Session 3. Targeted Protein Degradation

In this session, we would like to focus on emerging technologies and approaches that will shape the future of TPD and expand the therapeutic impact of both glue degraders and bifunctional degraders (PROTACs). We would like to cover the following aspects:
– Enriching the toolset of E3 ligases that can be hijacked for TPD beyond the most used CRBN and VHL could have an impact in terms of avoiding resistance or enabling tissue targeted degradation: how to identify new E3 ligases that bear promises for TPD?
– Further extending the “degradable proteome” to hard-to-drug proteins might require alternative approaches that trigger degradation via non-E3 dependent mechanisms of action, what are up-and-coming concepts in those directions?
– Glue degraders have historically demonstrated that they can lead to the degradation of proteins thought to be undruggable, such as transcription factors. Nevertheless, the identification of new glue degraders has been hampered by the lack of methodology to rationally identify those types of small molecules. What are the newest methodologies to screen for glue degraders?

Targeted protein degradation: a building block approach to develop novel drugs

Targeted protein degradation by means of Proteolysis targeting chimeras (Protacs) has emerged as a strategy to deplete proteins for therapeutic purposes and as a source of drug discovery with high potential. Conventional Protacs are heterobifunctional molecules that simultaneously interact with a ubiquitin ligase and the protein intended to degrade, the target. In the last decade, the concept of proteolytic chimeras has included novel degrading mechanisms, expanding the potency of the method. We present here an approach based on combinations of ligands and linkers, in which novel targeting systems are explored.

Optimisation strategies for the development of orally bioavailable VHL-recruiting PROTAC degraders

Targeted protein degradation (TPD) is a powerful emerging modality in drug discovery. TPD molecules including Proteolysis Targeting Chimeras (PROTACs) have been used to modulate protein targets that were long considered “undruggable” and can convey additional benefits over conventional small molecule methods including improved potency and selectivity.

Utilising the full advantages of TPD necessitates optimisation of degrader molecules, which in turn requires a detailed understanding of the mechanism of action of the compounds. The TPD field continues to make rapid progress to expand the toolbox of cell-based methods, biophysical assays and structural approaches to scrutinise and enhance the potency of PROTACs and other degraders.

In this presentation I will outline a perspective from the Centre for Targeted Protein Degradation (CeTPD) in the University of Dundee on the benefits and challenges of the PROTAC approach to drug discovery, and will outline some of the approaches we take to design and optimise degrader molecules. I will also provide case studies of our recently disclosed VHL-recruiting orally bioavailable PROTACs ACBI2 and XL01126.

Targeted protein degradation: adventures with undruggable E3 ligases

E3 ligases have been largely described as a relevant target family in disease. Besides, the irruption of the TDP strategy has situated this target family at the forefront. The recent development and identification of a handful number of specific drug-like molecules targeting E3 ligases (e.g. VHL) have exceptionally improved the perspectives of the PROTAC strategy. Here, I will first present a structure-based computational approach to study E3 ligases ligandability. We identified ligandable allosteric pockets in the major part of the E3 ligases studied. Remarkably, the Fbw7 E3 ligase presented an extremely interesting scenario of allosteric pockets for drug discovery purposes. Giving also its biological relevance in cancer recruiting crucial oncogenes such as c-Myc, cyclin-E and Notch, we selected the “undruggable” Fbw7 as a benchmark E3 ligase to develop a structure-based approach that combines computational and biophysical techniques intending to discover small molecules.

The Emerging Role of Proteomics in Drug Discovery

Proteomics has evolved to be one of biotechnology’s most essential tools to drive drug discovery over the years. Recent developments in mass spectrometry-based proteomics instrumentation, data analysis pipelines and artificial intelligence have helped the scientific community to dig (even) deeper into the proteome. Overall, this has enabled the granular study of disease phenotypes and their modulation by bioactive molecules, as well as a better understanding of potential toxicity of drugs in cells. Here we will discuss how proteomics plays a crucial role in targeted protein degradation based therapies by providing guidance for experimental strategies that are critical for success at both discovery and preclinical phases.

Organised by SDDN in collaboration with Fundacion Medina



CIF G18889444