Stapled peptide inhibitors of RAB25 target context-specific phenotypes in cancer

摘要: Recent evidence has established a role for the small GTPase RAB25, as well related effector proteins, in enacting both pro-oncogenic and anti-oncogenic phenotypes specific cellular contexts. Here we report development of all-hydrocarbon stabilized peptides derived from RAB-binding FIP-family proteins to target RAB25. Relative unmodified peptides, optimized stapled exhibit increased structural stability, binding affinity, cell permeability, inhibition RAB25:FIP complex formation. Treatment cancer lines which RAB25 is with an peptide, RFP14, inhibits migration, proliferation RAB25-dependent manner. In contrast, RFP14 treatment augments these breast cells tumor suppressive. Transcriptional profiling identified significantly altered transcripts response expression, opposes this expression profile. These data validate first cell-active chemical probes targeting RAB-family support regulating context-specific oncogenic phenotypes. The Ras-family can exert pro- functions. Here, authors develop RAB25 and influencing context-specificity lines.