ReviewFrontiers in chemistry2026
Disrupting the KRAS-SOS1 protein-protein interaction: mechanistic rationale for pan-KRAS pathway suppression and combination therapy.
Review in Frontiers in chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
1 citing paper in PubMed.
- Structural and Biophysical Characterization of Aminobenzo[ACS medicinal chemistry letters · 2026Article
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Authors and funding
8 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Oncogenic KRAS signaling is among the most prevalent drivers in human cancer, yet durable pathway suppression has historically been limited by incomplete target coverage, toxicity constraints for downstream kinase inhibitors, and rapid adaptive rewiring through receptor tyrosine kinase (RTK) feedback. A renewed focus on the KRAS activation cycle has positioned SOS1-an RTK-coupled guanine nucleotide exchange factor-as an attractive upstream node to modulate KRAS output across multiple alleles. By disrupting the KRAS-SOS1 protein-protein interaction (PPI) or otherwise limiting SOS1-mediated nucleotide exchange, SOS1-directed agents reduce RAS-GTP formation and suppress Mitogen-Activated Protein Kinase (MAPK) signaling, while also attenuating feedback-driven rebound that commonly follows MEK/ERK inhibition or allele-specific KRAS targeting. In this review, we summarize the structural and mechanistic basis of RAS-SOS engagement, the emergence of a druggable pocket on SOS1 exploited by modern inhibitors, and the evolution from peptide/interface-mimic approaches to potent small-molecule PPI disruptors. We synthesize key pharmacology across tool compounds and clinical candidates, emphasizing biomarker-linked pharmacodynamic readouts (RAS-GTP and Phosphorylated extracellular signal-regulated kinase (pERK)), context dependence (KRAS allele, RTK tone, and pathway baseline), and on-target validation strategies spanning biophysics, structural biology, and cellular engagement. We then discuss why SOS1 inhibitors act as "multiplier" drugs in rational combinations-particularly with MEK inhibitors and KRAS (G12C) inhibitors-outline expected resistance routes and candidate predictive biomarkers, and review the current clinical landscape for SOS1 inhibitors and combination trial design. Finally, we highlight emerging directions including next-generation, brain-penetrant chemistry and event-driven SOS1 degraders, and propose priorities for translating upstream exchange control into durable patient benefit.
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