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Cambridge Healthtech Institute (CHI) is closely monitoring the continuing developments on COVID-19. Currently, there is no plan to cancel or postpone this event. CHI is tracking all travel restrictions issued by the U.S. Government, as well as information and guidance from the U.S. Centers for Disease Control and Prevention(CDC) and the World Health Organization (WHO).  

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Cambridge Healthtech Institute’s conference on PROTACs and Beyond will bring together a diverse group of chemists, biologists and pharmacologists to discuss the prospects, as well as the challenges underlying the various strategies for targeted protein degradation. They will also discuss the new molecular degraders, linkers and ligases being developed, and the assays and tools that are being used to further expand their potential.



FINAL CONFERENCE AGENDA

Sunday, 8 March

LOOKING BEYOND UBIQUITIN-BASED DEGRADATION

13:00 Organizer’s Welcome Remarks

13:15 Chairperson’s Remarks

Markus Queisser, PhD, Scientific Leader, Protein Degradation DPU, R&D Future Pipelines Discovery, GlaxoSmithKline

13:20 Development of a Phenotypic and Agnostic Approach to Identify New E3 Ubiquitin Ligases for Targeted Protein Degradation

Markus Queisser, PhD, Scientific Leader, Protein Degradation DPU, R&D Future Pipelines Discovery, GlaxoSmithKline

We report a novel, unbiased, phenotypic screening approach for the identification of such chemical matter. The key concept of the assay is the chemical modification of screening compounds and the evaluation of their ability to recruit E3 ligases by a simple fluorescence-based readout in an easy to setup cellular screening system. This combines, for the first time, high-throughput chemistry with high-content screening in living cells.

13:50 How to Exploit the Ubiquitin Signal for PROTACs that Go beyond Degradation

Tauseef R. Butt, PhD, President and 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 cereblon, 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.

14:20 TECHNOLOGY PANEL: Advancements in Assays and Technologies for Protein Degradation

Moderator: Markus Queisser, PhD, Scientific Leader, Protein Degradation DPU, R&D Future Pipelines Discovery, GlaxoSmithKline

Panelists: Gary Allenby, PhD, Aurelia Bioscience

Hannah Maple, PhD, Innovation Manager, Bio-Techne

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

 

15:00 Opening Refreshment Break

FEATURED SESSION: EXPLORING NEW LIGASES

15:35 Expanding the Toolbox for PROTAC Development

Zhuoyao Chen, PhD, Research Scientist, Laboratory of Dr. Alex Bullock, Nuffield Department of Medicine, University of Oxford

The discovery of PROTACs remains empirical and can fail due to the limited choice of E3s. To date only ~1% of the 600 E3s have been explored for PROTACs. We are developing chemical handles for an expanded set of E3s with distinct structural properties as well as diverse temporal and spatial expression profiles to expand the potential applications of PROTACs for chemical biology and broaden the horizon for future drug discovery efforts.

16:05 Targeted Proteolysis through the Affinity-Directed PROtein Missile (AdPROM) System

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 E3 ubiquitin ligases linked to small, polypeptide binders of intracellular proteins of interest (POIs) as protein missiles to target the destruction of the POIs through the proteasome. The system achieves rapid and efficient degradation of target POIs and is versatile. The AdPROM system can not only degrade POIs but also rapidly inform whether different E3 ligases are capable of degrading POIs.

16:35 The Cullin-RING Ubiquitin Ligases and Small Molecule-Induced Target Elimination**

Yue Xiong, PhD, William R. Kenan Jr. Professorship of Biochemistry and Biophysics, University of North Carolina;     Co-Founder, Cullgen

Development of small molecules to target ubiquitin-dependent degradation of disease-linked proteins represents a promising opportunity for the drug discovery. Multiple such small molecules have been developed based on different E3 ubiquitin ligases. I will discuss the catalytic mechanism, assembly and regulation of cullin-RING E3 ubiquitin ligases (CRLs). I will also present our efforts in developing novel degraders targeting different human cancer protein. Finally, I will share the thoughts on developing novel E3 ligands.

