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Pre-Conference Technical Deep-Dive Day
October 22, 2019

WORKSHOP A

From Concept to Clinic: How Academia-Industry Collaboration Can Expedite PROTAC Drug Discovery

8.30 - 10.30

This workshop will seek to address how academia-industry collaboration has and may continue to uncover strategic and scientific paths to significantly accelerate PROTAC drug discovery. With new assays, chemistries and translational approaches being established on an almost monthly basis within this field, staying ahead of the curve requires more than a mere reactionary approach to what is published or attempting to innovate in isolation.

Attendees will discuss:
• How collaboration models may harness a unique team science culture to impact project success
• Technical lessons learned in multiple PROTAC projects allowing (de)validation faster in collaboration than could have been possible in isolation
• How open innovation platforms can enrich learnings as an increasing number of new PROTAC probes become available
• How the collaborative development and uptake of novel assay approaches can accelerate PROTAC discovery
• How novel E3 ligase and linker chemistry has been brought to projects faster and delivered active PROTACs more efficiently

William Farnaby

William Farnaby
Team Leader, Medicinal Chemistry and Chemical Biology
University of Dundee

William Farnaby is currently a team leader in medicinal chemistry and chemical biology at the School of Life Sciences, University of Dundee. Since 2016 he has led a multidisciplinary team of drug discovery scientists engaged in a collaboration between Professor Alessio Ciulli and Boehringer Ingelheim.

WORKSHOP B

Leveraging Protein Degradation to Tackle Challenging Targets

8.30 - 10.30

Technologies to selectively degrade target proteins using heterobifunctional ligands have been increasingly adopted into medicinal chemistry programs, owing to the advantages they offer over traditional small-molecule based strategies. However, their potential is only beginning to be realized. This interactive workshop session will delve into recent successes and ongoing challenges in the field. We will give an academic perspective on how to set up an efficient workflow to develop small molecule degraders, drawing on examples targeting kinases and previously undruggable proteins.

Attendees will discuss:
• Strategies to identify proteins amenable to targeted degradation
• Target validation approaches using degrader systems
• Key experimental workflows for characterizing degrader mechanism and specificity
• Degradation versus inhibition effects of targeted protein degraders
•Approaches for targeting challenging proteins such as KRAS and other disease driving targets in cancer and neurodegeneration diseases

Behnam Nabet
Fleur Ferguson

Behnam Nabet & Fleur Ferguson
Research Fellows
Dana-Farber Cancer Institute

Behnam Nabet and Fleur Ferguson are Postdoctoral Research Fellows in the laboratory of Dr. Nathanael Gray, where Behnam developed a generalizable technology platform known as the dTAG system to rapidly degrade any target protein of interest and Fleur’s research focuses on the development of chemical tools for interrogating the biological function and therapeutic potential of disease targets in cancer and neurodegeneration.

10.30

Networking & Morning Refreshments

WORKSHOP C

Empowering the Future of Drug Discovery with Bifunctional Degraders and Glues: Status and Strategy

11.30 - 13.30

Bifunctional degraders have emerged as an exciting drug modality, offering a novel approach to provide drug candidates for known and new disease targets through targeted degradation. Using literature examples, this workshop will provide a comparative overview of molecular glues and bifunctional degraders in targeted protein degradation, allowing for interactive discussion to weigh the practical and strategic considerations of bifunctional degrader- and glue-based drug discovery approaches as they exist now and to imagine what might be required for success in the future.

Attendees will discuss:
• Should bifunctional degraders and molecular glues be approached differently from a drug discovery perspective? What are the perceived risks, benefits and
challenges of each approach?
• How is selectivity achieved for these drug classes?
•What is the status and need in key enabling screening technologies for discovery in directed protein degradation for glues? For bifunctional degraders?
•What supporting tools are important to improve the design and optimization of bifunctional degraders and molecular glues?
•Can the scope of protein degradation by glues and bifunctional degraders be expanded to ensure growth and continued success in this important new area of drug discovery? What are the perceived barriers to future success?

Ted Sue

Ted Suh
Vice President, Chemistry
Orionis Biosciences

Ted Suh has more than 25 years of drug discovery experience in a variety of therapeutic
areas. He began his career at Glaxo, directly contributing to several programs in
metabolic disease. In his current role at Orionis Biosciences, Ted aligns core proteomescale screening capabilities with focused chemical approaches to enable the discovery of
such entities as molecular glues and allosteric modulators to produce novel therapeutics.

