Cambridge Healthtech Institute’s 2nd Annual

PROTACs and Targeted Protein Degradation - Part 1

Emerging Protein Degradation Pathways

September 16 - 17, 2020 ALL TIMES EDT

The ubiquitin-proteasome system (UPS) and the autophagy-lysosome system are the two major pathways responsible for protein degradation and maintenance of proteostasis. They consist of well-controlled, selective mechanisms for intracellular protein degradation and turnover. However, the diversity and complexity of the processes involved make it difficult to target these pathways for therapeutic intervention. The UPS and autophagy pathways hold a lot of promise in seeking out previously “undruggable” targets and for therapeutic intervention. The first part of the PROTACs and Targeted Protein Degradation conference will focus on identifying different ligases, chaperone proteins, deubiquitinating enzymes (DUBs), and proteins that can be modulated for hijacking the ubiquitin-proteasome and autophagy-driven protein degradation.

Wednesday, September 16

NEW TOOLS & ASSAYS FOR DEGRADATION PATHWAYS

9:30 am

A Platform to Fully Exploit the Cell's Quality-Control Machinery for Therapeutic Benefit

Laura Itzhaki, PhD, Professor of Structural Pharmacology, Department of Pharmacology, University of Cambridge; CSO, PolyProx Therapeutics

A common mechanism underpinning the cell’s proteostasis network is the recognition of specific protein substrates by components of the quality-control machineries. The Polyproxin® platform exploits our understanding of these interactions. By combining libraries of target-engagement modules and degradation-inducing modules in a mix-and-match format, we identify the best combination for efficient knockdown of the target. The platform can be applied to diverse targets by co-opting the broadest range of degradation machineries including, but not limited to, the ubiquitin-proteasome system.

9:50 am

Establishing a Screening Toolkit to Guide Rational PROTAC Optimization

Claire Whitworth, PhD, Cell Biologist, Laboratory of Dr. Alessio Cuilli, ACBI Team, Division of Biological Chemistry & Drug Discovery, Dundee University

Recent innovations in PROTAC functionality assays for target affinity, ternary complex stability and cellular potency have enabled significant progress towards a screening toolkit that guides rational PROTAC design. Exemplified by SMARCA PROTAC optimisation, this talk will outline the key profiling parameters to consider within a structure-guided approach to PROTAC drug discovery. It will also provide an overview of the assay platforms at hand to facilitate PROTAC development towards potential cancer therapeutics of the future.

10:10 am

An Affinity-Directed PROtein Missile (AdPROM) System for Targeted Modification of Intracellular Proteins

Gopal Sapkota, PhD, Programme Leader, MRC Protein Phosphorylation & Ubiquitylation Unit, Sir James Black Centre, School of Life Sciences, University of Dundee

The AdPROM system utilizes small, polypeptide binders of intracellular proteins of interest (POIs) linked to specific enzymes as “payload” to target intracellular proteins for desired outcomes; for instance, the use of an E3 ligase targets POI for ubiquitination and destruction. The AdPROM system achieves rapid and efficient modifications of target POIs and is extremely versatile. Therefore, it has the potential to not only reveal the functions of specific modifications within POIs, but to also rapidly inform various intervention strategies to develop heterofunctional molecules.

Dahmane Ouazia, PhD, Assistant Director, Business Development, LifeSensors, Inc.

Current methods for PROTAC drug discovery are inefficient and limited in information. We developed a plate-based methodology for rapid screening of PROTAC-mediated protein poly-ubiquitination, a true measure of PROTAC drug effect. This method is faster, more reproducible and adaptable to in vitro and cell-based approaches.

10:50 am

Chemical Tools to Discover E3 Ligase Inhibitors and Activators

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

In this lecture, I will summarize our efforts to discover small-molecule inhibitors, activators, and hijackers for HECT/RBR E3s ligases. To do so, we have developed two complimentary technologies: UbFluor and covalent fragments. UbFluor allows the ability to discover reversible inhibitors and activators of E3s, while covalent fragment technology allows the ability to discover covalent inhibitors.

11:10 am Coffee Break - View Our Virtual Exhibit Hall
11:25 am

Immediate and Selective Protein Control Using the dTAG System

Behnam Nabet, PhD, Katherine Loker Pinard Fellow, Laboratory of Dr. Nathanael Gray, Dana-Farber Cancer Institute

Targeted protein degradation is a novel chemical modality using pharmacological agents to alter protein abundance. While there are a lack of tools to perturb majority of the proteome, we developed the degradation tag (dTAG) system to selectively dispose of any target protein using small molecule degraders. This talk will summarize the dTAG technology platform and highlight studies demonstrating utility for preclinical target validation and biological investigation in cellular and mouse models.

