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Updated: Jun 25, 2026
Workflow and Tools for Crystallographic Fragment Screening at the Helmholtz-Zentrum Berlin
Published on: March 3, 2021
KRAS G12C fragment screening renders new binding pockets
Magali Mathieu1, Valérie Steier1, Florence Fassy1
1Integrated Drug Discovery, Quai Jules Guesde, Vitry Sur Seine Cedex, France.
Abstract:
KRAS genes belong to the most frequently mutated family of oncogenes in cancer. The G12C mutation, found in a third of lung, half of colorectal and pancreatic cancer cases, is believed to be responsible for a substantial number of cancer deaths. For 30 years, KRAS has been the subject of extensive drug-targeting efforts aimed at targeting KRAS protein itself, but also its post-translational modifications, membrane localization, protein-protein interactions and downstream signalling pathways. So far, most KRAS targeting strategies have failed, and there are no KRAS-specific drugs available. However, clinical candidates targeting the KRAS G12C protein have recently been developed. MRTX849 and recently approved Sotorasib are covalent binders targeting the mutated cysteine 12, occupying Switch II pocket.Herein, we describe two fragment screening drug discovery campaigns that led to the identification of binding pockets on the KRAS G12C surface that have not previously been described. One screen focused on non-covalent binders to KRAS G12C, the other on covalent binders.
Insights
Researchers discovered new binding sites on the KRAS G12C protein, a key driver in many cancers. These findings from fragment screening could lead to novel KRAS G12C-targeted cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- KRAS genes are frequently mutated oncogenes in various cancers, with the G12C mutation contributing significantly to cancer mortality.
- Despite decades of research and drug development efforts targeting KRAS, no KRAS-specific drugs have been approved until recently.
- Emerging covalent inhibitors like MRTX849 and Sotorasib target the KRAS G12C mutation by binding to Cysteine 12.
Purpose of the Study:
- To identify novel binding pockets on the KRAS G12C protein surface.
- To explore new therapeutic strategies for KRAS G12C-driven cancers through fragment screening.
Main Methods:
- Conducted two fragment screening drug discovery campaigns.
- One campaign focused on identifying non-covalent binders to KRAS G12C.
- The other campaign focused on identifying covalent binders to KRAS G12C.
Main Results:
- Identified previously undescribed binding pockets on the KRAS G12C protein surface.
- The fragment screening campaigns yielded insights into potential new drug targets on KRAS G12C.
- These new pockets offer alternative sites for therapeutic intervention beyond the Switch II pocket.
Conclusions:
- The identification of novel binding pockets on KRAS G12C presents new opportunities for drug development.
- Fragment screening provides a valuable approach for discovering new therapeutic strategies against KRAS G12C.
- These findings could pave the way for more effective treatments for lung, colorectal, and pancreatic cancers harboring the KRAS G12C mutation.
