Original Agenda
We are actively working with our speakers to confirm their availability for the virtual event. Initial response from our speakers has been very positive, and we are optimistic we will have the new programs ready to share here soon.

Cambridge Healthtech Institute’s 2nd Annual

PROTACs and Targeted Protein Degradation - Part 1

Emerging Protein Degradation Pathways

September 16 - 17, 2020

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.

Tuesday, September 15

1:00 pm Pre-Conference Short Course Registration (Premium Package or separate registration required)
2:00 Short Courses 1-9 (see Short Courses page for details)
5:00 Close of Day

Wednesday, September 16

7:00 am Registration and Morning Coffee

NEW TOOLS & ASSAYS FOR DEGRADATION PATHWAYS

8:00 Organizer's Welcome Remarks

Cambridge Healthtech Institute

8:05 Chairperson's Remarks

Denise Field, PhD, Senior Scientist, I&I Chemistry & Chemical Biology, Pfizer Research Labs

8:10

Target Engagement and Protein Degradation: Lessons Learned and Future Applications

Denise Field, PhD, Principal Scientist, I&I Chemistry & Chemical Biology, Pfizer Research Labs

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

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.

9:10

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.

9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
10:25

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.

10:55

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.

11:25

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.

Dahmane Ouazia, PhD, Assistant Director, Business Development, LifeSensors, Inc.
12:10 pm Sponsored Presentation (Opportunity Available)
12:25 Session Break
12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:05 Refreshment Break in the Exhibit Hall with Poster Viewing

NOVEL LIGASES, DUBs & CHAPERONES FOR DEGRADATION

1:50 Chairperson's Remarks

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

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.

2:25

Development of Hsp90 Inhibitors that Induce Protein Degradation or Protein Folding for the Treatment of Cancer and CNS

Brian Blagg, PhD, Charles Huisking Professor of Chemistry and Biochemistry, Director, Warren Center for Drug Discovery, Department of Chemistry and Biochemistry, University of Notre Dame

Hsp90 represents a promising therapeutic target for cancer as inhibition results in the degradation of Hsp90-dependent substrates. Hsp90 is also the master regulator of the pro-survival heat shock response, which provides cytoprotection. Therefore, Hsp90 can be a therapeutic target for the treatment of cancer, as well as neurodegenerative diseases. Based on the natural products geldanamycin, radicicol, novobiocin and cruentaren A, small molecules have been discovered that can segregate these opposing properties and provide a platform for development of anti-cancer agents, neuroprotective agents, and anti-glaucoma treatments.

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
4:05

MAGE Family of Cancer-Specific Ubiquitin Ligases

Ryan Potts, PhD, Associate Member, Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital

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.

4:35

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.

5:05 Transition to Breakout Discussion Groups
5:15 Interactive Breakout Discussion Groups
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. Visit the conference website for discussion topics and moderators.
6:15 Welcome Reception in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)
7:15 Close of Day

Thursday, September 17

7:30 am Registration and Morning Coffee

INNOVATIVE PLATFORMS FOR CHALLENGING TARGETS

8:00 Chairperson's Remarks

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

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.

8:35

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.

9:05 Sponsored Presentation (Opportunity Available)
9:35 Coffee Break in the Exhibit Hall with Poster Viewing
10:20

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.

11:20 Enjoy Lunch on Your Own
11:20 Conference Registration for Part B Programs

PLENARY KEYNOTE PROGRAM

12:20 pm Event Chairperson's Opening Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target 2020, Cambridge Healthtech Institute
12:30 Plenary Keynote Introduction (Sponsorship Opportunity Available)
12:40

Tackling Undruggable Oncoproteins: Lessons from the VHL Tumor Suppressor Protein

William G. Kaelin, Jr., MD, Professor and Investigator, Howard Hughes Medical Institute, Oncology, Dana-Farber Cancer Institute

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.


1:20 KEYNOTE PANEL 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
Andrew Plump, MD, PhD, President, Research & Development, Takeda Pharmaceuticals, Inc.
2:00 Close of Plenary Keynote Program
2:00 Dessert Break in the Exhibit Hall with Poster Viewing
2:45 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

RECOMMENDED PREMIUM PACKAGE:
Choose 2 Short Courses and 2 Conferences/Training Seminars
Sept. 15 Short Course: SC4: Biochemistry and Pharmacology of the Ubiquitin-Proteasome System
Sept. 16-17 Conference: PROTACs and Targeted Protein Degradation – Part 1
Sept. 17 Dinner Short Course: SC11: Insights into PROTACs and Targeted Protein Degradation
Sept. 17-18 Conference: PROTACs and Targeted Protein Degradation – Part 2