Drugging the undruggable: towards the development of selective modulators of cadherin-mediated cell-cell adhesion
Emilio Parisi, Italian Institute of Technology (Milano) and Latvian Institute of Organic Synthesis (Riga)
Cadherins are transmembrane calcium-dependent cell adhesion proteins that mediate cellular adherens junction formation and tissue morphogenesis. Loss of cadherin-mediated adhesion has been implicated in many different steps of tumor progression such as invasion and migration, and is strongly related to cell–cell detachment and metastasis. Altered expression profiles of epithelial E-cadherin (CDH1) and neuronal N-cadherin (CDH2) have often been observed in cancer cells, most notably in the context of the epithelial-to-mesenchymal transition (EMT) process that occurs during cancer progression. Interestingly, while in the majority of carcinomas E-cadherin is down-regulated, in some epithelial ovarian cancer (EOC) cells are characterized by high expression levels of E-cadherin, which facilitates EOC cell proliferation. So far, structural and mutational studies have provided a rather detailed picture of the highly dynamic cadherin homo-dimerization mechanism. However, because of this intrinsic dynamic behavior, the rational design of small ligands targeting cadherin homophilic interactions has proved difficult. We determined the crystal structure of an E-cadherin extracellular fragment in complex with a peptidomimetic compound that partially inhibits cadherin homophilic adhesion. The structure, which is the first and to date the only crystal structure of a cadherin extracellular portion in complex with a small molecule inhibitor, reveals an unexpected binding mode and allows the identification of a druggable cadherin interface. Effective cell−cell adhesion modulators may represent potential anti-angiogenic drugs or pharmaceutical excipients to improve drug delivery across biological barriers.
Emilio Parisini is a Group Leader at the Center for Nano Science and Technology of the Istituto Italiano di Tecnologia (IIT) in Milano. After completing a PhD in Chemistry at the University of Bologna (Italy), he worked at the Universities of Göttingen (Germany), Cambridge (UK) and Harvard (USA). In his laboratory, he studies structure-function relationship in several chemical and biological systems, focusing primarily on the study of the interactions between proteins and their ligands, substrates or inhibitors. His current research interests include the functional and structural characterization of different members of the Cadherin family of cell adhesion proteins and of several different classes of enzymes for diagnostic (biosensors), therapeutic (structure-based drug design) and technological (protein and enzyme engineering) applications.
He has been invited to IBEC by Pau Gorostiza.