Exploring the Potential of Protein Degradation-focused Drug Discovery
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Ubiquitination describes a post-translational modification, whereby a small 76 amino acid protein “ubiquitin” is covalently attached to a lysine residue within a substrate protein. The critical part played by the ubiquitin enzymatic cascade in numerous cellular processes has ignited interest in its potential to be harnessed therapeutically.
Ubiquigent's Jason Brown and Jason Mundin discuss the role of the ubiquitin cascade in cellular signaling and explain how it can be exploited to support protein degradation-focused drug discovery.
Laura Lansdowne (LL): What is ubiquitylation and what role does the ubiquitin cascade play in cellular signaling and drug discovery?
Jason Brown (JB): Ubiquitylation is a process where specific proteins are modified through the attachment of the protein ubiquitin (as mono or structurally distinct “chains” of ubiquitin), or ubiquitin-like proteins (Ubls). Ubiquitylation and related Ubl modifications can result in the degradation of the ubiquitylated protein by the proteasome complex, as well as giving rise to other signaling events. Ubiquitylated proteins can be “rescued” from degradation by the deubiquitylase (DUB) enzymes which deubiquitylate the ubiquitin and/or ubiquitin chains from specific substrate proteins. The ubiquitin system offers many new drug discovery target opportunities across multiple therapeutic areas including cancer, cardiovascular and metabolic, neurodegeneration and aging, neurological and musculoskeletal, fibrosis, and infection and immunity.
Molly Campbell (MC): What challenges exist in protein degradation-focused drug discovery?
JB: There is a tremendous opportunity to exploit the cell’s intrinsic protein degradation machinery for therapeutic advantage. A key challenge is determining how best to go about this given the range of options available. The optimal approach may not only be related to the therapeutic area of interest but perhaps more importantly the nature of the signaling pathway and the target(s) within it that one may wish to modulate.
LL: How can this system be exploited to support protein degradation-focused drug discovery?
JB: There are several approaches that can be taken to exploit the cell’s protein degradation machinery for therapeutic advantage. One can target elements of the system itself, for example, through the targeting of DUB enzymes, ubiquitin (or Ubl) activating enzymes, E3 ubiquitin ligases or the proteasome complex. One can also “hijack” the ubiquitin system in order to degrade a selected “protein of interest” on demand using a PROTAC and/or molecular glue approach. Other approaches include using small molecules to trigger the unfolding of target proteins, resulting in their subsequent tagging by the ubiquitin system for degradation. Targeting DUBs with small molecules provides an attractive approach, as one can target the enzymatic activity of the protein using approaches and workflows successfully demonstrated across other target classes in drug discovery (including kinases). The inhibition of the enzymatic activity of a DUB and thus the deubiquitylation of its substrate proteins can effectively “rescue” such proteins from degradation. As such, small molecule inhibitors of DUBs represent one strategy for promoting targeted protein degradation by preventing the targets’ deubiquitylation.
LL: Can you tell us more about your newly announced partnership with LEO Pharma and any specific details about the two novel compounds LEO Pharma are being granted access to?
Jason Mundin (JM): This latest partnership between Ubiquigent and LEO Pharma came about as a direct result of an earlier, successful Open Innovation agreement. Under the terms of that agreement, a number of Ubiquigent compounds were screened though a range of phenotypic assays by LEO Pharma. This identified a number of “active” compounds, two of which are now the focus of the current agreement.
MC: Please can you tell us more about the LEO Pharma Open Innovation and the services available to researchers in the field?
JM: Under LEO Pharma’s Open Innovation initiative, LEO Pharma commits to screening a partner’s test compounds (blind to structure) through a range of therapeutically relevant cell-based assays. The screening is undertaken at LEO Pharma’s expense with all resulting data being supplied to and owned by the partner, with LEO Pharma’s only stipulation being that they have the first right to enter into a relationship with the partner should the screen yield results worthy of further exploration. This type of approach offers a straightforward route for the parties to quickly determine whether there is the basis for collaboration or partnership.
Jason Brown and Jason Mundin, were speaking with Molly Campbell and Laura Elizabeth Lansdowne, Science Writers for Technology Networks.