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The interaction between Ras and SOS1 is an attractive and promising target in discovering candidate drugs for the Ras-driven cancers. Synthesized hydrocarbon-stapled peptides simulate αH helix structure of SOS1, improve proteolytical stability and enhance cell permeability. SSOSH-5 inhibited the proliferation of pan-Ras-mutated cancer cells and induce cell apoptosis. SSOSH-5 could regulate downstream signaling pathway, such as Ras-RAF-MEK-ERK and Ras-PI3K-AKT-mTOR. [Display omitted] • Ras is the most frequently mutated gene family in numerous cancers. • The interaction between Ras and SOS1 is an attractive and promising target in discovering candidate drugs for the Ras-driven cancers. • Synthesized hydrocarbon-stapled peptides simulate αH helix structure of SOS1, improve proteolytical stability and enhance cell permeability. • SSOSH-5 inhibited the proliferation of pan-Ras-mutated cancer cells and induce cell apoptosis. • SSOSH-5 could regulate downstream signaling pathway, such as Ras-RAF-MEK-ERK and Ras-P110-AKT-mTOR. Blocking the interaction between Ras and Son of Sevenless homolog 1 (SOS1) has been an attractive therapeutic strategy for treating cancers involving oncogenic Ras mutations. K-Ras mutation is the most common in Ras-driven cancers, accounting for 86%, with N -Ras mutation and H-Ras mutation accounting for 11% and 3%, respectively. Here, we report the design and synthesis of a series of hydrocarbon-stapled peptides to mimic the alpha-helix of SOS1 as pan-Ras inhibitors. Among these stapled peptides, SSOSH-5 was identified to maintain a well-constrained alpha-helical structure and bind to H-Ras with high affinity. SSOSH-5 was furthermore validated to bind with Ras similarly to the parent linear peptide through structural modeling analysis. This optimized stapled peptide was proven to be capable of effectively inhibiting the proliferation of pan-Ras–mutated cancer cells and inducing apoptosis in a dose-dependent manner by modulating downstream kinase signaling. Of note, SSOSH-5 exhibited a high capability of crossing cell membranes and strong proteolytic resistance. We demonstrated that the peptide stapling strategy is a feasible approach for developing peptide-based pan-Ras inhibitors. Furthermore, we expect that SSOSH-5 can be further characterized and optimized for the treatment of Ras-driven cancers. [ABSTRACT FROM AUTHOR]