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June 18, 2026Journal of Medicinal Chemistry

Discovery of CNS Penetrant SOS1 Inhibitors for the Treatment of KRAS-Dependent Cancers

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Authors

SBSharan K. BagalAstraZeneca (Singapore)CDCoura R. N. DièneTarget (United States)SSSandra Stefanovic-BarrettAstraZeneca (Singapore)

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Implication

Randomized trial demonstrates enhanced antitumor effects in cancer models using SOS1 inhibitors combined with KRAS inhibitors, suggesting a new therapeutic strategy.

Key Points

  • This research aims to identify effective CNS penetrant SOS1 inhibitors for treating KRAS-dependent cancers.
  • Focused high-throughput screening to identify SOS1 inhibitors with a pyridyl core.
  • Structure-based design was applied to refine binding potency by targeting a lipophilic pocket.
  • In vivo pharmacokinetic/pharmacodynamic studies combining SOS1 inhibitors with a KRAS G12C inhibitor were conducted.
  • Combination therapy resulted in a 50-fold enhancement in binding potency.
  • Mice treated with SOS1 and KRAS G12C inhibitors showed deeper reductions in DUSP6 mRNA (p<0.01) and phosphorylated ERK (p<0.01) compared to KRAS G12C inhibitor alone.

Cite This Study

Bagal et al. (2026) studied this question.

synapsesocial.com/papers/6a338b22630953a74978cd5ehttps://doi.org/10.1021/acs.jmedchem.5c03800
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance2024 · 60 citations
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  4. 4A retrospective observational study of the natural history of advanced non–small-cell lung cancer in patients with KRAS p.G12C mutated or wild-type disease2021 · 55 citations
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