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 2

Novel Protein Degraders

September 17 - 18, 2020

The UPS and autophagy pathways act as key regulators in cancer, CNS, and other diseases. Small molecules, such as proteolysis-targeting chimeras (PROTACs), E3 ligase modulators like thalidomides, DUB inhibitors, as well as other chemical and biological entities are being developed to hijack the UPS and trigger targeted protein degradation. However, some challenges do exist in terms of stability, biodistribution, and penetration of these molecules in vivo. The second part of the PROTACs and Targeted Protein Degradation conference will discuss ways to design and optimize these molecules for better in vitro to in vivo translation.

Thursday, September 17

11:20 am 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

PROTEIN DEGRADERS AS THERAPEUTICS

2:45 Organizer's Welcome Remarks

Cambridge Healthtech Institute

2:50 Chairperson's Remarks

Stewart Fisher, PhD, CSO, C4 Therapeutics, Inc.

Stewart Fisher, PhD, CSO, C4 Therapeutics, Inc.

Targeted protein degradation is an exciting new drug modality that is based on small molecules that act as catalytic activators for an E3 ligase and target protein.  This approach has the potential to transform drug discovery and his talk will discuss our approaches to lead identification and lead optimization that enables progression towards the clinic.

3:25

Expanding the Toolbox of Targeted Protein Degradation

Andrea Testa, PhD, Head, Chemistry, Amphista Therapeutics Ltd.

Targeting proteins for proteasomal degradation is an emerging and transformational therapeutic modality. However, the limited number of E3 ligases recruitable by small molecules constitutes a limitation in terms of scope of degradable targets, resistance profile, and cell type-specific toxicity. Amphista has identified drug-like bifunctional compounds that, independently from the traditional E3 ligases generally used, induce profound, fast and selective degradation of a broad range of clinically relevant targets.

3:55 Sponsored Presentation (Opportunity Available)
4:25 Refreshment Break in the Exhibit Hall with Poster Viewing
5:00

Targeted Degradation of Therapeutic Targets Using bioPROTAC mRNA

Anthony Partridge, PhD, Senior Principal Scientist, Merck Sharp & Dohme

bioPROTACs are fusion proteins consisting of a target-binding domain and a truncated E3 ligase.  As such, these intracellular biologics can deplete a protein-of-interest through targeted degradation. Here, I will provide an update on our efforts to advance bioPROTACs as a biological tool and potential novel therapeutic modality with a focus on mRNA as an approach to achieve intracellular expression in target cells.    

5:30

Proteolysis Targeting Chimeras in Drug Development

Fiona Pachl, PhD, Senior Scientist, Chemical Biology and Proteomics, AstraZeneca

Targeted protein degradation by small molecules has shown consolidated promise as a new pharmacological approach. We give an overview of our lead generation cascades for the protein degradation modality with a focus on proteomics strategies to define degraders' selectivity and mechanism of actions. We will discuss case studies on oncogenes and suppressors of tumorgenesis by targeted degradation of PRC2 complex.

6:00

Expanding the Chemical Space of PROTACs with Novel Ligase Ligands

Suresh Kumar, PhD, Senior Director R&D, Progenra, Inc.

Chemical knock-down of proteins by PROTACs is a paradigm shift in the drug discovery field. Currently, PROTACs based on Cereblon, VHL, HDM2 and cIAPs have been exploited by medicinal chemists to degrade a limited set of therapeutic targets. By focusing on novel ubiquitin ligases, Progenra has discovered entirely new classes of PROTACs with applications in oncology, inflammation, and neuroscience.

6:30 Dinner Short Course Registration (Premium Package or separate registration required)
7:00 Dinner Short Courses 10-12 (see Short Courses page for details)
9:30 Close of Day

Friday, September 18

7:00 am Registration
7:30 Interactive Breakfast Breakout Discussion Groups
Grab a cup of coffee and 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.
8:30 Transition to Sessions

DESIGNING PROTACs

8:40 Chairperson's Remarks

Lu Zhang, PhD, Senior Scientist, Cancer Biology, Oncology Discovery, Abbvie Inc.

8:45

Design of PROTAC Degraders for Clinical Development

Shaomeng Wang, PhD, Warner-Lambert/Parke-Davis Professor of Medicine, Pharmacology & Medicinal Chemistry; Co-director, Molecular Therapeutics Program; Director, Cancer Drug Discovery Program, University of Michigan

I will present our discovery and optimization of PROTAC degraders with the objectives to identify suitable candidate compounds for clinical development. First, I will present our discovery and development of degraders against STAT3 and other STAT members, a class of traditionally difficult-to-drug targets and our extensive in vitro and in vivo evaluations.  Second, I will present our discovery and development of highly potent and orally active PROTAC degraders of androgen receptor, estrogen receptor, and MDM2, among others.

