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.
FEATURED SESSION: EXPLORING NEW LIGASES
Expanding the Toolbox for PROTAC Development
Alex Bullock, PhD, Associate Professor, Nuffield Department of Medicine, University of Oxford and Principal Investigator at the Structural Genomics Consortium (SGC)
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.
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 cannot only degrade POIs, but also rapidly inform whether different E3 ligases are capable of degrading POIs.
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.
IMPROVING DEGRADER DESIGN AND SPECIFICITY
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 with effective dose of a PROTAC will help avoid saturating doses in the clinic.
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 of the 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.
LOOKING BEYOND UBIQUITIN-BASED DEGRADATION
Harnessing the Cell’s Degradation Machineries Nature’s Way
Laura Itzhaki, FRSC, Professor of Structural Pharmacology, Department of Pharmacology, University of Cambridge and 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.
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 cerebelon, 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.
FINDING THE RIGHT ASSAYS FOR STUDYING DEGRADATION
Targeted Protein Degradation as a Novel Therapeutic Approach
Roy Pollock, PhD, Senior VP, 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.
Targeted Protein Degradation as an Emerging Therapeutic Modality
Nikki Carter, PhD, Associate Director, Discovery Biology, AstraZeneca
This presentation will highlight internal efforts to build state-of the art assay cascades towards understanding the molecular mechanism underlying this intriguing biology, the build of a proteomics platform to define the binding and degradation selectivity of protein degraders, and the hit finding for novel E3 ligase ligands. The identification of novel degraders against two oncogenic targets and their utility as target validation tools and as potential therapeutics for many solid and haematological malignancies will be described.
NOVEL DEGRADERS FOR ONCOLOGY TARGETS
The Cullin-RING Ubiquitin Ligases and Small Molecule-Induced Target Elimination
Yue Xiong, PhD, William R. Kenan Professor of the 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 drug discovery. Multiple 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.
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.
Stay and register to attend the recommended short course.
* The program is subject to change without notice, due to unforeseen reason.