11:45 am

Protein Engineering Our Way to SARS-CoV-2 Antivirals

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

The rapid spread of SARS-CoV-2 has underscored the need to quickly develop antiviral countermeasures. Here, we present our work using engineered ubiquitin to first identify inhibitory sites on a virally encoded enzyme that is absolutely required for host infection. We then use this information to screen for small molecule antiviral leads. Broadly, our versatile strategy can be used to identify lead compounds in response to future outbreaks.


Fabienne Charrier-Savournin, Life Sciences Technology Platform High Content Reagents Leader, Life Science, PerkinElmer
12:25 pm

How to Exploit the Ubiquitin Signal for PROTACs that Go Beyond Degradation

Tauseef R. Butt, PhD, President & CEO, Progenra, Inc.

Nature synthesizes multiple poly-ubiquitin chains that extend from seven lysines on the ubiquitin surface. Lys 48 and Lys 63 poly-ubiquitin are primary degradation signals for PROTACs, driven by ubiquitin ligases cerebelon, VHL and HDM2. Little is known about the roles of mono-ubiquitin or atypical poly-ubiquitin chains or their cognitive ubiquitin ligases. The roles of classic ubiquitin ligases and atypical ubiquitylation will be discussed with the aim of expanding the horizon of PROTAC drugs beyond protein degradation.

12:45 pm Lunch Break - View Our Virtual Exhibit Hall

NOVEL LIGASES & CHAPERONES FOR DEGRADATION

Gabriela Chiosis, PhD, Member and Tri-Institutional Professor, Sloan Kettering Institute for Cancer Center, Cornell and The Rockefeller University

This talk will focus on detecting and rebalancing proteostasis dysfunctions through epichaperomes. Unlike chaperone proteins, which safeguard how proteins are synthesized and ensure cellular activities are coordinated properly, epichaperomes change how proteins interact with each other. The presence of epichaperomes therefore signifies improper organization of proteins in PPI networks and a pathologic phenotype. Epichaperome detection and targeting in the context of diseases, such as cancer and neurodegenerative disorders including Alzheimer’s and Parkinson’s, will be presented.

1:35 pm

MAGE Family of Cancer-Specific Ubiquitin Ligases

Ryan Potts, PhD, Executive Director and Head, Induced Proximity Platform, Amgen Inc.

Testis-restricted melanoma antigen (MAGE) proteins are frequently hijacked in cancer and play a critical role in tumorigenesis. MAGEs assemble with E3 ubiquitin ligases and function as substrate adaptors (‘protein glue’) that direct the ubiquitination of novel targets. Here, I will discuss how MAGE-A11 promotes tumorigenesis through reprogramming the HUWE1 ubiquitin ligase to ubiquitinate the mRNA 3' end processing complex protein, PCF11. This leads to alternative polyadenylation of many transcripts affecting core oncogenic and tumor suppressors.

Michael Dabrowski, CEO, Pelago Bioscience

We will present recent data from CETSA profiles on both PROTACs and molecular glue molecules. The CETSA HT technology allows parallel quantification of the degradation specificity and efficacy. The CETSA MS profiling of degraders allow simultaneous study of direct binding both its intended protein target, involved E3-ligase and off-targets. 

2:15 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Gabriela Chiosis, PhD, Member and Tri-Institutional Professor, Sloan Kettering Institute for Cancer Center, Cornell and The Rockefeller University
Panelists:
Ryan Potts, PhD, Executive Director and Head, Induced Proximity Platform, Amgen Inc.
Michael Dabrowski, CEO, Pelago Bioscience
2:35 pm Refresh Break - View Our Virtual Exhibit Hall
3:00 pm Interactive Breakout Discussions - View Our Virtual Exhibit Hall

Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Discussion topics and moderators will be listed on the website.

3:35 pm Close of Day

Thursday, September 17

DEGRADING CHALLENGING TARGETS

10:15 am

Targeting a Treg-Specific Deubiquitinase for Anti-Tumor Immune Therapy

Deyu Fang, PhD, Hosmer Allan Johnson Professor, Department of Pathology, Northwestern University, Feinberg School of Medicine

A major hurdle in tumor immunotherapy is understanding how immunosuppression is mediated by regulatory T (Treg) cells, that suppress the function of effector T cells. However, current approaches in targeting Treg to activate antitumor immune responses have shown only transient efficacy and are highly unspecific. Herein we identified USP22 as a potential therapeutic target and its suppression partially diminishes Treg-suppressive functions without impairing effector T cell immunity.

