A team of experts from the University of Dundee's Centre for Targeted Protein Degradation (CeTPD), in collaboration with Boehringer Ingelheim scientists, has developed a groundbreaking small-molecule drug known as a protein degrader. This new molecule, ACBI3, targets KRAS, the most frequently mutated gene in cancer, responsible for driving tumor growth in 17%–25% of all cancers.

Targeting the "Undruggable" KRAS

KRAS mutations play a critical role in the uncontrolled proliferation of tumor cells, but current treatments only address one specific mutation, G12C, leaving many patients without a targeted option. ACBI3, based on PRoteolysis TArgeting Chimeras (PROTACs) technology, is designed to degrade KRAS proteins rather than merely inhibit them, showing potential for targeting 13 of the 17 most common KRAS mutations.

Key Discovery Description
Molecule Name ACBI3
Target 13 of 17 common KRAS mutations
Technology PROTACs (Protein degradation)
Developer University of Dundee CeTPD & Boehringer Ingelheim

How ACBI3 Works

ACBI3 employs the PROTAC mechanism, where the molecule binds to the KRAS protein and recruits E3 ligase, a protein that triggers the natural disposal system within cells, known as the ubiquitin-proteasome system. This process tags and degrades the KRAS protein, offering a more efficient approach than inhibition and inducing tumor regression in preclinical models.

PROTAC Mechanism Description
Prongs of PROTAC One prong binds to KRAS, the other recruits E3 ligase
E3 Ligase Function Tags KRAS for degradation via the ubiquitin-proteasome system
Effect on Tumors Efficient tumor regression in preclinical mouse models

Discovery and Development of ACBI3

The team at Boehringer Ingelheim and Dundee worked together to rationally design ACBI3 by linking KRAS-binding molecules to the E3 ligase von Hippel-Lindau (VHL). Using X-ray crystallography, they successfully co-crystallized the KRAS-PROTAC-VHL complex, allowing them to visualize the interaction and further refine the molecule’s efficacy step by step.

Development Steps Description
Initial Design Linked KRAS-binding molecule to VHL E3 ligase
Co-crystallization Visualized interaction using X-ray crystallography
Optimization Refined the degrader to improve potency and selectivity

ACBI3 Freely Available to Researchers

In a significant move, Boehringer Ingelheim will make the ACBI3 degrader freely available to the scientific community via its opnMe portal, promoting further research on KRAS degradation. The open science platform allows researchers to access high-quality molecules and pursue independent studies without restrictions, fostering global collaboration.

opnMe Portal Description
Purpose Make ACBI3 available for global scientific research
Access Freely available to researchers through the opnMe platform
Objective Promote further study and innovation in KRAS-targeted cancer research

The Future of KRAS-Targeted Therapies

The development of ACBI3 represents a breakthrough in KRAS-targeted cancer therapies, particularly for those patients without current treatment options. As a pan-KRAS degrader, ACBI3 offers hope for millions of cancer patients by potentially transforming how KRAS-driven tumors are treated.

“Sharing this tool with the research community will enable scientists to study the consequences of degrading a key cancer-driving protein with the aim of transforming the lives of people living with cancer,” said Dr. Peter Ettmayer from Boehringer Ingelheim.

More Information:

  • Title: Targeting Cancer with Small-Molecule Pan-KRAS Degraders
  • Published By: Johannes Popow, Christiane Kofink, Andreas Gollner, and William Farnaby
  • Journal: Science (2024)
  • DOI: 10.1126/science.adm8684

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