SRC inhibitors and angiogenesis.
Angiogenesis is a tightly regulated process that leads to the formation of new blood vessels in limited physiological conditions, and can also occur under pathological situations as retinopathies, arthritis, endometriosis and cancer. Enhanced angiogenesis is present in tumors that need new blood capillaries to grow, remove metabolic waste and transport the cells to locations distal to the primary tumor, facilitating metastasis formation. For these reasons, blockade of angiogenesis is an attractive approach for the treatment of both solid and haematological malignancies. Antiangiogenic therapy should be less toxic in comparison with conventional treatments such as chemotherapy, being angiogenesis a process relatively restricted to the growing tumor. The Src family of tyrosine kinases has been implicated in the intracellular signaling cascade that acts downstream of cell surface receptors to elicit different cellular functions, including growth, proliferation, adhesion and motility. Src kinases are frequently activated in human malignancies, causing tumor progression, metastasis formation and deregulating expression of proangiogenic molecules. This review reports several studies performed by different authors demonstrating the involvement of Src tyrosine kinases in angiogenesis by regulating different signalling pathways. Moreover, we report selective Src inhibitors for which a direct involvement with angiogenesis has been demonstrated, even if every Src inhibitor could potentially possesses also antiangiogenic properties. Biological data, structures and mechanisms of action of selected molecules, in terms of Src protein-inhibitor interactions, are also reported.
Schenone
S
S
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Genova, Italy. schensil@unige.it
Manetti
F
F
Botta
M
M
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D009369:Neoplasms / Q000201:enzymology; D018919:Neovascularization, Physiologic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; C412373:AG 1879; D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D011799:Quinazolines; D019061:src-Family Kinases