A alternative approach in drug development: Targeted protein degradation


The concept of targeted protein degradation as an alternative approach to small molecule protein inhibition has many attractive potentials. The catalytic nature of protein degraders means that a lower systemic exposure may be needed to achieve the desired therapeutic effect when compared to a small molecule inhibitor – which may need a higher concentration to maintain occupancy of a binding site. These lower systemic exposures can have the benefit of a reduced risk of off-target and toxic side effects. Another advantage of targeted protein degradation is that the protein ligand need not bind at a site that inhibits the protein. This approach could now open the door to investigate desirable targets that were previously thought to be undruggable.

Lewis 1

Figure 1

In order to achieve targeted protein degradation a ligand would need to be designed that binds to the protein to be degraded. This ligand is then attached via a linker to an E3 ligase ligand (Figure 1). When a target protein ligand has a linker of an optimal composition/length, and is also attached at position that does not affect binding to the target protein, protein degraders with picomolar activity can be synthesised. An excellent review on targeted protein degradation was published at the end of 2016 by Craig Crews (doi:10.1038/nrd.2016.211).

Although the concept of targeted protein degradation has been around since the 1990’s it wasn’t until 2008 when the first small molecule E3 ligase ligand (nutlin-3a recruiting MDM2) was able to show cell penetration that many more groups became interested in this area. In 2013 Arvinas was started to exploit their Proteolysis-Targeting Chimera (PROTAC) technology and this was followed in 2015 by C4 Theraputics using their Degronimid platform. Large pharma have also shown their interest in this area with the signing of multiple large deals with these two companies.

I recently attended an SCI conference “Targeting the Ubiquitin – Proteasome Pathway” where there was excellent presentations from Craig Crews who likened the PROTAC technology to a chemical equivalent to CRISPR. Craig also mentioned that at Arvinas they have also been able to achieve CNS penetration with their PROTACS but wouldn’t describe how this had been achieved. Another presentation that was also very interesting was by Tom Heightman from Astex Pharmaceuticals where he highlighted their protein degradation technology CLIPTACs (figure 2). This approach uses two cell permeable ligands which undergo a cycloaddition reaction in the cell to form a CLIPTAC.  This technology is has the advantage of guaranteeing cell permeability which can be much harder to achieve when using the PROTAC / Degronimid approach.

Lewis 2.JPG

Figure 2

The number of publications in the area of protein degradation has noticeably increased over the past 12 months. In recognition of this increase in popularity a special edition devoted to “Inducing Protein Degradation as a Therapeutic Strategy” is due to be published by the Journal of Medicinal Chemistry imminently which I am very much looking forward to reading.

Blog written by Lewis Pennicott

 

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s