Cambridge Healthtech Institute’s 3rd Annual

Ubiquitin-Induced Targeted Protein Degradation

Optimizing PROTACs and Small Molecule Degraders for Pursuing Undruggable Targets

NEW DATES - AUGUST 25-26, 2020

The ubiquitin-proteasome system (UPS) is a well-controlled, selective mechanism for intracellular protein degradation and turnover, and acts as a key regulator in cancer, CNS, and other diseases. Over the past few years, a new generation of inhibitors and activators have been developed for disrupting protein-protein interactions and for hijacking the UPS for protein degradation. Proteolysis-targeting chimeric molecules (PROTACs), molecular glues, and other chemical entities are being developed for targeted protein degradation and have potential to seek out previously “undruggable” protein targets for drug discovery and therapeutic applications. However, some challenges do exist in terms of stability, biodistribution, and penetration of these molecules in vivo. The conference on Ubiquitin-Induced Targeted Protein Degradation will bring together experts who can discuss the potential, as well as the challenges underlying targeted protein degradation as a new approach for therapeutic intervention.

Final Agenda

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Tuesday, April 14

7:00 am Registration Open and Morning Coffee

ASSAYS & MODELS FOR STUDYING DEGRADATION & TARGET SPECIFICITY

8:00 Welcome Remarks

Tanuja Koppal, PhD, Senior Conference Director, Cambridge Healthtech Institute

8:05 Chairperson’s Opening Remarks

Denise Field, PhD, Senior Scientist, I&I Chemistry and Chemical Biology, Pfizer Inc.

8:10 Target Engagement and Protein Degradation: Lessons Learned and Future Applications

Denise Field, PhD, Senior Scientist, I&I Chemistry and Chemical Biology, Pfizer Inc.

Protein degradation occurs through additional mechanisms other than bifunctional molecules. This talk will highlight some recent discoveries of compound induced degradation, as well as current approaches to validate compound target engagement mechanisms.

8:40 Engineered Ubiquitin Variants as Tools to Find Small Molecules Targeting Ubiquitin Enzymes

Jacky Chung, PhD, Scientist, Laboratory of Dr. Sachdev Sidhu, Donnelly Center, University of Toronto

Although proteins in the ubiquitin system have been the focus of therapeutic efforts for decades, little progress has been made to identify therapeutically relevant small molecules. Here, we present a general strategy where we use engineered protein binders as a platform for small molecule discovery. Our approach can lead to the quick identification of small molecules targeting an array of ubiquitin enzymes.

9:10 Shifting Focus - CETSA MS Proteomics in Protein Degradation Drug Discovery

Stina Lundgren, Principal Project Advisor, Pelago Bioscience

The CETSA MS profiling of degraders allow simultaneous study of both direct binding both its intended protein target, involved E3-ligase and potential off-targets.  In this talk we will present recent CETSA MS profiles on both protacs and molecular glue molecules in living cells including the degradation specificity and efficacy.

9:25 Sponsored Presentation (Opportunity Available)

9:40 Networking Coffee Break

10:05 Computational Exploration of Novel Drug Targets, Modalities, and Design

Yuan Wang, PhD, Senior Principal Scientist, Head of TPD Data Science, UCB Pharma

Modern drug discovery calls for increased use of phenotypic screens, and novel targets and modalities are being explored in the process. The use of potent and selective chemical tools (probes) can help understand underlying biological processes, deconvolute unknown mechanisms, or design new modulators of targets; e.g., linkers are attached to known inhibitors to make PROTACs. In this talk, we would like to explore rules that define those mechanisms using computational methods.

10:35 Use of Tip60 PROTACs in Cereblon-Knockin Mice

Wayne W. Hancock, MD, PhD, Professor, Pathology and Chief of Transplant Immunology, Children’s Hospital of Philadelphia and University of Pennsylvania

Finding new ways to target histone acetyltransferases, such as Tip60, is important for advances in immuno-oncology, and the PROTAC approach makes this possible. However, mice have a single amino acid substitution that blocks efficient iMID-dependent recruitment of the E3-ligase, Cereblon, limiting experimental studies. We report use of Tip60 PROTACs in WT vs. Cereblon knock-in mice in which PROTAC-dependent recruitment is now rendered active, allowing use of murine models for testing of this and other PROTAC molecules.

11:05 Chemical Tools to Evaluate E3: (Neo)Substrate Pairs

Alexander Statsyuk, PhD, Assistant Professor, Department of Pharmacological and Pharmaceutical Sciences, University of Houston

Two major principles of targeting the ubiquitin system have emerged: direct targeting of the enzymes that control protein ubiquitination and hijacking E3 ligases to induce protein degradation. In this lecture, I will outline the discovery of novel probes UbFluor, cross-linking reagents, and kinase targeting PROTACS to discover small molecule inhibitors/activators and hijackers for Cullin-RING/RBR/HECT E3 ligases.

