Protein Degradation

Protein Degradation via the ubiquitin-proteasome pathway (UPP) as a target for drug discovery is the main focus of Agbiopro Management BD IP and licensing activities.

As experts in both drug discovery and business development sitting at the heart and origin of the UPP research, we are uniquely positioned to serve as a hub for UPP-related innovation and value creation.

Over the last 15 years, we have accumulated invaluable specific experience in drug discovery in the ubiquitin proteasome system. Our work includes diverse modalities such Degraders, GLUTACs, E3 binders, E3 inhibitors, small molecules, combination molecules, siRNA’s and proprietary discovery platforms and technologies, thus making us a drug discovery hub of excellence in the ubiquitin proteasome system. We work with entrepreneurs and researchers from academia, and collaborate with industry experts to promote the discovery and development of novel therapeutics that target or manipulate components of the UPP.

With a growing list of companies and projects in our portfolio, our specific unique expertise in protein degradation allow us to promote our clients to the next level.

Overview

Intracellular Protein degradation is controlled by the largest regulatory system ever to be discovered in biology, aka the Ubiquitin-Proteasome System (UPS). The selectivity and specificity of the system are attributed to ~1000 regulatory proteins, which are key factors in the generation of numerous diseases and pathological conditions.

Since its’ discovery by Hershko, Ciechanover and Rose the fundamental cellular process of protein degradation became a target for extensive research including efforts to develop novel drugs.

 

The UPP attracted Pharma’s attention due to its’ vast therapeutic potential. The clinical application of the UPP was realized in 2003 with the approval of Proteasome inhibitors, such as Velcade (bortezomib), Carfilzomib (Kyprolis) and ixazomib (Ninlaro), which have become a cornerstone therapy with annual sales of over $1.5 billion. Drugs such as Thalidomide derivative Revlimid, sold by Celgene, created $8.2 billion in 2017. Another cancer drug developed from thalidomide, Pomalyst, generated $1.6 billion. However, whereas efforts to identify ubiquitination inhibitors were largely unsuccessful, the potential to redirect protein degradation by artificially recruiting an E3 ligase, first demonstrated nearly 20 years ago with the E3 ligase BTRC2, has opened up new possibilities.

 

In the past 5 years, the field of targeted protein degradation (TPD) has expanded dramatically, with dozens of exemplified substrates being amenable to this mechanism.

Degraders (e.g. PROTACs, SNIPERs, etc.) are bifunctional small molecules that harness the Ubiquitin-Proteasome System to selectively degrade target proteins within cells. They represent an exciting new modality, repurposing small-molecule ligands to achieve selective degradation (knockdown) of target proteins. Moreover, they have the potential to expand the ‘druggable proteome’, since they can be used to degrade proteins that, although bound, are not effectively inhibited by small molecules. Additional beneficial aspects of TPD include the ability to target overexpressed and mutated proteins, as well as the potential to demonstrate prolonged pharmacodynamics effect beyond drug exposure. Lastly, due to their catalytic nature and the pre-requisite ubiquitination step, exquisitely potent molecules with a high degree of degradation selectivity can be designed.

To date, only a handful of ligases, mainly Cereblon and VHL, have been used for all small-molecule-based selective degradation of target proteins. Hence, there is a need to identify additional E3 ligases that will expand the current repertoire.

 

More than US$ 1.7 billion have been raised so far by Targeted Protein Degradation (TPD) technology companies in financing rounds and from partnering deals.

At the same time, nearly all major pharmaceutical companies have some kind of stake in the field, with many of them pursuing in-house TPD technology development and TPD drug discovery.

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Alonei Abba

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