Proteins play a crucial role in maintaining the proper functioning of our cells. To keep them in balance, the body constantly produces and eliminates proteins through a natural process called protein degradation. However, when a cell’s degradation system fails or malfunctions, certain proteins can accumulate, leading to the development of diseases such as cancer.
“In recent years, targeted protein degradation has emerged as a promising therapeutic approach to eliminate disease-causing proteins that were once considered inaccessible or untreatable. Researchers like us are now tapping into the cell's own machinery to break down these proteins,” describes Agatheeswaran Subramaniam, an associate researcher at the Lund Stem Cell Center.
The team of researchers first embarked on their investigation in 2019, focusing on a protein called LSD1 and its role in stem cell expansion. To their surprise, they discovered that UM171, a small molecule currently undergoing phase two clinical trials for stem cell expansion and transplantation therapies for patients with leukemia, can also degrade or break down LSD1 and its associated COREST complex. This important finding was previously published in the journal Blood in 2020.
Expanding the Understanding of UM171
Building upon their previous research, the team set out to uncover how UM171 functions as a protein degrader and identify additional proteins targeted by UM171. Through global proteomics analysis, they identified several target proteins affected by UM171, including a previously unknown target called RCOR3. Additionally, they discovered that the essential components necessary for UM171 to recognize and break down proteins are found within a specific region of the target proteins known as the ELM2 domain.
Kristijonas Žemaitis, the first author of the paper, explains, “Our findings shed light on the factors that determine the drug's sensitivity and reveal potential new targets that could be relevant for addressing certain subtypes of leukemia and other forms of cancer. Some of these targets also play a role in regulating stem cell fates, deepening our understanding of how UM171 expands blood stem cells."
A Promising Future Ahead
As the scientific community continues to explore the vast potential of targeted protein degradation and the applications of UM171, Agatheeswaran Subramaniam aims to establish his own research program to contribute to the growing body of knowledge in this area. With the unique insights gained from their latest publication, the team hopes to inspire further research and the development of innovative therapeutic approaches.
"We anticipate that targeted protein degradation will become a widely utilized technique across different fields, much like the adoption of CRISPR technology. Its simplicity and efficiency make it an attractive research tool for studying protein functions and complexes. Over time, its applications will pave the way for remarkable advancements in diverse fields," concludes Agatheeswaran Subramaniam.
