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Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction

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.

 

Comments:

It sounds like you're discussing an exciting development in cancer treatment! The report highlights the significance of disrupting the interaction between SOS1 and KRASG12C, which affects the cycling of KRAS between its active and inactive states. By disrupting this protein-protein interaction (PPI), the aim is to increase the proportion of inactive KRASG12C loaded with GDP.

The compound MRTX0902 seems to be a promising inhibitor designed to specifically target and disrupt the SOS1:KRASG12C interaction. It's described as potent, selective, capable of penetrating the brain, and orally bioavailable, which are all desirable properties for a drug candidate.

When combined with MRTX849, an inhibitor targeting the GDP-loaded form of KRASG12C, MRTX0902 demonstrates increased antitumor activity. The synergy between these two agents results in more significant tumor regression compared to using either agent alone. This combined approach shows promise, especially in the MIA PaCa-2 tumor mouse xenograft model, where it led to tumor regressions in some cases.

This research suggests a potential strategy for enhancing the efficacy of treating cancers driven by KRAS mutations by combining inhibitors that target different aspects of the KRAS signaling pathway. Such a combination approach might offer improved therapeutic benefits compared to individual treatments.

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Cat.No. Product Name Information
E1183 MRTX0902 MRTX0902 is a potent SOS1 inhibitor for therapeutic intervention of KRAS-driven cancers with an IC50 of 46 nM.

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