The identification of KRASG12C inhibitors has reignited interest in targeting RAS proteins. This work describes the discovery of the KRASG12D-specific inhibitor MRTX1133 and demonstrates the feasibility of potently and selectively targeting this oncogenic variant. MRTX1133 treatment markedly inhibited KRAS-dependent signaling and induced tumor regression in xenograft models harboring the KRASG12D mutation.
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Bos, J. L. Ras oncogenes in human cancer: a review. Cancer Res. 49, 4682–4689 (1989). A review article that provides an overview of RAS family gene mutations and links to oncogenesis.
Fernandez-Medarde, A. & Santos, E. Ras in cancer and development diseases. Genes Cancer 2, 344–358 (2011). A review article that summarizes the contributions of RAS mutations and altered RAS signaling to carcinogenesis.
Ostrem, J. M. & Shokat, K. M. K-RasG12C inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013). A report that describes the structure-based validation of an allosteric regulatory site on KRASG12C that was found to be selectively targetable.
Wang, X. & Marx, M. A. Identification of MRTX1133, a noncovalent, potent, and selective KRASG12D inhibitor. J. Med. Chem. 65, 3123–3133 (2022). The structure-based discovery and characterization of MRTX1133.
Hallin, J. & Christensen, J. G. The KRASG12C inhibitor, MRTX849, provides insight toward therapeutic susceptibility of KRAS mutant cancers in mouse models and patients. Cancer Discov. 10, 54–71 (2020). The functional evaluation and characterization of MRTX849, including patient data, illustration of resistance mechanisms, and identification of potentially effective treatment combinations.
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This is a summary of: Hallin, J. et al. Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor. Nat. Med. https://doi.org/10.1038/s41591-022-02007-7 (2022).
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The KRASG12D inhibitor MRTX1133 elucidates KRAS-mediated oncogenesis. Nat Med 28, 2017–2018 (2022). https://doi.org/10.1038/s41591-022-02008-6