10:35 am

Immunotherapeutic Approaches for Degrading Tau Pathology in Alzheimer's Disease

Gilbert Gallardo, PhD, Assistant Professor, Hope Center for Neurological Disorders, Washington University School of Medicine

Alzheimer’s disease is a tauopathy and the leading cause of dementia worldwide with no disease-modified treatments currently available; however, an emerging therapeutic approach is anti-tau immunotherapies. While conventional immunotherapies are promising, they are limited to targeting extracellular proteins, whereas the majority of pathological tau remain in the cytosol of cells. Therefore, we have engineered anti-tau intrabodies for expression intracellularly that contain distinct tags that shuttle tau to either the proteasome or lysosome for degradation.

Priscilla Yang, PhD, Associate Professor, Department of Microbiology and Immunology, Harvard Medical School

Despite the success of direct-acting antivirals against HIV and HCV, these regimens require combination therapy with multiple highly potent, direct-acting antivirals to be effective and to avoid drug resistance. Here, I will describe our proof-of-concept work developing targeted protein degradation of both viral enzymes and structural proteins as an alternative anti-viral strategy and the potential advantage of this pharmacological approach in avoiding anti-viral resistance.

Jan Baur, Applications Specialist, CAS

Pharmaceutical research teams rely on SciFinder-n, the most advanced research solution in the SciFinder family, to help improve productivity, inspire innovation and feel confident in advancing projects and programs forward. This talk will demonstrate, with practical examples, how SciFinder-n helps solve problems and inspire ideas in protein degradation technology.

11:35 am LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Priscilla Yang, PhD, Associate Professor, Department of Microbiology and Immunology, Harvard Medical School
Panelists:
Deyu Fang, PhD, Hosmer Allan Johnson Professor, Department of Pathology, Northwestern University, Feinberg School of Medicine
Gilbert Gallardo, PhD, Assistant Professor, Hope Center for Neurological Disorders, Washington University School of Medicine
Jan Baur, Applications Specialist, CAS
Dahmane Ouazia, PhD, Assistant Director, Business Development, LifeSensors, Inc.
Fabienne Charrier-Savournin, Life Sciences Technology Platform High Content Reagents Leader, Life Science, PerkinElmer
11:55 am Coffee Break - View Our Virtual Exhibit Hall

PLENARY KEYNOTE PROGRAM

12:20 pm

PLENARY KEYNOTE: Tackling Undruggable Oncoproteins: Lessons from the VHL Tumor Suppressor Protein

William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics

VHL tumor suppressor protein (pVHL) inactivation is common in kidney cancer and upregulates the HIF2 transcription factor. PT2977/MK-6482 is an allosteric HIF2 inhibitor now in Phase 3 testing. Thalidomide-like drugs (IMiDs) bind to cereblon which, like pVHL, is the substrate-binding unit of a ubiquitin ligase. IMiDs redirect cereblon to destroy the myeloma oncoproteins, IKZF1 and IKZF3. We have developed new assays for identifying drugs that can destabilize oncoproteins of interest.

12:45 pm LIVE Q&A:

Plenary Keynote Discussion

Panel Moderator:
Stewart Fisher, PhD, CSO, C4 Therapeutics, Inc.
Panelist:
William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics
12:55 pm LIVE PANEL AND Q&A:

Plenary Keynote Discussion: De-Risking Early Drug Discovery

Panel Moderator:
Nadeem Sarwar, PhD, Founder & President, Eisai Center for Genetics Guided Dementia Discovery, Eisai, Inc.
  • Data Sciences
  • ​Novel Chemical Modalities
  • Investment and Partnering Models
  • COVID-19 Progress as Examples of Successful Partnerships
Panelists:
Anthony A. Philippakis, PhD, Chief Data Officer, Data Sciences & Data Engineering, Broad Institute; Venture Partner, GV
Stephen A. Hitchcock, PhD, Head, Research, Takeda Pharmaceuticals, Inc.
1:35 pm Lunch Break - View Our Virtual Exhibit Hall
2:05 pm Close of PROTACs and Targeted Protein Degradation - Part 1 Conference

Please click here to continue to the agenda for PROTACs and Targeted Protein Degradation - Part 2






Submit a Speaker Proposal