11:35 Session Break

11:45 LUNCHEON CO-PRESENTATION: E3scan™ Ligand Binding Assay Platform and EFC Biosensor Cell Lines for Targeted Protein Degradation and PROTAC Discovery

Ksenya Cohen Katsenelson, PhD, Senior Scientist Group Leader, San Diego R&D, Eurofins Discovery
Chao-Tsung Yang, PhD, Principal Scientist, Research & Development, Eurofins DiscoverX

Eurofins Discovery will present how the novel E3scan technology has been applied to diverse E3 ligases, including CRBN, VHL, MDM2, MDMX, cIAP1, cIAP2, and XIAP. We will also present how engineered biosensor cell lines employing gene editing with CRISPR/Cas9 and our well-established EFC technology will enable sensitive quantitation of PROTAC-mediated degradation of the target of interest in physiologically relevant cell models using a homogeneous assay format.

12:30 pm Session Break

TARGETED PROTEIN DEGRADATION FOR ONCOLOGY

1:15 Chairperson’s Remarks

Chris Nasveschuk, PhD, Vice President, Chemistry, C4 Therapeutics

1:20 Degrader Drug Space: What Rules?

Chris Nasveschuk, PhD, Vice President, Chemistry, C4 Therapeutics

Targeted protein degradation, through the use of heterobifunctional degraders that act as catalytic activators for an E3 ligase and target protein ubiquitination event, have the potential to transform drug discovery. This seminar will focus on in vitro to in vivo correlation, oral bioavailability as well as initial insights into likely drivers of these two key parameters of drug discovery.

1:50 Targeted Degradation of Bromodomain-Containing Proteins for Cancer Therapy

Chandrasekhar Abbineni, PhD, Senior Group Leader, Aurigene Discovery Technologies Limited

Inhibition of bromodomain-containing proteins, such as BET and SMARCA2, is being evaluated as a therapeutic strategy in cancer. While these inhibitors affect only the reader function of these proteins, their degradation causes a global assembly defect, leading to anti-proliferative activity. Here we present the discovery of lower molecular weight, orally bioavailable, and efficacious degraders of bromodomain-containing targets using our proprietary ALMOND (ALgorithm for Modelling Neosubstrate Degraders) technology.

2:20 Ubiquitin-Mediated Small Molecule-Induced Target Elimination (uSMITE) for Cancer

Michael Plewe, PhD, Vice President, Medicinal Chemistry, Cullgen, Inc.

Targeted protein degradation using bifunctional molecules to remove specific proteins by hijacking the ubiquitin proteasome system has emerged as a novel drug discovery approach. Several challenges remain in designing optimal degraders that also show efficacy in vivo. We will present case studies from our ongoing efforts in the design and biological evaluation of novel degraders that are orally active in mouse xenograft models.

2:50 A Modular PROTAC Design for Target Destruction Using Single Amino Acid-Based Degradation Signal

Hai Rao, PhD, Professor, Molecular Medicine, University of Texas Health

Proteolysis targeting chimeras (PROTACs) are bivalent molecules that bring a cellular protein to a ubiquitin ligase E3 for ubiquitylation and subsequent degradation. Here we adopt single amino acid based PROTACs to target ERRa for proteasomal degradation by the N-end rule pathway and inhibit the proliferation of breast cancer cells. The method offers unique advantages, including smaller molecular size with shortest degradation sequences and degradation speed modulation with different amino acids.

3:20 Fragment Screening and Biophysical Hit Validation

Michael Raba, Deputy Head, Biophysics and Screening, Crelux, WuXi AppTec

CRELUX, is an integral part of the WuXi AppTec Research Services Division (RSD). We deliver tailored solutions in structure-based drug discovery. By screening our proprietary fragment library using powerful biophysical techniques such as MST, SPR or nanoDSF we successfully support clients already in early stage drug discovery campaigns

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)

4:35 Plenary Welcome Remarks from Event Director with Poster Finalists Announced

Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute

4:45 Plenary Technology Spotlight: Accelerating Drug Discovery from Hit Finding to Candidate Selection with Physics and Machine Learning-Based Calculations

Matt Repasky, PhD, Vice President, Life Sciences Products, Schrödinger

The impact of the Schödinger computational platform in drug discovery is illustrated using recent case studies from internal and collaborative discovery projects.  The Platform facilitates halving the number of synthesized molecules and time to candidate relative to industry standards.  Key elements of the Platform are described including Free Energy Perturbation to accurately predict relative protein-ligand binding, machine learning to generate and rapidly assess millions of ideas, and collaborative sharing of project information through LiveDesign.

