With over 90% of cancer deaths resulting from metastatic spread, compounds targeting this aspect of the disease have the potential to significantly impact survival. The central role of the WASF family of actin binding proteins in cancer motility and invasion makes them an attractive target for potential therapeutic modulation. Although all three WASF isoforms play important roles in the remodeling of actin filament networks, only WASF3 plays a central role in the development of the metastatic phenotype. WASF3 is stabilized and kept in an inactive state though interactions with the WASF regulatory complex (WRC). Disruption of these interactions leads to loss of WASF3 activation and in some cases degradation of complex members resulting in a suppression of invasion and metastasis. We previously demonstrated the potential for all hydrocarbon stapled alpha-helical peptides to inhibit motility, migration, and invasion in vitro and metastasis in vivo though disruption of interactions within the WRC. Going forward, we sought to explore whether other helical interactions within the WRC could be more effective inhibitors of WASF3-dependent cancer metastatic signaling while also improving cell permeation. A set of peptides was identified using in silico design techniques and evaluated for inhibition of the WASF3 complex. These peptides demonstrate increased cell permeation and improved inhibition for motility and migration as compared to previous designs. Given the previous validation of this strategy for suppression of invasion and metastasis both in vitro and in vivo, we anticipate that these optimized peptides will be valuable tools for the development of antimetastatic therapies regulated by WASF3.

In silico design of WASF3-targeting constrained peptides

ACS Spring Meeting 2021

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