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Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the
John M Ketcham1, Jacob Haling1, Shilpi Khare1
1Mirati Therapeutics, 3545 Cray Court, San Diego, California 92121, United States.
Abstract:
SOS1 is one of the major guanine nucleotide exchange factors that regulates the ability of KRAS to cycle through its "on" and "off" states. Disrupting the SOS1:KRASG12C protein-protein interaction (PPI) can increase the proportion of GDP-loaded KRASG12C, providing a strong mechanistic rationale for combining inhibitors of the SOS1:KRAS complex with inhibitors like MRTX849 that target GDP-loaded KRASG12C. In this report, we detail the design and discovery of MRTX0902─a potent, selective, brain-penetrant, and orally bioavailable SOS1 binder that disrupts the SOS1:KRASG12C PPI. Oral administration of MRTX0902 in combination with MRTX849 results in a significant increase in antitumor activity relative to that of either single agent, including tumor regressions in a subset of animals in the MIA PaCa-2 tumor mouse xenograft model.
Insights
Researchers developed MRTX0902, a novel drug targeting the SOS1:KRAS interaction. Combining MRTX0902 with MRTX849 significantly enhanced anti-tumor activity and induced regressions in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- KRAS is a key regulator of cellular signaling, and its aberrant activation, particularly KRAS G12C, drives many cancers.
- SOS1 acts as a guanine nucleotide exchange factor, facilitating KRAS activation.
- Targeting the SOS1:KRAS protein-protein interaction (PPI) is a promising therapeutic strategy.
Purpose of the Study:
- To design and discover a novel inhibitor of the SOS1:KRAS PPI.
- To evaluate the efficacy of MRTX0902, a potent and selective SOS1 binder, alone and in combination with MRTX849.
Main Methods:
- Design and synthesis of MRTX0902, a brain-penetrant and orally bioavailable SOS1 inhibitor.
- Preclinical evaluation of MRTX0902 in combination with MRTX849 in a MIA PaCa-2 mouse xenograft model.
Main Results:
- MRTX0902 effectively disrupts the SOS1:KRAS G12C PPI.
- Combination therapy with MRTX0902 and MRTX849 demonstrated significantly enhanced antitumor activity compared to single agents.
- Tumor regressions were observed in a subset of animals treated with the combination therapy.
Conclusions:
- MRTX0902 is a potent and selective SOS1 inhibitor with favorable pharmacokinetic properties.
- The combination of MRTX0902 and MRTX849 shows strong preclinical efficacy, supporting further clinical investigation for KRAS G12C-driven cancers.
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