Revolutionary new drug targets hard-to-treat cancers – helping millions world-wide

KRAS is the most commonly mutated gene in cancer, responsible for mutations in 17% to 25% of all cases. This gene plays a critical role in driving uncontrolled tumor cell growth, making it a primary target in cancer drug discovery. However, current treatments are limited. Only one KRAS mutation, known as G12C, has a targeted therapy, leaving many patients without effective options.

To address this gap, researchers have developed ACBI3, a new molecule based on PROTACs (PRoteolysis TArgeting Chimeras). This promising innovation has been shown to eliminate 13 out of the 17 most common KRAS mutations with both high potency and selectivity.

PROTACs represent a groundbreaking approach to targeting proteins in cancer cells that were once considered "undruggable." They degrade the problematic proteins rather than inhibiting them.

The development of ACBI3 is the result of collaboration between Boehringer Ingelheim and Professor Alessio Ciulli's lab at the University of Dundee. ACBI3 works by using the body’s own cellular machinery to destroy cancer-causing KRAS proteins.

In mouse models, this compound demonstrated more effective tumor regression than current small-molecule inhibitors targeting KRAS. This success marks a significant advancement in cancer treatment strategies.

The innovative class of drugs known as PROTACs represents a new frontier in treating cancer. They are small molecules with two important components. One part binds to the target protein causing the disease, in this case, KRAS.

The other part recruits an E3 ligase, which is part of the cell’s natural system for breaking down proteins. The E3 ligase tags the target protein for destruction by the cell’s disposal system, known as the ubiquitin-proteasome pathway.

This mechanism allows PROTACs to eliminate harmful proteins rather than simply blocking their activity. PROTACs hold promise for treating cancers with proteins that have been difficult to target using traditional drugs.

Developing ACBI3 required a highly targeted and rational approach. The team, led by scientists at Boehringer Ingelheim in Vienna and Dundee, set out to target multiple oncogenic KRAS mutations. Their goal was to design a molecule that would degrade these mutations rather than inhibit them, which is the more common method used to tackle cancer targets.

Starting with small molecules that could bind to KRAS, they linked them to an E3 ligase, von Hippel-Lindau (VHL), using a design known as a “molecular glue.” This allowed the two proteins to come together, prompting the degradation of KRAS.

By co-crystallizing the components, including KRAS, the PROTAC, and VHL, the team visualized their structure at the atomic level. Using this detailed understanding, they made incremental improvements to ACBI3, enhancing its ability to degrade KRAS and offering a new approach to treating KRAS-driven cancers.

ACBI3’s development is a significant achievement, but the collaboration doesn’t stop there. Boehringer Ingelheim plans to make ACBI3 freely available to the scientific community through its opnMe® portal. This platform encourages global collaboration by offering free access to high-quality molecules for research. By sharing ACBI3 with researchers around the world, Boehringer Ingelheim hopes to accelerate the discovery of new treatments for cancer patients.

This collaboration has the potential to catalyze future research into KRAS and other cancer-driving proteins. "Sharing this tool with the research community at large will enable scientists to study the consequences and potential of degrading a key cancer-driving protein with the ultimate aim of transforming the lives of people living with cancer,” explained Dr. Peter Ettmayer, co-corresponding author of the study and head of Drug Discovery Vienna at Boehringer Ingelheim.

The collaboration between Boehringer Ingelheim and external partners like Professor Ciulli is a key element in this discovery. By bringing together leading scientists in the field, these partnerships are paving the way for new therapeutic approaches. “It is exciting to collaborate with Boehringer Ingelheim to explore a novel therapeutic avenue for so many cancer patients in need,” said Professor Ciulli, Director of the CeTPD at the University of Dundee.

Boehringer Ingelheim’s opnMe® platform is more than just a repository for molecules. It is a way for scientists to collaborate, share ideas, and push the boundaries of cancer research. Offering free access to molecules like ACBI3 fosters independent innovation, and the platform also provides funding for new research ideas and PostDoc grants.

The availability of ACBI3 to the global research community underscores the importance of collaboration in advancing cancer treatments. By working together, scientists may unlock new ways to combat not only KRAS-driven cancers but other types of cancer as well.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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