In SilicoOptimized Stapled Peptides Targeting WASF3 in BreastCancer br

Wiskott-Aldrich Syndrome Protein Family (WASF)members regulate actin cytoskeletal dynamics, and WASF3 is directlyassociated with breast cancer metastasis and invasion. WASF3 forms aheteropentameric complex with CYFIP, NCKAP, ABI, and BRK1, calledthe WASF Regulatory Complex (WRC), which cooperatively regulatesactin nucleation by WASF3. Since aberrant deployment of the WRC isobserved in cancer metastasis and invasion, its disruption provides a novelavenue for targeting motility in breast cancer cells. Here, we report thedevelopment of a second generation WASF3 mimetic peptide, WAHMIS-2, which was designed using a combination of structure-guided design,homology modeling, andin silicooptimization to disrupt binding of WASF3 to the WRC. WAHMIS-2 was found to permeate cellsand inhibit cell motility, invasion, and MMP9 expression with greater potency than its predecessor, WAHM1. Targeted disruption ofWASF3 from the WRC may serve as a useful strategy for suppression of breast cancer metastasis.