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.
During cancer cell invasion, tumor cell migration through tissues, frequently requires the degradation of the extracellular matrix (ECM) and several proteins play a key role in this process, known as invadopodia. Since N-WASP is involved in invadopodia formation in metastatic carcinoma cells, specific inhibition of N-WASP is an important target to develop new compounds with therapeutic application in breast cancer metastasis. Therefore, in this project new compounds with clinical relevance for the treatment of metastatic breast cancer will be discovered and developed, and results might contribute to advance scientific knowledge on targeted therapy.
|Vlaar, Cornelis P; Castillo-Pichardo, Linette; Medina, Julia I et al. (2018) Design, synthesis and biological evaluation of new carbazole derivatives as anti-cancer and anti-migratory agents. Bioorg Med Chem 26:884-890|