Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The KRAS G12C mutation is a key driver in various cancers.
• Targeting KRAS G12C requires access to the switch II pocket (S-IIP), which is only available in the GDP-bound state.
• Previous in vitro studies showed feasibility, but in vivo efficacy remained uncertain.

Purpose of the Study:

• To design and identify a potent and selective covalent inhibitor for KRAS G12C.
• To evaluate the in vivo target occupancy and therapeutic potential of the identified inhibitor.
• To investigate oncogenic KRAS dependency in vivo using the developed inhibitor.

Main Methods:

• Structure-based drug design was employed to identify ARS-1620.
• In vivo studies assessed target occupancy and tumor regression.
• Monolayer cell culture and in vivo models were used to dissect KRAS dependency.

Main Results:

• ARS-1620, a potent and selective covalent inhibitor of KRAS G12C, was identified.
• ARS-1620 demonstrated rapid and sustained in vivo target occupancy, leading to tumor regression.
• In vivo KRAS dependency was significantly underestimated by traditional monolayer culture methods.

Conclusions:

• Mutant KRAS G12C can be selectively targeted in vivo.
• ARS-1620 represents a new generation of KRAS G12C-specific inhibitors with significant therapeutic potential.
• In vivo models are crucial for accurately assessing oncogenic KRAS dependency and drug efficacy.