Experts have introduced a groundbreaking small-molecule medication known as a ‘protein degrader.’ This innovative molecule, referred to as ACBI3, could pave the way for new treatments that are not dependent on the type of KRAS mutation, potentially enhancing the outcomes for all patients with KRAS-related cancers.
KRAS is the gene that undergoes mutations most frequently in cancer, with alterations found in 17%-25% of all cancer cases, impacting millions of individuals worldwide. It plays an essential role in tumor development, as it is vital for the unchecked growth of tumor cells. Thus, targeting the function of KRAS is a major emphasis in cancer therapy research. However, the treatments currently available can only target one specific KRAS mutation known as G12C, leaving over half of the patients with KRAS-driven cancers without effective targeted therapies.
Developed by multidisciplinary teams at the laboratory of Professor Alessio Ciulli and Boehringer Ingelheim, ACBI3 is based on a type of small molecules known as Proteolysis Targeting Chimeras (PROTACs). Studies have demonstrated that ACBI3 can swiftly eliminate 13 out of the 17 most prevalent KRAS mutations with high effectiveness and precision. In fact, degrading KRAS with ACBI3 proved to be more effective than conventional small molecule inhibition and resulted in significant tumor shrinkage in mouse models, supporting the concept of KRAS degradation as a promising new treatment strategy.
“It’s exhilarating to partner with Boehringer Ingelheim for the exploration of a new therapeutic route for the many cancer patients in need,” commented Professor Ciulli, Director of the CeTPD and corresponding author of the study.
“By collaborating with external stakeholders who share our vision for innovative drug discovery, as well as scientific leaders like Prof. Ciulli—one of the pioneers in PROTACs and molecular glues—we can fully explore the potential of these new therapeutic approaches,” noted Dr. Peter Ettmayer, co-corresponding author of the study and head of Drug Discovery Vienna at Boehringer Ingelheim.
A novel approach to combat tumor cells
PROTACs are an emerging class of drug candidates that offer the possibility to target cancer proteins that were previously deemed “undruggable” by degrading them.
These compounds are constructed with two distinct parts. One part binds to the harmful protein associated with the disease, while the other attracts a protein known as E3 ligase, which is a component of the cell’s natural waste disposal system (the ubiquitin-proteasome). When these components come close together, E3 ligase marks the target protein for degradation by tagging it as “expired,” leading to its rapid breakdown by the ubiquitin-proteasome.
The discovery of ACBI3
To develop this compound, the research team, co-led by Johannes Popow, Christiane Kofink, and Andreas Gollner at Boehringer Ingelheim in Vienna along with William Farnaby from Dundee (co-first authors), aimed to target a broad range of oncogenic KRAS mutations by thoughtfully designing degrader molecules specifically for them, rather than relying on the more common approach of inhibition.
Starting with high-quality small-molecule components that interact with KRAS on one end and link to the E3 ligase von Hippel-Lindau (VHL) on the other, the researchers identified a compound that effectively brought these two proteins together, a process often referred to as ‘molecular glue.’ This discovery provided a promising foundation for further research.
The team successfully co-crystallized the three components: KRAS, the PROTAC, and VHL. By utilizing X-ray crystallography, they were able to visualize the structure of this complex at an atomic level, which helped them understand how the small molecule effectively recruited the two proteins. This knowledge enabled the team to progressively refine the compound, enhancing its ability as a degrader through a systematic approach.
Collaborating with the global research community
Importantly, Boehringer Ingelheim intends to make the KRAS degrader ACBI3 freely accessible to the scientific community via its opnMe® portal, with no restrictions, which could stimulate further investigations into this crucial target.
opnMe® is the open-science platform developed by Boehringer Ingelheim. It promotes innovation by connecting top experts worldwide with Boehringer scientists. opnMe® encourages independent scientific discovery by providing high-quality molecules for research, funding for innovative ideas related to select compounds or scientific inquiries, and PostDoc grants.
“By sharing this tool with the broader research community, we empower scientists to explore the implications and potential of degrading a key driver of cancer, ultimately aiming to transform the lives of individuals battling cancer,” Dr. Ettmayer remarked.
