Innovative Approaches to Targeted Protein Degradation for Drug Development

Introduction

Proteolysis-targeting chimeras (PROTEIN-TARGETING CHIMERASs) are a new class of small molecules that provide alternative ways to discover drugs by leading target proteins to be selectively destroyed. In contrast to conventional inhibitors that only suppress protein function, PROTEIN-TARGETING CHIMERASs act by calling on the cell’s protein-degrading machinery to purge proteins completely. It’s not just this mechanism that flings the door wide open to once-insurmountable targets but can provide an escape hatch from some of the drawbacks of older drugs. In this blog, we’ll dive into the background, new developments, applications, and opportunities in the PROTEIN-TARGETING CHIMERAS technology for the treatment of complex conditions such as cancer and neurodegenerative diseases.

The Ubiquitin-Proteasome Mechanism: The Foundation of PROTEIN-TARGETING CHIMERAS Technology

We need to look more closely at the function of PROTEIN-TARGETING CHIMERASs to learn more about the ubiquitin-proteasome system (UPS), the machine in the cell responsible for protein metabolism. UPS is a critical control system for cell homeostasis, by monitoring the breakdown of damaged or waste proteins. It involves marking proteins with ubiquitin molecules so that the proteasome, a giant enzyme that cleaves proteins, can destroy them.

In PROTEIN-TARGETING CHIMERAS degradation, the target protein (POI) is assigned destruction through a sequence that starts with the assembly of a ternary complex (target protein, PROTEIN-TARGETING CHIMERAS molecule, and E3 ubiquitin ligase). The E3 ligase then passes the ubiquitin molecules to the protein of interest and announces that the proteasome is interested. It is a process that lets PROTEIN-TARGETING CHIMERASs break down proteins that are not subject to the normal binding of drugs, which is a promising strategy for hard-to-reach targets such as oncogenes and mutant proteins.

PROTEIN-TARGETING CHIMERAS Structure and Function: Design and Function of PROTEIN-TARGETING CHIMERAS.
A standard PROTEIN-TARGETING CHIMERAS molecule includes the following:

Target Protein Ligand: A small molecule that binds specifically to the protein of interest (POI), the substrate to be broken down.
E3 Ligase Ligand: Ligand binding to E3 ubiquitin ligase. This brings the E3 ligase to the protein of interest.
Linker: Spherical spacer that binds the target protein ligand to the E3 ligase ligand to form the ternary complex.

When the PROTEIN-TARGETING CHIMERAS molecule links the target protein to the E3 ligase, the ubiquitination starts. The E3 ligase then converts the ubiquitin molecules to lysine residues on the target protein that identifies it for the proteasome to degrade. This can happen many times because the PROTEIN-TARGETING CHIMERAS molecule leaves the complex at the end of each successive cycle of degradation, and PROTEIN-TARGETING CHIMERASs are so efficient even at very low levels.

The Pros and Cons of PROTEIN-TARGETING CHIMERAS Technology Compared to Conventional Drugs.
The big differences between PROTEIN-TARGETING CHIMERASs and other drugs are how they act, and whether they can target “undruggable” proteins:

Aimed at Undruggable Proteins: Most proteins in the body are undruggable, which is because they don’t have any obvious active site or surfaces where conventional medications can easily stick. PROTEIN-TARGETING CHIMERASs, however, don’t remain only on the live site. They can be ligated anywhere on the protein surface, and are thus applicable to an expanded list of protein targets, including those that small-molecule inhibitors previously were incapable of ligating.

Beating Drug Resistance: Old inhibitors are often resistant to drug resistance due to mutation or overexpression of the target protein. PROTEIN-TARGETING CHIMERASs overcome this because they actually degrade the target protein, instead of blocking its activity, and so can’t develop resistance in the cell.

Lower Doses for Efficiency: Conventional inhibitors have to be dosed very high to work, but PROTEIN-TARGETING CHIMERASs can produce rounds of degradation, so the dose has to be lower, and side effects are less likely.

Applications in Drug Development
There is now a renewed interest in PROTEIN-TARGETING CHIMERASs as an anti-cancer and anti-degenerative drug. Because they can scavenge through proteins that promote disease, they have proved promising candidates for treatment.

