Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.
Key points:
- Researchers are exploring targeted protein degradation as a way to get at hard-to-treat proteins.
- A team from Korea focused on a modified version of p38, a protein already linked to Alzheimer’s.
- Compounds developed specifically for the modified p38 protein successfully downregulated the pathway in mice.
Certain diseases, including Alzheimer’s, are considered “undruggable” because traditional small molecule drugs can’t interfere with the proteins responsible for the illnesses. So, instead of interfering, researchers at Kyung Hee University are trying to completely degrade the dangerous proteins.
Researchers have been exploring targeted protein degradation (TPD) as a way to get at hard-to-treat proteins. Though the degraders have shown some initial promise, no TPD technique has been able to target proteins that go through “post-processing,” or post-translational modifications, after being formed.
p38 is a popular target for researchers due to its involvement with several cellular signaling pathways, as well as its link to the development of Alzheimer’s disease. However, previous attempts to degrade the protein including a drug candidate that went through two phases of clinical trials—have suffered from off-target effects and limited efficacy.
But like many proteins, p38 goes through post-translational modifications, including phosphorylation, to form p-p38. This adds a phosphate group to the protein, activating it and changing its shape. So, Nam-Jung Kim, Kyung-Soo Inn, Jong Kil Lee and colleagues homed in on that form instead.
The team screened several compounds specific for p-p38, eventually finding PRZ-18002, which selectively induced degradation of p-p38 over both similar proteins and its inactivated form. According to the study published in ACS Central Science, PRZ-18002 maintained its selectivity even when tested against 96 different protein kinases similar to p38.
When delivered to the brains of mouse models of Alzheimer’s disease, the compound downregulated the p38 pathway, improving cognitive abilities, including spatial reasoning, and disease-related brain chemistry, such as the accumulation of amyloid-beta plaques.
The researchers say that this work could someday provide a novel treatment for Alzheimer’s disease and open up opportunities for future treatments of other diseases that also involve modified proteins.
Information provided by ACS.