Cambridge Healthtech Institute’s 2nd Annual

PROTACs and Targeted Protein Degradation - Part 2

Novel Protein Degraders

September 17 - 18, 2020 ALL TIMES EDT

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

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

PROTEIN DEGRADERS AS THERAPEUTICS

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.

2:25 pm

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.

2:45 pm

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.

3:05 pm Session Break
3:45 pm Happy Hour - View Our Virtual Exhibit Hall
4:15 pm Close of Day

Friday, September 18

DESIGNING NOVEL PROTACs

10:00 am

Targeted Degradation of KRAS through mRNA Delivery of Protein-based Degraders

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

Biodegraders 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 biodegraders as a biological tool and potential novel therapeutic modality with a focus on mRNA as an approach to achieve intracellular expression in target cells.   


10:20 am

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.

10:40 am

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.

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

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.

11:20 am

TRKing Down an Old Oncogene in a New Era of Targeted Protein Degradation

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.

11:40 am Coffee Break - View Our Virtual Exhibit Hall

TARGETED KINASE DEGRADATION

11:55 am

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. 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.

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

The Jian Jin Laboratory at Mount Sinai is a leader in developing novel small-molecule degraders targeting oncogenic proteins. Our recent progress in this area, including discovery of first-in-class EZH2 and MEK1/2-selective degraders, will be presented. 

12:35 pm Session Break
12:55 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Fleur Ferguson, PhD, Research Fellow, Biological Chemistry & Molecular Pharmacology, Dana-Farber Cancer Institute
Panelists:
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
Ksenya Cohen Katsenelson, PhD, Senior Scientist & Group Leader, San Diego R&D, Eurofins Discovery
Chao-Tsung Yang, PhD, Principal Scientist, San Diego R&D, Eurofins DiscoverX
1:15 pm Refresh Break - View Our Virtual Exhibit Hall
1:25 pm Brown Bag Lunch and Interactive Breakout Discussions - View Our Virtual Exhibit Hall

Grab your own lunch 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. Discussion topics and moderators will be listed on the website.


BREAKOUT: What Are Some of the Challenges in Bringing Protein-Degrader Drugs to the Clinic?

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
Daohong Zhou, MD, Professor, Department of Pharmacodynamics, College of Pharmacy, University of Florida at Gainesville
  • Improving degrader efficacy
  • Minimizing on-target drug toxicity
  • Translational challenges
Ashish Chougule

OPTIMIZING PHYSICOCHEMICAL PROPERTIES

2:00 pm

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.

2:20 pm

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.

2:40 pm

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.

3:00 pm Close of Conference

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