Alzheimer’s and “Undruggable” Diseases May Be Treated by Degrading Modified Proteins

A new study has demonstrated the efficacy of a compound that can break down a previously “undruggable” modified protein – p38, involved in the development of Alzheimer’s disease – using targeted protein degradation. The study is published in ACS Central Science.

Drugging the undruggable

Many diseases are considered “undruggable” owing to the difficulty of targeting and interfering with them using conventional small-molecule inhibitors. Alternative approaches, such as targeted protein degradation (TPD), have been put forward to target such “undruggable” disease-causing proteins.

These degraders label the desired proteins, tagging them for destruction by the cell’s waste disposal systems – the proteasome and the lysosome. Such degraders have shown some promise in trials. For example, proteolysis-targeting chimeras (PROTACs), small molecules that help to tag target proteins for destruction by the proteasome, are at present one of the most advanced TPD technologies.

However, many proteins also undergo “post-processing”, or post-translational modifications (PTMs). These modify their function or activity through the addition of different chemical groups to the protein, such as phosphorylation. This makes TPD difficult for these proteins, and no TPD molecules have been reported that can target PTM proteins specifically.

With this in mind, the researchers in the current study aimed to develop a molecule that could break down a protein called p38 mitogen-activated protein kinase (p38 MAPK). Phoshporylation of this protein activates its activity, producing p-p38. This has been suggested to have a role in the development of Alzheimer’s disease (AD), which makes it a very attractive therapeutic target. However, attempts to target p38 have not been met with success, possibly due to non-specific, off-target effects.

As phosphorylation of p38 triggers the protein’s activity, the researchers sought to develop a TPD for only the active form p-p38, helping to limit the chance of off-target effects.

Showing potential in preclinical models

The team first created seven chemical compounds designed to target p-p38, then screened them to determine their ability to successfully degrade it, finally identifying a compound called PRZ-18002 as the most effective p-p38 degrader.

Further laboratory experiments showed that PRZ-18002 selectively inhibited p-p38 over both its unphosphorylated, inactive form p38 as well as 96 other proteins with similar structures.

To test how well this compound could work in a living system, the researchers progressed to mouse models of Alzheimer’s disease. Delivering PRZ-18002 through the nose and into the brains of these mice successfully reduced p-p38 levels in the brain, confirming it can effectively hit its target. It also suppressed brain inflammation, which has a significant role in the development of AD.

Behavioral experiments with the treated mice showed they had improved cognition and spatial reasoning, as well as reduced AD-associated findings in the brain such as reduced accumulation of clumps (plaques) of the protein amyloid beta – a key characteristic of the disease.

A novel therapeutic strategy?

“In this report, we have demonstrated that phosphorylated p38 can be targeted and sequentially eliminated by a TPD approach,” the authors write in the paper. “To the best of our knowledge, we have presented, for the first time, a chemical degrader that directly targets a specific PTM of a disease-associated protein for proteasomal degradation, further advancing a TPD approach as a novel therapeutic strategy.”

Overall, this study demonstrates the success of this degrader compound in a preclinical model of AD, potentially opening the door to the future development of similar treatments for AD, or other diseases which also involve PTM proteins.

Reference: Son HW, Lee N-R, Gee MS, Song CW, Lee SJ, Lee S-K et al. Chemical knockdown of phosphorylated p38 mitogen-activated protein kinase (MAPK) as a novel approach for the treatment of Alzheimer’s disease. ACS Central Science. 2023. doi: 10.1021/acscentsci.2c01369