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

Crystal structure image of the RAB25 interacting with FIP2.

Mitra et al. (2017) Nat Commun. http://creativecommons.org/licenses/by/4.0/

Mitra S, Montgomery JE, Kolar MJ, Li G, Jeong KJ, Peng B, Verdine GL, Mills GB, Moellering RE

Nature Communications

September 22, 2017

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

Program:
CTD²
Last updated: October 10, 2017