Therapeutic target identification
Cell migration is a fundamental event in a variety of biological processes, including the inflammatory response by the organism to repair damages from bacteria, viruses or other injuries, and the formation of new blood vessels (neo-angiogenesis). Proteolytic enzymes degrade the endothelial basement membrane and the extra-cellular matrix (ECM), thus allowing endothelial cells to migrate through lysed matrix proteins. One of the main orchestrators of the whole process is the system formed by uPA (urokinase-plasminogen activator) and its receptor uPAR. While regulating extracellular proteolysis, the uPA/uPAR system activates a number of intracellular signaling pathways, ultimately enabling inflammation and angiogenesis to occur. In healthy individuals, the production and activity of uPA/uPAR and its inhibitor are finely balanced; conversely, when dysregulated, uPA/uPAR may decisively contribute to the onset of many pathologic conditions. The uPA/uPAR system has been identified as a key factor for the invasive ability of malignant tumors; in addition, dysregulated uPAR has been associated to a large number of disorders, which are all characterized by chronic inflammation states.
(adapted from: D’Alonzo, D.; De Fenza, M.; Pavone, V. Drug Discov. Today 2020, 25, 1528-1534)
Diseases and medical needs
There are currently dozens of disorders of different severity associated with aberrant cell migration and thereby with a dysregulated activity of the uPA/uPAR system. In many cases, for many of these disorders adequate therapeutic strategies are not available or they involve expensive, invasive treatments, often requiring surgery and prolonged hospitalization. [examples?]
Looking for new antiangiogenic, antinflammatory, multi-indication drugs
Some compounds have been found to interfere with the uPA/uPAR system and have been proposed for the treatment of some important pathologies. The most studied molecule is the tetrapeptide UPARANT, which has proposed for the therapy of diabetic retinopathy, Retinitis Pigmentosa, Rubeosis Iridis, age-related macular degeneration, macular edema, retinopathy of prematurity, and diabetic nephropathy. UPARANT retroinverse peptide (RI-3) has been proposed for the treatment of melanoma and metastatic sarcoma and ovarian cancer. A6 peptide has been proposed for the treatment of persistent or recurrent epithelial ovarian cancer, fallopian tube carcinoma, primary peritoneum carcinoma, retinal edema and age-related macular degeneration. The cyclic peptide [SRSRY] is reported for the treatment of osteosarcoma, chondrosarcoma and inflammatory bowel diseases. Despite their success in in vitro and in vivo studies, none of the above peptides has not yet found a valid application as drug. In this context, research at IRIDEA Pharmaceuticals is aimed to the identification of novel biomimetic compounds, acting as orally available antiangiogenic and antinflammatory agents. Our molecules are selected on the basis of a rational design process and synthesized by standard organic chemistry approaches. Compared to the existing candidates developed to the same end, our compounds are conceived as inexpensive drug substances,
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