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, AUGUST 25

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

John Brognard, PhD, NIH Stadtman Investigator, Laboratory of Cell and Developmental Signaling, National Cancer Institute, National Institutes of Health

8:10 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.

8:40 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.

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 Talk Title to be Announced

Nir London, PhD, Senior Scientist, Weizmann Institute of Science

10:35 Late Breaking Presentation

11:05 LZK Targeting PROTAC Suppresses HNSCC Tumor Growth Through Inhibition of MYC and GOF p53

John Brognard, PhD, NIH Stadtman Investigator, Laboratory of Cell and Developmental Signaling, National Cancer Institute, National Institutes of Health

Here we define the kinase LZK (MAP3K13) as a therapeutic target in HNSCC and demonstrate that inhibition of LZK kinase activity with a small molecule inhibitors decreases the viability of HNSCC cells with amplified LZK and suppresses tumor growth in vivo.  We then designed a proteolysis targeting chimera (PROTAC) that specifically promotes the degradation of LZK, leading to decreased expression of MYC, GOF mutant p53, suppression of cell cycle progression and limits tumor growth.  

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 Discovery of Bcl-xL Degraders: A PROTAC Strategy for Tissue-Selective Targeting

Guangrong Zheng, PhD, Associate Professor, Department of Medicinal Chemistry, College of Pharmacy, University of Florida

Bcl-xL plays a key role in cancer cell survival. However, development of drugs targeting Bcl-xL has been thwarted by the on-target platelet toxicity because platelets depend on Bcl-xL to maintain their viability. To circumvent this toxicity, we have applied the proteolysis targeting chimera (PROTAC) technology to design small-molecules that target Bcl-xL to E3 ligases for degradation. This proof-of-concept study demonstrates the potential of utilizing a PROTAC approach to achieve tissue selectivity.

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 Sponsored Presentation (Opportunity Available)

5:10 Plenary Keynote Introduction (Sponsorship Opportunity Available)

5:15 PLENARY KEYNOTE:

Discovery of Bioactive, Passively Permeable Cyclic Peptides: Translating Theory into Practice

Scott Lokey, PhD, Professor, Chemistry and Biochemistry, University of California, Santa Cruz

Cyclic peptides have undergone a renaissance in medicinal chemistry. More and more cyclic peptides are being discovered with surprisingly high passive permeabilities and, in some cases, small molecule-like oral bioavailability. Can we harness that understanding to generate molecules that are both membrane permeable and capable of inhibiting a given therapeutic target? I will describe our latest efforts to predict and control properties in this interesting class of molecules.

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

7:00 Close of Day

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Wednesday, AUGUST 26

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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