WORKSHOP D

Expanding the Horizon with New Insights into the Function of the Neuronal Proteasomes

11.30 - 13.30

Exploring new avenues in the area of protein degradation to treat human disease is exciting and important. As such it is important to think about proteasomes and their function in the cell, to gain a more comprehensive perspective on the process of degradation. This collaborative workshop aims to discuss the utility of targeting proteins to the proteasome beyond degrading them.

Attendees will discuss:
•What are tissue specific proteasomes?
•What do specific proteasomes do in the cell?
•What are brain specific proteasomes and ubiquitin ligases?
•What are brain specific proteins that could be targeted for degradation and how are they relevant to human disease?
•Where and when should these proteins be targeted?

Seth Margolis

Seth Margolis
Associate Professor
Johns Hopkins University

Since joining the Johns Hopkins faculty in 2011, Dr. Margolis and his group use
genetically engineered mouse models of disease and a multidisciplinary approach that
combines aspect of molecular biology, biochemistry and in vivo synapse imaging in
order to develop hypothesis about protein degradation in the nervous system and its
relationship to the underlying cause of synapse degeneration and cognitive decline.

13.30

Networking & Afternoon Refreshments

WORKSHOP E

Enabling Technologies for Targeted Degradation: Ligand Discovery using DNA-Encoded Small Molecule Libraries

14.30 - 16.30

Use of DNA-encoded libraries in the pharmaceutical industry has rapidly increased. Multiple methods exist for directing and encoding library synthesis, demonstrating the robust nature of this informational and functional platform. This exciting workshop discusses the fundamentals, strategies and opportunities where DNA- encoded libraries can advance your targeted protein degradation strategies.

Attendees will discuss:
• The fundamentals of DNA-encoded library design with a focus on library size, diversity, synthetic efficiency and purity, as well as considerations for controlling compound properties in combinatorial chemistry space
• General strategies for effective affinity selection with special considerations for the use of this technology to identify ligands suitable for targeted degradation applications • Best practices for data analysis and hit identification when using DNA encoded libraries
• Discussion on approaches for hit follow-up and early SAR exploration, including strategies for hit resynthesis as well as data mining and virtual screening
• Latest advancements in the field with a highlight on activity-based DNA-encoded library screening

Gwenn Hansen

Gwenn Hansen
Vice President, Drug Discovery Technologies
Nurix

Gwenn Hansen is currently Vice President of Drug Discovery Technologies at Nurix Therapeutics, a company focused on discovering and developing next-generation therapies that target protein homeostasis through modulation of the ubiquitin proteasome system. Since joining Nurix more than 3 years ago, Gwenn has focused on establishing the company’s DNA encoded library technology platform for small molecule discovery, and leads teams of scientists in both early discovery as well as medicinal chemistry.

WORKSHOP F

Maximizing the Therapeutic Index – Degrader Design and In Vivo Models

14.30 - 16.30

Targeted protein degradation is an exciting but still emerging field, with no published clinical data, making “lessons learned” a future goal for all of us. This interactive workshop will provide an overview of recent preclinical efficacy data, will discuss target selection and E3 ligase selection, and will compare efficacy and tox models to those used for other drug classes.

• Is there a “best” E3 ligase for targeted protein degradation, based on efficacy?
• Target selection: should we focus on degrader versions of existing drugs to established druggable targets (like AR or BTK) versus degraders of “undruggable” targets (like K-Ras or AR-v7) • Optimizing in vitro DC50: Is higher affinity to protein target always better? To E3 ligase? Linker length/composition?
• Is maximizing therapeutic index (T.I.) best achieved through target selection versus E3 ligase selection? •What are the most relevant in vivo models for efficacy? For cancer, mouse syngeneic tumors vs human cell-line xenografts vs patient-derived xenografts. What is a better readout: tumor regression vs DC50 or DC90?
• Translating preclinical T.I. into clinic: efficacy/tox in same species? In vivo efficacy versus in vivo target engagement?

Kurt Gish

Kurt Gish
Chief Scientific Officer
Trilo Therapeutics

Dr. Kurt Gish is co-founder and Chief Scientific Officer at Trilo Therapeutics. Kurt started his career in cancer research with scientist positions at Affymetrix and Eos Biotechnology, followed by positions as Director of Biologics Technologies at PDL BioPharma and Research Fellow at AbbVie. With >20 years’ experience in target discovery and therapeutics development, he has led two products from concept into phase I human
trials and is the inventor on 24 issued US patents and author on 18 peer-reviewed articles.