WASF3 plays a critical role in promoting metastasis and has been found to be at least partly responsible for successful metastatic colonization in distant organs. WASF3 is normally held in an autorepressed conformation through interactions with CYFIP1 and NCKAP1, which are essential components of the WASF Regulatory Complex (WRC). Knockdown of any of these proteins leads to destabilization of the WASF3 complex and suppression of invasion and metastasis. Regulation of WASF3 function is controlled through binding of a trimeric complex that includes the WASF regulatory domain as well as CYFIP1 and NCKAP1 proteins. Crystal structure analysis of the trimeric complex has defined protein-protein interfaces that define the binding surfaces of the CYFIP1-NCKAP1 proteins in complex with WASF3. These specific interactions are essential for WASF3-mediated invasion, activation and development of metastasis. Using a peptide-based approach, constrained peptides were developed to mimic key components of trimeric protein complex interface. Peptides were constrained into alpha-helical conformers using hydrocarbon stapling. We found that targeting the CYFIP1-WASF3 or CYFIP-NCKAP1 interaction interfaces using constrained peptides led to inhibition of suppression of invasion in vitro and metastasis in vivo. Since the WASF3 complex is formed by elongated, hydrophobic interfaces, no small molecules have yet been identified that can effectively target its activity. A constrained peptide-based approach may serve as an alternative strategy to effectively downregulate WASF3 activity and prevent secondary metastatic sites for various cancers.

Design of constrained peptides targeting the tumor metastasis regulator WASF3

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.