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.