Targeted Protein Degradation

Targeted protein degradation is a novel drug discovery strategy being used to develop medicines aimed at so-called ‘undruggable’ proteins.

Protein degraders use a cell’s endogenous machinery – essentially, its waste disposal system – to eliminate a target protein rather than inhibit it.

By taking advantage of the body’s ubiquitin proteasome system, which effectively ‘tags’ or ‘marks’ proteins destined to be degraded, scientists can promote the degradation of target proteins that would otherwise remain within the cellular environment.

In principle, this approach can be used to drive any type of protein modification; recent proof-of-concept studies have successfully shown that phosphorylation can be modulated in this way.

How Targeted Protein Degradation (TPD) works?

This is proximity-based medicine that puts together two proteins which don’t normally interact to drive degradation.

The idea of TPD, which originated in academia but is now being used commercially, is presenting exciting new drug discovery opportunities as it can offer the potential to overcome limitations associated with traditional small molecule drugs.

The concept of proximity drugs – including bispecific anti-CD3 antibodies that target T-cells to cancer cells for removal – has a slightly longer history, with significant interest in B-cell epitopes in the 1990s.

One key advantage with degraders is that they work catalytically, in a hit-and-run sense, where a single degrader molecule can drive the destruction of many target proteins. This property of degraders may allow for lower dosing, and consequently a lower risk of toxicity.

Degraders are also thought to be more resilient to the rise of resistance mechanisms commonly seen in oncology. One argument for this being the case is that a relatively low occupancy of the target is required to initiate degradation.

A traditional inhibitor has to bind to a high proportion of the target protein to have an effect, and this occupancy can be decreased by mutations in the target to the point where there is no pharmacological effect anymore.

A degrader may still be effective in this scenario because a low occupancy may still produce degradation, with the added advantage of a catalytic mechanism of action.

Another key advantage of degraders is that they can be developed to bind anywhere on a target protein, whereas traditional inhibitors are limited to active sites.

In fact, ‘traditional’ small molecules are unable to bind with either the required affinity or in the right location to around 80% of disease-causing proteins – including those linked to cancers and neurological conditions such as Alzheimer’s disease.

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 upregulation of a target protein in response to its removal, and also mimic genetic knockdown so the cell/animal phenotypic effect is more predictable.

In fact, the most advanced PROTACs are now in the clinic, and oral drug-like propeties 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 targed protein degradation looks bright; we expect to see a rise of multispecific drugs, more modalities and non-protein targets.

Turn to the drug discovery experts

Sygnature Discovery has experience of 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…