Breakthrough Discovery Targets Undruggable Cancer Protein, Opening Doors for New Treatments

Breakthrough Discovery Targets Undruggable Cancer Protein, Opening Doors for New Treatments

(IN BRIEF) Researchers have made a significant breakthrough in cancer drug discovery by identifying a new binding site on the eukaryotic initiation factor 4E (eIF4E), a protein long considered undruggable. The collaborative study between The Institute of Cancer Research (ICR) and Astex Pharmaceuticals revealed that targeting this new site could potentially lead to effective anticancer therapies for various cancers, including breast and prostate cancer. By using an innovative fragment-based screening method, the team discovered new binding fragments that could disrupt eIF4E’s interaction with eIF4G, a protein critical for protein synthesis initiation. Although the initial compound did not fully block protein synthesis, the findings suggest that further optimization could yield a more potent inhibitor. This discovery may pave the way for future cancer treatments by targeting the regulatory role of eIF4E in protein synthesis and its implications in cancer growth.

(PRESS RELEASE) LONDON, 28-Feb-2025 — /EuropaWire/ — A groundbreaking discovery in cancer drug research has unlocked a new potential target for anticancer therapies, focusing on a protein previously considered undruggable. Researchers have used an innovative approach to identify a previously unknown binding site on the eukaryotic initiation factor 4E (eIF4E), a protein critical to the production of cell growth-related proteins in various cancers, including breast and prostate cancer. This novel site could serve as a future target for cancer drugs, opening the door to new treatments for multiple cancer types.

Collaborators at The Institute of Cancer Research (ICR) in London and Astex Pharmaceuticals in Cambridge have pinpointed a compound capable of disrupting eIF4E’s interaction with eIF4G, a protein essential for the initiation of protein synthesis. Though this compound did not fully block protein synthesis, researchers believe a more potent small molecule could potentially generate a stronger cellular response, providing new avenues for cancer treatment. This breakthrough research, published in Nature Communications, was mainly funded by Astex Pharmaceuticals, with additional contributions from Cancer Research UK and ICR.

In contrast to previous research that targeted specific regions on eIF4E, this study employed an unbiased, fragment-based screening method, allowing the team to explore the entire surface of eIF4E. Fragment-based screening differs from traditional high-throughput screening by focusing on smaller, simpler compounds that are more likely to fit the protein’s surface. While the binding affinity of these fragments may be lower, they offer a strong starting point for developing more complex and effective drug candidates.

After identifying new fragment binding sites, ICR’s Centre for Cancer Drug Discovery used advanced techniques to study the protein’s activity by selectively knocking out and restoring specific proteins. This allowed the team to assess how each binding site influences eIF4E’s function, paving the way for further drug development.

The researchers’ success in uncovering a vulnerability in eIF4E could lead to the development of novel drugs that inhibit its activity or even degrade the protein. Such drugs could provide the research community with a better understanding of eIF4E’s role in cancer and the regulation of protein synthesis, with the potential to create more effective treatments in the future.

Moreover, the study introduces a new method to produce pure eIF4E in large quantities, addressing previous challenges that hindered fragment-based screening. This technological advancement could empower other scientists to explore new anticancer targets more efficiently.

Dr. Paul Clarke, Group Leader at ICR, commented, “Our work highlights the power of fragment-based drug discovery and its potential to identify new druggable sites on traditionally hard-to-drug proteins. This innovative approach, combined with genetic characterization and degrader technology, has opened up exciting possibilities for developing new cancer treatments.”

Dr. Olivia Rossanese, Director of the ICR’s Centre for Cancer Drug Discovery, added, “This discovery has the potential to revolutionize cancer treatment strategies. By exposing eIF4E’s weakness, we are one step closer to blocking its role in cancer’s growth, and we have confirmed a powerful method for identifying new druggable targets. This research could lead to more treatment options for patients, ultimately saving lives and improving cancer care.”

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SOURCE: The Institute of Cancer Research