17:05 Close of Day

Monday, 9 March

DEVELOPING THE RIGHT ASSAYS FOR STUDYING DEGRADATION

9:00 Chairperson’s Remarks

Roy Pollock, PhD, Senior Vice President, Biology, C4 Therapeutics

9:10 Targeted Protein Degradation as a Novel Therapeutic Approach

Roy Pollock, PhD, Senior Vice President, Biology, C4 Therapeutics

The ability to direct proteins for degradation by the ubiquitin-proteasome system using heterobifunctional small molecules has created a unique opportunity to treat human diseases. Targeted protein degradation (TPD) offers the potential for more profound ablation of protein function and broadens the spectrum of addressable therapeutic targets. In this presentation, I will use BRD4 as a case study to illustrate our approach to TPD including the critical assays used and how they inform on degrader development.

9:40 Plasticity of the Cullin-RING Ligase Repertoire Shapes Sensitivity to Degraders

Cristina Mayor-Ruiz, Postdoctoral Fellow, Laboratory of Dr. Georg Winter, CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences

We set out to systematically delineate all cellular effectors required for targeted protein degradation (TPD). We found that sensitivity to degraders is mainly dictated by shared modulator networks, with some exciting, ligase-specific differences. Perturbation of these effectors impairs cullin-RING ligase (CRL) plasticity and arrests many of them in a constitutively active state. Collectively, our study informs on regulation of CRLs amenable for TPD, and outlines biomarkers and putative resistance mechanisms for upcoming clinical investigation.

10:10 Coffee Break

FINDING NOVEL DEGRADERS

10:40 Efficient Targeted Degradation via Reversible and Irreversible Covalent PROTACs**

Ronen GabizonRonen Gabizon, PhD, Staff Scientist, Department of Organic Chemistry, Weizmann Institute

Covalent PROTACs are assumed to be inferior due to the non-catalytic nature of their activity. We designed and tested covalent PROTACs targeted against BTK and compared them to non-covalent analogs. We discovered a reversible covalent PROTAC with sub-µM potency and an irreversible covalent PROTAC with nM potency, among the most potent BTK PROTACs reported to date. Our results confirm the potential of covalent PROTACs against proteins that are difficult to target with noncovalent binders. 

11:10 Structure-Based Design of a Macrocyclic PROTAC

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

Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy that to date remains unprecedented for bifunctional molecules such as PROTAC degraders. The talk will illustrate the design, synthesis, biophysical studies and crystal structure of a macrocyclic PROTAC targeting BET proteins.

12:10 Enjoy Lunch on Your Own

IMPROVING DEGRADER DESIGN AND SPECIFICITY

13:10 Chairperson’s Remarks

Tanuja Koppal, PhD, Senior Conference Director

13:15 Activating E3 Ligases to Improve PROTACs

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

Although the development of PROTACs has garnered significant attention, several challenges remain, including therapeutic dosing. This is largely due to the hook effect resulting from saturating PROTAC molecules. Here, we present our work on finding ways to activate E3 ligases, which should improve the efficiency of a PROTAC. Improving efficiency will decrease the effective dose of a PROTAC and help avoid saturating doses in the clinic.

13:45 Harnessing the Cell’s Degradation Machineries Nature’s Way**

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

The common underpinning basis of the cell’s proteostasis network is molecular recognition involving the specific interactions of proteins with one another. The Polyproxin™ platform exploits our understanding of these interactions to harness proteostasis networks and thereby manipulate protein stability and disease outcome. The platform comprises libraries of target-engagement modules and degradation-inducing modules in a mix-and-match format to identify the best combination for effective knockdown of the target. The platform can thereby be directed to diverse targets and disease states by co-opting the broadest range of degradation machineries including, but not limited to, the ubiquitin-proteasome system.

14:15 Large-Scale Proteomics Approaches to Enable Degrader Development for Challenging Targets in Cancer**

Katherine Donovan, PhD, Scientist, Laboratory of Dr. Eric Fischer, Cancer Biology, Dana-Farber Cancer Institute/Harvard Medical School

Small molecules that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. We and others have demonstrated that efficacious degradation of kinases and other targets can be achieved in vitro and in vivo, however, many targets remain recalcitrant to degradation. In this presentation, I will discuss the use of large-scale chemical-proteomics approaches to accelerate the development of degraders as novel chemical probes for kinases and other disease targets.

14:45 End of Conference/Registration for Short Course

 

**Presentations delivered via a live, interactive video conferencing platform.