Drug discovery of N-WASP inhibitors in metastatic breast cancer cell lines

University Of Puerto Rico Med Sciences, San Juan PR

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Abstract

PROJECT SUMMARY In cancer cells, formation of these membrane protrusions called invadopodia is upregulated due to excessive activation of signaling pathways that control actin polymerization. The Wiskott-Aldrich syndrome protein (WASP) family proteins are important regulators of actin polymerization and invadopodia formation. The neural-WASP (N-WASP) is a central regulator of Arp2/3 complex-mediated actin polymerization into invadopodia to initiate cell migration, and thus, cancer metastasis. N-WASP is activated at the cell membrane during invadopodia initiation, thus, implicating N-WASP in the initiation of cell invasion. Therefore, in this research we proposed to synthesize small molecule carbazole derivatives that inhibit the activity of N-WASP and test their potential inhibitory action on metastatic breast cancer cell lines. The new carbazole derivatives will be synthesized through several chemical transformations to produce a short link between the aromatic carbazole and the aliphatic polar segment. Additionally, we will identify, through a virtual screening method, new compounds to be tested in pyrene-actin polymerization assays and analyze its ability to reduce migration by targeting N-WASP activity. The overall goal of this project is to discover and develop new drugs for the treatment of breast cancer metastasis via specific inhibition of N-WASP. The central hypothesis of this proposal is that specific and selective inhibition of N-WASP activity can be effectively used to block breast cancer invasion and metastasis. The new N-WASP inhibitors will be designed based on the available 3-D coordinates of N-WASP structure and docking software. The binding, and inhibitory potential of novel compounds as N-WASP inhibitors will be investigated by their ability to block actin nucleation in cancer cell lysates following EGF stimulation or addition of upstream effectors Cdc42 or PIP2 pyrene-labeled actin polymerization assay. The pharmacological activity of N-WASP inhibitors will be determined on breast cancer invasion and metastasis.