The ability of integrins to activate and integrate intracellular communication illustrates the potential of these receptors to serve as functional distribution hubs in a bi-directional signal transfer outside-in and inside-out the cells. A tight regulation of the integrin signalling is paramount for normal physiological functions such as migration, proliferation, and differentiation and a misregulated integrin activity could be associated with several pathological conditions. Because of the important roles of integrins and their ligands in biological development, immune responses, leukocyte traffic, haemostasis, and cancer, their potential as therapeutic tools is now widely recognized. Nowadays extensive efforts have been made to discover and develop small molecule ligands as integrin antagonists whereas less attention has been payed to agonists. In recent years, it has been recognized that integrin agonists could open up novel opportunities for therapeutics, which gain benefits to increase rather than decrease integrin-dependent adhesion and transductional events. For instance, a significant factor in chemo-resistance in melanoma is a loss of integrin-mediated adhesion; in this case, stimulation of integrin signalling by agonists significantly improved the response to chemotherapy. In this review, we overview results about small molecules which revealed an activating action on some integrins, especially those involved in cancer, and to examine from a medicinal chemistry point of view their structure and behavior.

Can integrin agonists have cards to play against cancer? A literature survey of small molecules integrin activators.

TOLOMELLI, ALESSANDRA;GALLETTI, PAOLA;BAIULA, MONICA;GIACOMINI, DARIA
2017

Abstract

The ability of integrins to activate and integrate intracellular communication illustrates the potential of these receptors to serve as functional distribution hubs in a bi-directional signal transfer outside-in and inside-out the cells. A tight regulation of the integrin signalling is paramount for normal physiological functions such as migration, proliferation, and differentiation and a misregulated integrin activity could be associated with several pathological conditions. Because of the important roles of integrins and their ligands in biological development, immune responses, leukocyte traffic, haemostasis, and cancer, their potential as therapeutic tools is now widely recognized. Nowadays extensive efforts have been made to discover and develop small molecule ligands as integrin antagonists whereas less attention has been payed to agonists. In recent years, it has been recognized that integrin agonists could open up novel opportunities for therapeutics, which gain benefits to increase rather than decrease integrin-dependent adhesion and transductional events. For instance, a significant factor in chemo-resistance in melanoma is a loss of integrin-mediated adhesion; in this case, stimulation of integrin signalling by agonists significantly improved the response to chemotherapy. In this review, we overview results about small molecules which revealed an activating action on some integrins, especially those involved in cancer, and to examine from a medicinal chemistry point of view their structure and behavior.
Tolomelli, Alessandra; Galletti, Paola; Baiula, Monica; Giacomini, Daria
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/603664
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