5:10 Plenary Keynote Introduction (Sponsorship Opportunity Available)

5:15 PLENARY KEYNOTE:

Medicinal Chemistry: Where Are We Headed?

Wendy Young, PhD, Senior Vice President, Small Molecule Discovery, Genentech

Major shifts in the way medicinal chemists discover novel medicines have evolved over the past few decades. Technological advances have significantly increased the ability to triage compound design and synthesize compounds faster. New approaches in structural biology have enhanced our ability to visualize molecules and their corresponding binding sites. Drug discovery teams have moved from local to global and our deepened understanding of biology has extended our reach. This lecture will explore past trends in drug discovery, current status of the industry, and the future of medicinal chemistry.

6:00 Welcome Reception in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)

7:00 Close of Day

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Wednesday, April 15

7:30 am Continental Breakfast Breakout Discussions - View All Breakouts

TARGETED KINASE DEGRADATION STRATEGIES

8:30 Chairperson’s Remarks

Philip Chamberlain, DPhil, Executive Director, Structural and Chemical Biology, Celgene

8:35 New Activities for Cereblon Modulators

Philip Chamberlain, DPhil, Executive Director, Structural and Chemical Biology, Celgene

Cereblon can be redirected to degrade neo-substrate proteins using low-molecular-weight small molecules. An understanding of the structural basis of substrate recruitment has enabled the discovery of new neo-substrates, including proteins that lack canonical small-molecule binding sites.

9:05 So Many Ubiquitin Ligases and So Few PROTACs: Carving a New Path with Novel Ligases

Tauseef Butt, PhD, President and CEO, Progenra, Inc.

PROTAC field is at its infancy. Only the well-known ligases (Cereblon, VHL, HDM2 and cIAPs) have been exploited by medicinal chemists. Too many resources are devoted to these ligases as vehicles for PROTACs. We have validated applications of novel ligases by designing PROTACs with promiscuous kinase inhibitor that degrades a number of kinases not degraded by traditional ligase PROTACs. Kinetics and dose response studies have established their application in oncology, inflammatory and neuroscience.

9:35 Coffee Break in the Exhibit Hall with Poster Awards Announced

Poster Awards Sponsored by Enamine Ltd

10:30 Molecular Mechanisms of Small Molecule-Mediated Ubiquitin Ligase Targeting

Eric Fischer, PhD, Assistant Professor, Cancer Biology/ Biological Chemistry and Molecular Pharmacology, Dana-Farber Cancer Institute/Harvard Medical School

Small molecules that induce protein degradation through ligase-mediated ubiquitination, have shown considerable promise as a new pharmacological modality. Thalidomide and related IMiDs provided the clinical proof of concept, while significant progress has recently been made towards chemically induced targeted protein degradation using heterobifunctional small molecule ligands. We will present recent work towards a better understanding of the molecular principles that govern neo-substrate recruitment, and other small molecule degraders.

11:00 Targeting Focal Adhesion Kinase with PROTACs: From Tool to in Vivo

Robert Law, PhD, Investigator, Medicinal Chemistry, GSK Medicine Research Centre

New modalities, such as PROTACs, are powerful tools that allow biology assessment of oncogenic targets beyond the conventional kinase inhibition. Focal Adhesion Kinase (FAK) is a key mediator of tumour progression and is overexpressed in many solid tumours; to date, inhibitors targeting FAK kinase activity have shown low success in the clinic. Here we report the design and characterization of a highly potent FAK degrader with increased efficacy over FAK inhibitor, as well as extended in vivo efficacy.

11:30 ADME Properties of PROTACs and Oral Bioavailability Improvement Strategies

Upendra Dahal, PhD, Senior Scientist, Pharmacokinetics and Drug Metabolism, Amgen, Inc.

PROTACs are bifunctional molecules, designed to bind with target protein and E3 ligase to degrade target protein by hijacking the cell’s own ubiquitin proteasome system. PROTACs have several advantages, but challenges remain in designing optimal PROTACs that have acceptable absorption, distribution, metabolism and excretion (ADME) properties to demonstrate efficacy in vivo. Literature-published PROTACs have high MW (beyond rule of 5), low permeability, and low oral bioavailability. This presentation will focus on ADME properties of PROTACs with special focus on strategy to improve oral bioavailability.

12:00 pm Close of Conference

12:45 Dessert Break in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)

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