NHERF1 (Na+/H+ exchanger 3 regulating factor 1) is an integral membrane adaptor protein carrying two NH2-terminal PDZ (postsynaptic density 95/discs large/zona occludens 1) tandem domains. PDZ1 and PDZ2 bind to specific carboxyl-terminal motifs on target proteins, such as beta-catenin and PTEN, that may have a pivotal role in tumorigenesis. A pharmacophore model was used to filter out an in-house training set of about 6000 compounds, leading to identify a potent inhibitor of NHERF1. We herein report the design and synthesis of new NHERF1 inhibitors. Compounds 5, 9, 10 and 13 exhibited a remarkable cytotoxicity in Ls174Tshbeta-Cat cells. The binding to NHERF1 PDZ was confirmed by means of a dansylated peptide corresponding to the C-terminal sequence of beta2-AR. When used in combination with antagonists of beta-catenin, the new derivatives increased the apoptotic death of colorectal cancer cells refractory to currently available Wnt/beta-catenin-targeted agents.
First in class pdz1 targeting NHERF1 inhibitors as anticancer agents / LA REGINA, Giuseppe; Naccarato, Valentina; Puxeddu, Michela; Bufano, Marianna; Nalli, Marianna; Coluccia, Antonio; Silvestri, Romano. - (2019), pp. 77-77. (Intervento presentato al convegno 12th European Workshop in Drug Design tenutosi a Siena).
First in class pdz1 targeting NHERF1 inhibitors as anticancer agents
Giuseppe La Regina
;Valentina Naccarato;PUXEDDU, MICHELA;BUFANO, MARIANNA;Marianna Nalli;Antonio Coluccia;Romano Silvestri
2019
Abstract
NHERF1 (Na+/H+ exchanger 3 regulating factor 1) is an integral membrane adaptor protein carrying two NH2-terminal PDZ (postsynaptic density 95/discs large/zona occludens 1) tandem domains. PDZ1 and PDZ2 bind to specific carboxyl-terminal motifs on target proteins, such as beta-catenin and PTEN, that may have a pivotal role in tumorigenesis. A pharmacophore model was used to filter out an in-house training set of about 6000 compounds, leading to identify a potent inhibitor of NHERF1. We herein report the design and synthesis of new NHERF1 inhibitors. Compounds 5, 9, 10 and 13 exhibited a remarkable cytotoxicity in Ls174Tshbeta-Cat cells. The binding to NHERF1 PDZ was confirmed by means of a dansylated peptide corresponding to the C-terminal sequence of beta2-AR. When used in combination with antagonists of beta-catenin, the new derivatives increased the apoptotic death of colorectal cancer cells refractory to currently available Wnt/beta-catenin-targeted agents.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
