereblon

Saki Ichikawa, PhD, Postdoctoral Fellow, Laboratory of Dr. Christina Woo, Department of Chemistry and Chemical Biology, Harvard University

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.

10:35 am

Using Novel E3s in Targeted Protein Degradation Therapies

Byron DeLaBarre, PhD, Head, Drug Discovery, Pin Therapeutics

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.

11:05 am

Discovery of Novel E3 Ligands for Targeted Protein Degradation

Jing Liu, PhD, Senior Vice President of Platform Chemistry, Cullgen, Inc.

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.

11:35 am CryoEM: Revolutionizing Structure-Based Drug Design for Accelerated Discovery

Jack Yan, PhD, Vice President, CryoEM, Biortus Biosciences Co., Ltd.

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.

Enjoy Lunch on Your Own12:05 pm

NOVEL DEGRADATION APPROACHES

1:15 pm

Chairperson's Remarks

Benedict Cross, PhD, CTO, PhoreMost Ltd.

1:20 pm

Applying Targeted Protein Degradation Strategies for Drug Discovery

Agnieszka Konopacka, PhD, Scientific Leader, Targeted Protein Degradation, GSK

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.

1:50 pm

Bifunctional Degrader Discovery with PROTEINi Screening

Benedict Cross, PhD, CTO, PhoreMost Ltd.

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.

2:20 pm Evaluation of Binary and Ternary Affinities of WDR5 Degraders with Spectral Shift

Bridget Milorey, PhD, Application Specialist, Applications, NanoTemper Technologies

Dysregulation of WDR5 expression and function has been implicated in the development of cancer, particularly through interaction with the MYC oncogene. This presentation shows the biophysical evaluation of five WDR5 degraders via recruitment of VHL. We assessed binary and ternary binding affinities, cooperativity, and hook effect. This data is discussed in the context of in vivo degradation efficiency, and the effect of linker’s structure and length on binary and ternary affinities.

 

 

2:35 pm Beyond Protein Degradation: Studying Ubiquitination to Advance TPD Drug Discovery

Karteek Kadimisetty, Dr., Director, R&D, LifeSensors Inc.

Targeted protein degraders are a new class of drugs that target “undruggable” proteome by hijacking the ubiquitin proteasome system. Conventional techniques, such as western blotting and reporter gene assays, are prone to artifacts. New approaches that can study PROTAC function on endogenous targets are essential to accelerate the PROTAC discovery process. LifeSensors TUBE technology allows studying ubiquitination beyond degradation guiding medicinal chemists in rationale design of PROTACs and Molecular glues.

In-Person Group Discussions2:50 pm

In-Person Group Discussions are informal, moderated discussions, allowing participants to exchange ideas and experiences and develop future collaborations around a focused topic. Each discussion will be led by a facilitator who keeps the discussion on track and the group engaged. To get the most out of this format, please come prepared to share examples from your work, be a part of a collective, problem-solving session, and participate in active idea sharing. Please visit the In-Person Group Discussions page on the conference website for a complete listing of topics and descriptions.

IN-PERSON GROUP DISCUSSION 1A:

New Chemistries and Assays for Next-Generation Degraders and Glues

Rima Al-Awar, PhD, Head, Therapeutic Innovation & Drug Discovery, Ontario Institute for Cancer Research

Benedict Cross, PhD, CTO, PhoreMost Ltd.

Daniel A. Erlanson, PhD, Senior Vice President, Innovation and Discovery, Frontier Medicines Corporation

  • Leveraging covalent chemistry, induced proximity to develop new degrader modalities
  • Utilizing new assays and platforms for structural and mechanistic characterization
  • Finding new ligases and cellular pathways for inducing degradation
  • Pursuing degradation as a strategy for important therapeutic targets​

Grand Opening Refreshment Break in the Exhibit Hall with Poster Viewing3:35 pm

4:15 pm

Drugging Protein-Protein Interactions: Two Examples from the WD40 Repeat Protein Family

Rima Al-Awar, PhD, Head, Therapeutic Innovation & Drug Discovery, Ontario Institute for Cancer Research

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).

4:45 pm

FEATURED PRESENTATION: Discovering Tissue-Specific E3 Ligases and β-Catenin Degraders with Fragment-Based Approaches

Stephen W. Fesik, PhD, Professor of Biochemistry, Pharmacology & Chemistry; Orrin H. Ingram II Chair in Cancer Research, Vanderbilt University

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

Wednesday, September 27

Registration and Morning Coffee7:30 am

INNOVATIVE DEGRADER MODALITIES & MECHANISMS

7:55 am

Chairperson's Remarks

Daniel La, PhD, Vice President & Head, Medicinal Chemistry, Triana Biomedicines, Inc.

8:00 am

FEATURED PRESENTATION: Development of Self-Assembling and Ubiquitin-Independent Degraders

Thomas Kodadek, PhD, Professor, Department of Chemistry, University of Florida, Scripps Biomedical Research

Degraders, including PROTACs and molecular glues, are chemical dimerizes that bring a target protein (TP) into close proximity with an E3 Ubiquitin ligase complex, thus triggering TP poly-Ubiquitylation and proteasome-mediated degradation. However, current degrader technology has some important limitations. For example, resistance to degraders targeting oncogenic proteins can arise rapidly through mutation or down-regulation of the E3 ligase. Most degraders also have high molecular weights and sub-optimal drug-like properties. This lecture will discuss the exploration on alternative degrader strategies, including Ubiquitin-independent degradation and self-assembling, dynamic PROTACs.

8:45 am Enabling and Accelerating Targeted Protein Degraders Drug Discovery through a Global Open Platform

Tao Guo, PhD, Senior Vice President, Head, WuXi Chemistry- RCS BD&IPM, WuXi Chemistry- RCS BD&IPM, WuXi AppTec

How to enable and accelerate targeted protein degraders and molecular glues drug discovery through a global open access platform will be discussed in this presentation.

9:00 am

Targeted Plasma Protein Degradation Accelerates the Clearance of PCSK9 via the Asialoglycoprotein Receptor Mediated by Heterobifunctional Ligands

Jeffrey Bagdanoff, PhD, Investigator III, Medicinal Chemistry & Oncology, Novartis Institutes for BioMedical Research, Inc.

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.

9:30 am

MOPED: A Novel Platform for the Discovery of Molecular Glues

Corey Strickland, PhD, Vice President, Molecular Technology, Proteovant Therapeutics Inc.

Molecular glues have potential to impact biology, especially for difficult to drug targets, through bringing two proteins into close proximity. However, a significant challenge is the ability to efficiently discover molecular glues. The Proteovant MOPED (MOlecular Proximity Enabled Detection) platform enables the detection of molecular glues through high dimensionality screening integrating machine learning for data analysis & target prioritization. Screening approximately half-million compounds across multiple drug targets has yielded exciting starting points for compound elaboration.

Coffee Break in the Exhibit Hall with Poster Viewing10:00 am

PLENARY KEYNOTE PROGRAM

10:40 am

Plenary Chairperson’s Remarks

An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech Institute

10:45 am

PLENARY: The New Science of Therapeutics

Jay E. Bradner, MD, Physician Scientist, Former President, Novartis Institutes for BioMedical Research, Inc.

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.

11:30 am

PLENARY: Accelerating Drug Discovery Using Machine Learning and Cell Painting Images

Anne E. Carpenter, PhD, Senior Director, Imaging Platform & Institute Scientist, Broad Institute

Shantanu Singh, PhD, Senior Group Leader, Machine Learning, Imaging Platform, Broad Institute

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 Conference12:15 pm