Therapy against cancers The oncogenes and mutant tumor suppressor genes that can be targeted are of particular interest. Protein-targeting chimerass could be programmed to break down oncogenic proteins like mutant p53 or MYC, which are typically thought unresolvable by current approaches. Also being developed are PROTEIN-TARGETING CHIMERASs to attack proteins that cause chemoresistant disorders.

Neurodegenerative Diseases: In Alzheimer’s and Parkinson’s, for example, PROTEIN-TARGETING CHIMERASs are being created to attack misfolded or aggregated proteins such as tau and -synuclein. These proteins do indeed form in patients’ brains and can lead to neurodegeneration. In encouraging their degradation, PROTEIN-TARGETING CHIMERASs might be an alternative treatment for these crippling disorders.

Autoimmune and Inflammatory Diseases: PROTEIN-TARGETING CHIMERASs are also being studied for their anti-inflammatory activity against inflammatory proteins such as cytokines and immune checkpoint inhibitors. This might provide more targeted treatments with fewer side effects than current immunosuppressive agents.

Challenges and Limitations
Although PROTEIN-TARGETING CHIMERASs have potential, a few barriers must be crossed by researchers:

E3 Ligase Type: One of the biggest hurdles when making PROTEIN-TARGETING CHIMERASs is choosing the right E3 ligase. Because the E3 ligase is what makes the PROTEIN-TARGETING CHIMERAS specific and effective, it’s important to know which ligase should be used for every target. Not only that, but the ubiquitin ligase machinery is very complicated, and not all ligases are produced for all targets or all targets.

Toxicity and Off-target Effects: While PROTEIN-TARGETING CHIMERASs have excellent specificity when E3 ligases are recruited to unwanted proteins, they might be destroyed and off-target. The selectivity of PROTEIN-TARGETING CHIMERASs is an important aspect of their design.

Bioavailability: As with many small molecules, PROTEIN-TARGETING CHIMERASs have not been well-bioavailable. They have to be able to get to their targeted tissues at safe levels without being rapidly metabolized or eliminated. Improved PROTEIN-TARGETING CHIMERAS design – e.g., the design of more stable linkers or prodrugs—can reduce this problem.

PROTEIN-TARGETING CHIMERAS and the Future of Designed Protein Degradation The Promise of PROTEIN-TARGETING CHIMERAS & Designed Protein Degradation?

The PROTEIN-TARGETING CHIMERAS future is bright — and research is being done on optimizing their efficacy, specificity, and overall clinical usefulness. Some new forms of PROTEIN-TARGETING CHIMERAS-based technologies are being developed, like phosphoTACs, which activate by phosphorylation reactions to drive selective degradation, or light-controlled PROTEIN-TARGETING CHIMERASs, which can be switched on by light, giving an even greater degree of control over when and where degradation happens.

There are other avenues that researchers are taking up that leverage PROTEIN-TARGETING CHIMERASs, beyond the proteasome, towards other cellular degradation mechanisms such as the autophagy-lysosome pathway. By taking these other pathways, researchers will be able to expand PROTEIN-TARGETING CHIMERAS use cases, especially for proteins that are not easily breakable by the proteasome.

The more clinical trials that take place, the more PROTEIN-TARGETING CHIMERASs are likely to enter the mainstream of treatment as effective, specific, and less toxic treatments for various complicated diseases.

Conclusion
PROTEIN-TARGETING CHIMERASs are the future of drugs: a powerful new approach to bind and destroy “untouchable” proteins. As they bypass the shackles of conventional drug therapies such as drug resistance and specificity, PROTEIN-TARGETING CHIMERASs are on track to be a bedrock of medicine. The next generation of PROTEIN-TARGETING CHIMERASs, more powerful and more effective as they continue to be studied and demonstrated in clinical trials, promises to revolutionize cancer treatment, neurodegenerative diseases, and many other conditions.

Here’s a table listing the services and products offered by Creative Biolabs in the field of protein degraders. This overview provides insights into some of the key offerings available on their PROTEIN-TARGETING CHIMERAS solutions page.

These services and products are designed to assist in the development of targeted small molecule drugs, using the innovative technology of protein degraders.