Protein Degrader Technology May Reduce Drug Development Failure Rate

Protein Degrader Technology May Reduce Drug Development Failure Rate

  • Technology
  • May 25, 2022
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  • 7 minutes read

Researchers have pushed for cutting-edge technology to demonstrate whether potential treatments are worth advancing in human trials, in a game-changing move that could drastically reduce high rates of drug discovery and development failure.

The WEHI-led team is using protein degradation technology to test the efficacy and safety of drugs by better mimicking clinical settings, with a collaborative Australian project already using the system to set promising drug targets for a number of difficult-to-treat cancers.

At a glance

  • Pioneering technology can evaluate how effective and safe a drug target could be for patients, much earlier in the research process.
  • A collaborative effort is currently leveraging technology to validate drug targets for a number of cancers.
  • Protein degrader technology offers a revolutionary approach to substantially reduce the high rate of drug development failure in the pharmaceutical industry.

Nearly 95% of biomedical projects fail before entering human clinical trials, with the average cost of bringing a new drug to market estimated at around $ 1.8 billion. A key issue is the difficulty of evaluating the true safety and efficacy of a drug in preclinical studies.

Although the development of conventional drugs aims to inhibit the activity of disease-causing proteins, protein degradation technology seeks to completely destroy these proteins, with precise guidance. Technology allows scientists to deliver much more relevant results from preclinical trials, to potentially offer new safe and effective treatments to patients more quickly.

In a new study published in Communications of natureWEHI researchers Dr. Charlene Magtoto, Dr. Rebecca Feltham and Dr. Christoph Grohmann (now at Nurix Therapeutics) has significantly expanded our understanding of a type of protein degradation technology by expanding current validation strategies, which could increase the number of drugs that successfully enter human trials. .

A collaboration between WEHI and several institutes in Australia is already capitalizing on revolutionary technology to validate a number of previously “non-drug” proteins and help develop new therapies to treat cancers.

Reimagine drug discovery

About 80% of disease-causing proteins currently cannot be attacked by conventional drugs. Targeted Protein Degraders (TPDs), commonly known as Proteolysis Orientation Chimera (PROTACs), are a pioneering technology that can hit these previously invincible targets.

Although current drugs and technology only inhibit the specific activity of a protein, TPDs work by causing the destruction of the proteins that cause the disease itself.

TPD has the potential to offer precision treatments only by targeting disease-causing proteins, leaving unhealthy parts of the body untouched.

The WEHI-led team focused on developing a labeling system to help researchers overcome a major hurdle in the drug development process.

Dr. Charlene Magtoto said that this system allows scientists to use drugs that interact with a label, opening up virtually the entire proteome for target validation.

“Finding a drug to bind to the protein itself can be difficult and often a reason why researchers come to a crossroads in drug development,” Dr. Magtoto said. “Attaching a small generic tag to any protein of interest to allow a destructive protein to remove it allows us to remove any protein just by going to the tag.” This is a game-changing technology that will ensure that only the best targets enter drug discovery pipelines “.

Dr. Christoph Grohmann said a partnership with Promega was crucial to developing the new labeling system, collaborating with scientists from the global biotechnology company and using its NanoLuc® luciferase technology. “WEHI is an emerging leader in TPD technology, and this significant collaboration has allowed our team to leverage the expertise in industrial drug discovery and academic medical research to improve technology at a much faster rate,” he said. Dr. Grohmann.

Crucial targets of cancer

The lack of effective new drugs is a particular barrier for cancer researchers, with only 1 in 15 developmental drugs progressing in the clinic.

WEHI researchers are working with other institutions across the country to develop TPD for cancer treatment as part of a current project funded by the Australian Medical Research Future Fund (MRFF).

Dr. Rebecca Feltham, who runs the MRFF label degradation program, said the collaboration was helping researchers quickly identify whether it is worth pursuing their cancer goals.

“Most of the 150,000 Australians diagnosed with cancer each year are still being treated with drugs that went on the market more than 25 years ago, which can cause significant side effects,” he said.

“Because this pioneering technology allows us to better identify genuine targets at the beginning of the research process, we could radically accelerate the development of new treatments to save lives for cancer and other diseases.”

Dr. Feltham has used TPD labeling technology to investigate 24 potential drug targets, 19 of which are cancer-related.

Unlike other systems currently in use in the field, the protein degradation caused by TPD label technology is reversible. Once the drug is removed, the protein returns.

“This is exactly what happens in clinical settings and this technology allows us to mimic real TPD treatment scenarios at the beginning of the development process, much better than any technology we have available today.”

said Dr. Feltham. Researchers hope their findings will trigger a broader awareness of the benefits of TPD technology to help reduce the cost burden currently posed by high drug failure rates.

The research, a collaborative effort between WEHI, Promega and the University of Dundee, was supported by the European Research Council (ERC), The Galbraith Family Charitable Trust, NHMRC, the Victorian government and the Australian government.

Reference: Grohmann C, Magtoto CM, Walker JR, et al. Development of NanoLuc-targeted protein degraders and a universal reporter system for comparing label-oriented degradation platforms. Common Nat. 2022; 13 (1): 2073. doi: 10.1038 / s41467-022-29670-1

This article has been republished from the following materials. Note: The material may have been edited by duration and content. For more information, please contact the source.

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