A novel small-molecule drug, ACBI3, has shown promising efficacy against a broad range of KRAS mutant-driven cancers. Developed by researchers at the University of Dundee’s Centre for Targeted Protein Degradation (CeTPD) in collaboration with Boehringer Ingelheim, ACBI3 targets 13 of the 17 most common KRAS mutations, offering a potential therapeutic avenue for a significant portion of cancer patients who currently lack targeted treatment options. The research was published in the journal Science.
KRAS mutations, implicated in 17% to 25% of all cancers, have been a challenging target for drug development. Current therapies primarily address the G12C mutation, leaving a substantial number of patients with other KRAS mutations without effective targeted treatments. ACBI3 takes a different approach by degrading the mutant KRAS proteins rather than inhibiting their activity.
Mechanism of Action
ACBI3 is based on PRoteolysis TArgeting Chimeras (PROTACs), which consist of two prongs. One prong binds to the target protein (KRAS), while the other recruits an E3 ligase, a component of the cell's natural disposal system. This process tags the target protein for degradation by the ubiquitin-proteasome system.
Preclinical Efficacy
Unlike traditional inhibitors that target a single mutation, ACBI3 has demonstrated the ability to rapidly eliminate 13 out of the 17 most common KRAS mutants with high potency and selectivity. In preclinical mouse models, ACBI3 induced effective tumor regression, highlighting the potential of KRAS degradation as a transformative therapeutic method.
Collaborative Development and Structural Insights
The development of ACBI3 involved a multidisciplinary team, including Johannes Popow, Christiane Kofink, and Andreas Gollner from Boehringer Ingelheim, and William Farnaby from the University of Dundee. The team started with high-quality small-molecule prongs linked to the E3 ligase von Hippel-Lindau (VHL) proteins. Using X-ray crystallography, they visualized the structure of the complex formed by KRAS, ACBI3, and VHL at atomic detail, which helped them to optimize the compound's activity.
Open Access Initiative
Boehringer Ingelheim has made ACBI3 freely available to the global research community through its opnMe portal. This initiative aims to accelerate innovation in cancer research by enabling scientists to study the consequences and potential of degrading a key cancer-driving protein.
"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," said Peter Ettmayer, head of Drug Discovery Vienna at Boehringer Ingelheim.
