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Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor
Matthew R Janes1, Jingchuan Zhang1, Lian-Sheng Li1
1Wellspring Biosciences, San Diego, CA, USA.
Abstract:
KRASG12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRASG12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRASG12C-specific inhibitors with promising therapeutic potential.
Insights
A new drug, ARS-1620, effectively targets the KRAS G12C mutation in vivo, showing promise for cancer therapy. This covalent inhibitor achieves sustained target occupancy and tumor regression, validating KRAS G12C as a druggable target.
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.
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