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Characterisation of a novel KRAS G12C inhibitor ASP2453 that shows potent anti-tumour activity in KRAS G12C-mutated
Ayako Nakayama1, Takeyuki Nagashima2, Yoshihiro Nishizono2
1Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan. ayako.nakayama@astellas.com.
Background:
KRAS is one of the most frequently mutated oncogenes in various cancers, and several novel KRAS G12C direct inhibitors are now in clinical trials. Here, we characterised the anti-tumour efficacy of ASP2453, a novel KRAS G12C inhibitor, in preclinical models of KRAS G12C-mutated cancer.
Methods:
We evaluated the in vitro and in vivo activity of ASP2453, alone or in combination with targeted agents and immune checkpoint inhibitors, in KRAS G12C-mutated cancer cells and xenograft models. We also assessed pharmacological differences between ASP2453 and AMG 510, another KRAS G12C inhibitor, using an SPR assay, washout experiments and an AMG 510-resistant xenograft model.
Results:
ASP2453 potently and selectively inhibited KRAS G12C-mediated growth, KRAS activation and downstream signalling in vitro and in vivo, and improved the anti-tumour effects of targeted agents and immune checkpoint inhibitors. Further, ASP2453 had more rapid binding kinetics to KRAS G12C protein and showed more potent inhibitory effects on KRAS activation and cell proliferation after washout than AMG 510. ASP2453 also induced tumour regression in an AMG 510-resistant xenograft model.
Conclusions:
ASP2453 is a potential therapeutic agent for KRAS G12C-mutated cancer. ASP2453 showed efficacy in AMG 510-resistant tumours, even among compounds with the same mode of action.
Insights
ASP2453, a novel KRAS G12C inhibitor, effectively reduced tumor growth in preclinical models. It demonstrated superior efficacy over AMG 510, including in resistant tumors, highlighting its therapeutic potential for KRAS G12C-mutated cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- KRAS mutations are common drivers in many cancers.
- Novel KRAS G12C inhibitors are emerging as promising targeted therapies.
- Understanding the efficacy of new inhibitors like ASP2453 is crucial.
Purpose of the Study:
- To characterize the anti-tumor efficacy of ASP2453, a novel KRAS G12C inhibitor.
- To compare ASP2453 with another KRAS G12C inhibitor, AMG 510.
- To evaluate ASP2453 in combination therapies.
Main Methods:
- In vitro and in vivo evaluation of ASP2453 in KRAS G12C-mutated cancer models.
- Comparison of ASP2453 and AMG 510 using SPR assays and washout experiments.
- Assessment of ASP2453 in an AMG 510-resistant xenograft model.
Main Results:
- ASP2453 demonstrated potent and selective inhibition of KRAS G12C, reducing tumor growth and signaling.
- Combination therapy with ASP2453 enhanced anti-tumor effects.
- ASP2453 exhibited faster binding kinetics and more sustained inhibition than AMG 510.
- ASP2453 induced regression in AMG 510-resistant tumors.
Conclusions:
- ASP2453 is a promising therapeutic candidate for KRAS G12C-mutated cancers.
- ASP2453 shows efficacy even in tumors resistant to other KRAS G12C inhibitors.
- ASP2453's unique properties warrant further clinical investigation.
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