Researchers at the University of Dundee’s Centre for Targeted Protein Degradation (CeTPD) and Boehringer Ingelheim have developed a promising new drug that could make a big difference in the fight against cancer.
This drug, known as a “protein degrader,” represents a fresh approach to targeting cancer genes, particularly one called KRAS.
KRAS is a gene that is often mutated in cancer. In fact, mutations in KRAS are found in 17% to 25% of all cancers, making it one of the most commonly mutated genes in the disease.
When this gene mutates, it drives the uncontrolled growth of cancer cells, leading to tumor development. This makes KRAS a key target in cancer research, as scientists strive to find ways to stop it from causing harm.
However, targeting KRAS has proven to be a major challenge. Current treatments are only effective against one specific mutation in the KRAS gene, known as G12C.
This means that many patients with cancers driven by other KRAS mutations do not have targeted treatment options available to them. The new drug, ACBI3, developed by the Dundee and Boehringer Ingelheim teams, could change that.
ACBI3 belongs to a class of drugs called PROTACs (PRoteolysis TArgeting Chimeras). Unlike traditional drugs that simply inhibit the activity of harmful proteins, PROTACs work by tagging these proteins for destruction, effectively removing them from the body.
ACBI3 has shown the ability to rapidly eliminate 13 out of the 17 most common KRAS mutations, making it a potentially powerful treatment for a wide range of cancers.
The development of ACBI3 was a complex and collaborative effort. The research teams started by designing a small molecule that could bind to both the KRAS protein and another protein involved in the body’s natural waste disposal system, known as E3 ligase.
The goal was to bring these two proteins close together so that the KRAS protein could be tagged for destruction by the E3 ligase.
Using advanced techniques like X-ray crystallography, the researchers were able to visualize the structure of the complex formed by KRAS, the PROTAC, and E3 ligase at the atomic level.
This detailed understanding allowed them to make precise adjustments to the drug, improving its ability to target and degrade KRAS.
The results have been promising. In experiments using mouse models, ACBI3 not only degraded the KRAS protein more effectively than previous drugs but also led to significant tumor regression.
This success validates the approach of targeting KRAS for degradation as a new and potentially more effective way to treat cancers driven by this gene.
Professor Alessio Ciulli, the Director of CeTPD and one of the leaders of the study, expressed excitement about the potential of this new treatment. He emphasized the importance of collaboration with external partners like Boehringer Ingelheim in pushing the boundaries of cancer research.
Dr. Peter Ettmayer, who co-authored the study and leads Drug Discovery in Vienna for Boehringer Ingelheim, highlighted the significance of working with scientific leaders like Professor Ciulli.
He noted that such collaborations are essential for exploring new therapeutic avenues and bringing innovative medicines to patients in need.
In a move that could accelerate further research, Boehringer Ingelheim plans to make ACBI3 freely available to scientists worldwide through their open science portal, opnMe.
This platform is designed to foster collaboration by providing researchers with access to high-quality molecules, funding opportunities, and other resources without any strings attached.
Dr. Ettmayer believes that sharing ACBI3 with the global scientific community will enable researchers to explore its full potential and ultimately transform the lives of cancer patients.
By working together, scientists can build on this breakthrough and continue to develop new treatments that could offer hope to millions of people affected by cancer.
This development marks an important step forward in cancer research, offering a new strategy to target a gene that has long been considered difficult to treat. With continued collaboration and innovation, ACBI3 and similar drugs could pave the way for more effective cancer therapies in the future.
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The research findings can be found in Science.
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