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The urokinase (uPA)-type plasminogen activator receptor (uPAR) is a GPI-anchored receptor that focuses urokinase (uPA) proteolytic activity on the cell surface. uPAR also regulates cell adhesion, migration and proliferation, protects from apoptosis and contributes to epithelial mesenchymal transition (EMT), independently of uPA enzymatic activity. Indeed, uPAR interacts with beta1, beta2 and beta3 integrins, thus regulating their activities. uPAR cross-talks with receptor tyrosine kinases through integrins and regulates cancer cell dormancy, proliferation and angiogenesis. Moreover, uPAR mediates uPA-dependent cell migration and chemotaxis induced by fMet-Leu-Phe (fMLF), through its association with fMLF-receptors (fMLF-Rs). Further, uPAR is an adhesion receptor because it binds vitronectin (VN), a component of provisional extracellular matrix. High uPAR expression predicts for more aggressive disease in several cancer types for its ability to increase invasion and metastasis. In fact, uPAR has been hypothesized to be the link between tumor cell dormancy and proliferation that usually precedes the onset of metastasis. Thus, inhibiting uPAR could be a feasible approach to affect tumor growth and metastasis. Here, we review the more recent advances in the development of uPAR-targeted anti-cancer therapeutic agents suitable for further optimization or ready for the evaluation in early clinical trials.

Cell migration through the extracellular matrix (ECM) or endothelial cells is a basic process in several physiological and pathological events, including the immune host response to pathogens, both in the case of innate and adaptive immunity. The urokinase-type plasminogen activator (uPA) receptor (uPAR) is a GPI-anchored cell-surface receptor largely expressed on most of leukocytes, including monocytes/macrophages, granulocytes, immature dendritic cells. uPAR has been detected also in soluble and cleaved forms, which are increased in several pathologies. uPAR focuses the proteolytic activity of its ligand, the serine-protease uPA, on the cell membrane, thus promoting localized plasminogen activation and allowing the cell to degrade surrounding ECM and to move across physical barriers. However, the discovery that uPAR can bind with high affinity a component of the ECM, vitronectin (VN), and associates to cell surface molecules to activate signalling pathways inside the cells, largely expanded the role that uPAR can play in cell proliferation/survival and adhesion/migration, which are crucial events for an efficient immune response to infectious agents. This review is focused on the expression and possible functions of the various forms of uPAR in infectious diseases.

Background. Systemic sclerosis (SSc) is an autoimmune disease characterized by excessive fibrosis in derma fibroblasts. There are two major subsets of SSc, the diffuse cutaneous systemic sclerosis (dSSc) and the limited cutaneous systemic sclerosis (lSSc). Fibroblasts play a key role in SSc. The expression and function of the urokinase (uPA)-mediated plasminogen activation (PA) system, a well characterized system of serine-proteases involved in several pathologic processes, has been investigated in SSc fibroblasts. Methods. The expression of the components of the PA system, including uPA, its receptor (uPAR) and its type-1 and type-2 inhibitors (PAI-1 and PAI-2) was examined by Western blot in fibroblasts from patients affected by limited and diffuse forms of SSc. SSc fibroblasts adhesion to vitronectin (VN) was examined by cell adhesion assays. Results. uPA and PAI-1 secretion increased only in fibroblasts from lSSc lesions, as compared to normal fibroblasts. PAI-2 levels were decreased in fibroblasts from both SSc forms. Interestingly, fibroblasts from areas not adjacent to the lesions (not-affected) of the diffuse form showed reduced levels of PAI-1 and increased uPAR expression. Adhesion experiments showed reduced adherence to VN of fibroblasts from lSSc and dSSc lesions in from not affected areas, as compared to normal controls. Conclusions. These results suggest a role for uPA and PAI-1 in the lSSc form, likely related to the activation of cytokines and metalloproteases with the accumulation of extra-cellular matrix components, whereas a role for uPAR can be hypothesized in the evolvement of the diffuse form, based on its up-regulation in the not-affected areas.

Systemic sclerosis (SSc) is an autoimmune disease characterized by excessive fibrosis in derma fibroblasts. There are two major subsets of SSc, the diffuse cutaneous systemic sclerosis (dSSc) and the limited cutaneous systemic sclerosis (lSSc). Fibroblasts play a key role in SSc. The expression and function of the urokinase (uPA)-mediated plasminogen activation (PA) system, a well characterized system of serine-proteases involved in several pathologic processes, has been investigated in SSc fibroblasts. Methods. The expression of the components of the PA system, including uPA, its receptor (uPAR) and its type-1 and type-2 inhibitors (PAI-1 and PAI-2) was examined by Western blot in fibroblasts from patients affected by limited and diffuse forms of SSc. SSc fibroblasts adhesion to vitronectin (VN) was examined by cell adhesion assays. Results. uPA and PAI-1 secretion increased only in fibroblasts from lSSc lesions, as compared to normal fibroblasts. PAI-2 levels were decreased in fibroblasts from both SSc forms. Interestingly, fibroblasts from areas not adjacent to the lesions (not-affected) of the diffuse form showed reduced levels of PAI-1 and increased uPAR expression. Adhesion experiments showed reduced adherence to VN of fibroblasts from lSSc and dSSc lesions in from not affected areas, as compared to normal controls. Conclusions. These results suggest a role for uPA and PAI-1 in the lSSc form, likely related to the activation of cytokines and metalloproteases with the accumulation of extra-cellular matrix components, whereas a role for uPAR can be hypothesized in the evolvement of the diffuse form, based on its up-regulation in the not-affected areas.

La presente invenzione ha per oggetto composti antitumorali che inibiscono la prenilazione della proteina oncogenica Ras, la cui attivazione governa la crescita incontrollata dei tumori e delle loro metastasi. Infatti, questa proteina è sovraespressa nel 25% dei tumori più diffusi, comprendenti tumori particolarmente recalcitranti alla terapia come gli adenocarcinomi del colon, del pancreas e del polmone. I comuni agenti antitumorali, usati attualmente in terapia, hanno come fattore limitante quello di inibire indifferentemente la proliferazione di cellule tumorali e cellule normali. Al contrario, i composti di questa invenzione hanno il vantaggio di inibire la proliferazione delle cellule tumorali, mentre lasciano inalterate le cellule normali, alla concentrazione citotossica. I composti di questa invenzione sono tutti i derivati possibili delle formule generali (I) e (II) riportate nell’allegata Tavola 1. La presente invenzione comprende anche le composizioni chemioterapeutiche di detti composti, le loro caratteristiche chimico-fisiche, l’uso ed i processi per la loro preparazione.