9:15

A Modular PROTAC Design for Target Destruction Using Single Amino-Acid 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.

9:45

Targeted Protein Degradation for the Treatment of Cancer

Jing Liu, PhD, Executive Director, Medicinal Chemistry, Cullgen, Inc.

Our research focuses on leveraging our ubiquitin-mediated, small molecule-induced protein degradation technology for the treatment of cancer and other diseases. I will present the discovery and evaluation of first-in-class potent and selective degraders of an oncogenic target that inhibited cell growth with low nanomolar IC50 values and demonstrated sustained degradation in xenografted tumor models.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

OPTIMIZING PHYSICOCHEMICAL PROPERTIES

10:55

Using PROTAC Technology to Overcome On-Target Drug Toxicity: The Story behind DT2216

Daohong Zhou, MD, Professor, Department of Pharmacodynamics, College of Pharmacy, University of Florida at Gainesville

The on-target and dose-limiting thrombocytopenia limits the use of BCL-XL inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce this toxicity, we converted ABT263 into DT2216, a BCL-XL PROTAC that targets BCL-XL to VHL for degradation. DT2216 was more potent against cancer cells, but less toxic to platelets than ABT263, because VHL is poorly expressed in platelets. This demonstrates the use of PROTACs to reduce on-target drug toxicities.

11:25

Acquired Resistance to BET-PROTACs Caused by Genomic Alterations in Core Components of E3 Ligase Complexes

Lu Zhang, PhD, Senior Scientist, Cancer Biology, Oncology Discovery, AbbVie Inc.

With PROTACs progressing rapidly towards therapeutic applications, it is important to understand whether and how resistance to these novel agents may emerge. Using BET-PROTACs as a model system, we demonstrate that resistance to both VHL- and CRBN-based PROTACs was primarily caused by genomic alterations that compromise core components of the relevant E3 ligase complexes. This study reveals a novel resistance mechanism distinct from current targeted therapies and warrants future investigations.

Chao-Tsung Yang, PhD, Principal Scientist, Research & Development, Eurofins DiscoverX

 

 

 

 

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

TARGETED KINASE DEGRADATION

1:50 Chairperson's Remarks

Fleur Ferguson, PhD, Research Fellow, Biological Chemistry & Molecular Pharmacology, Dana-Farber Cancer Institute

Jian Jin, PhD, Mount Sinai Endowed Professor in Therapeutics Discovery; Professor, Departments of Pharmacological Sciences & Oncological Sciences; Director, Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai
2:25

Hi-JAK-ing the Ubiquitin System: The Design and Physicochemical Optimisation of JAK PROTACs

Rishi Shah, PhD, Senior Scientist, Medicine Design, GSK

This talk outlines the design, physicochemical optimisation, and biological activity of a set of novel PROTACs targeting the JAK family of proximal membrane-bound proteins. JAK PROTACs from two distinct chemotypes were designed, optimising the physicochemical properties for each template to enhance cell permeation. These PROTACs are capable of inducing significant JAK1/JAK2 degradation, demonstrating an extension of the PROTAC methodology to an unprecedented class of protein targets and their mechanisms of action.

2:55

Degradation of Important Oncology Targets via PROTACs: TrkC and CDK4/6

Kevin Burgess, PhD, Rachal Professor of Chemistry, Texas A&M University

PROTACs will draw an E3 ligase and the protein target into proximity to deliver ubiquitin to the target, if there is a synergistic binding between the two proteins; that ubiquitinylation will cause degradation of the target protein in the proteasome. This talk describes PROTACs we have formed for two target proteins: TrkC and CDK4/6. We will explain why these proteins are important, why degradation (or inhibition) of CDK4/6 is desirable, but insufficient for chemotherapy, and our strategy to attempt to work around this. Also covered will be some of our work on “tumor-seeking cyanine dyes” conjugated to kinase inhibitors.

3:25

Chemoproteomic Approaches to Interrogate the Degradable Kinome

Fleur Ferguson, PhD, Research Fellow, Biological Chemistry & Molecular Pharmacology, Dana-Farber Cancer Institute

Targeted protein degradation has rapidly gained traction as a promising therapeutic approach for targeting these functions. Despite this, relatively little is understood about the factors governing a target's propensity for ubiquitination and degradation by specific E3-ligases, and the influence of chemical and cell type-specific variables on the effects of a given degrader molecule. We employed a chemo-proteomic approach to systematically characterize the factors that influence endogenous kinase degradation in different cellular contexts, profiling a library of well-characterized, diverse kinase degraders using a quantitative global proteomics approach.

3:55 Close of Conference





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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