Targeted Protein Degradation

Targeted Protein Degradation (TPD) is an innovative drug discovery approach focused on previously considered ‘undruggable’ proteins. Instead of inhibiting these proteins, TPD leverages the cell’s waste disposal system to remove them. This method utilises the body’s ubiquitin-proteasome system, marking proteins for degradation. Essentially, scientists are harnessing this natural ‘tagging’ system to break down target proteins that might otherwise persist in cells. Beyond this, the technique has the potential for various protein modifications, with recent studies demonstrating its effectiveness in modulating phosphorylation.

How Does Targeted Protein Degradation (TPD) Work?

TPD is a cutting-edge proximity-based medicine technique. It pairs two proteins that typically don’t interact, promoting their degradation. Originating from academic studies, TPD is now commercially utilized, unlocking promising avenues in drug discovery by potentially overcoming challenges seen with conventional small-molecule drugs.

Historically, the concept of proximity drugs, such as bispecific anti-CD3 antibodies that steer T-cells towards cancer cells for elimination, began gaining traction in the 1990s, particularly with interest in B-cell epitopes.

Key Advantages of Degraders in TPD:

  1. Catalytic Action: Degraders operate in a “hit-and-run” manner. A single degrader molecule can lead to the destruction of multiple target proteins. This unique attribute suggests the possibility of lower dosages and subsequently, reduced toxicity risks.
  2. Resilience to Resistance: In oncology, resistance mechanisms are a significant challenge. Degraders are believed to be more resistant to such mechanisms. Traditional inhibitors often need to bind with a large portion of the target protein for effectiveness. This binding can be impeded by mutations, reducing the drug’s efficacy. However, degraders, thanks to their catalytic mode of action, might still be effective even with lower target occupancy.
  3. Flexibility in Binding: Unlike traditional inhibitors that are constrained to binding at active sites, degraders can attach anywhere on a target protein. This flexibility is crucial as around 80% of disease-causing proteins, linked to ailments like cancer and Alzheimer’s, don’t bind with ‘traditional’ small molecules either strongly enough or at the necessary sites.

Promise – and progress

It’s no surprise that targeted protein degradation is a rapidly expanding and evolving area of drug discovery, with significant amounts of work being conducted to develop proteolysis targeting chimeras (PROTAC® protein degraders) and molecular glues.

PROTACs, in particular, are advantageous because they suppress the upregulation of a target protein in response to its removal, and also mimic genetic knockdown so the cell/animal phenotypic effect is more predictable.

The most advanced PROTACs are now in the clinic, and oral drug-like properties can be achieved.

Other protein degradation strategies include lysosome targeting chimeras (LYTACs) for the degradation of membrane-bound and extracellular proteins, photochemically targeting chimeras (PHOTACs or PhotoPROTACs) for using light-induced control of protein degradation, autophagy-targeting chimeras (AUTACs) that rely on the autophagic degradation pathway inside the cell, and homo-PROTACs for dimerising an E3 ligase and then inducing its self-degradation.

The future of targeted protein degradation looks bright; we expect to see a rise of multi-specific drugs, more modalities and non-protein targets.

Turn to the drug discovery experts

Sygnature Discovery has experience in designing, testing and evaluating targeted protein degraders in customers’ drug discovery projects.

We have expertise in the ubiquitin system and the wider field of protein degradation, while our computational and medicinal chemistry capabilities, our hit-finding expertise (HTS and fragment-based screening) and our broad expertise in various disease areas mean we’re the perfect partner to help you with targeted protein degradation.

Crucially, TPD involves the complexities of DMPK and pharmacokinetics, as it is essential to fully understand the effects of protein degraders on the human body as early as possible. Our skills and services in these areas can pay dividends in your programme.

What if you could rapidly assess the feasibility of a degrader project for your protein of interest? Welcome to CHARMED from Sygnature Discovery…

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