Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action?

Abstract

Tyrosine kinases are important cellular signaling proteins that have a variety of biological activities including cell proliferation and migration. Multiple kinases are involved in angiogenesis, including receptor tyrosine kinases such as the vascular endothelial growth factor receptor. Inhibition of angiogenic tyrosine kinases has been developed as a systemic treatment strategy for cancer. Three anti-angiogenic tyrosine kinase inhibitors (TKIs), sunitinib, sorafenib and pazopanib, with differential binding capacities to angiogenic kinases were recently approved for treatment of patients with advanced cancer (renal cell cancer, gastro-intestinal stromal tumors, and hepatocellular cancer). Many other anti-angiogenic TKIs are being studied in phase I-III clinical trials. In addition to their beneficial anti-tumor activity, clinical resistance and toxicities have also been observed with these agents. In this manuscript, we will give an overview of the design and development of anti-angiogenic TKIs. We describe their molecular structure and classification, their mechanism of action, and their inhibitory activity against specific kinase signaling pathways. In addition, we provide insight into what extent selective targeting of angiogenic kinases by TKIs may contribute to the clinically observed anti-tumor activity, resistance, and toxicity. We feel that it is of crucial importance to increase our understanding of the clinical mechanism of action of anti-angiogenic TKIs in order to further optimize their clinical efficacy.

Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

“…Multiple kinases are deeply involved in tumor development and angiogenesis and their inhibition has been developed as a systemic treatment strategy for cancer [1]. Thus, the most targeted area of developing antineoplastic drugs is through the inhibition of EGFR and VEGFR signaling.…”

“…Understanding the mechanisms of normal and aberrant tyrosine kinase signalling and strategies to inhibit them in angiogenesis and cancer, further promote the development of novel agents [1,2].…”

“…Based on these considerations, tyrosine kinases of growth factor receptors, such as EGFR and VEGFR-2, are highly attractive targets for the development of new specific anticancer agents [1].…”

Model-based angiogenic inhibition of tumor growth using modern robust control method

“…After a certain size (1-2 mm diameter) tumor development stops, because a part of the tumor gets too far from capillaries and cannot pick up enough oxygen. Hence, the tumor needs its own blood vessels -the process of forming new blood vessels is called angiogenesis (Gotink and Verheul (2010); Kopper and Tímár (2007)). …”

Vascular-targeted agents for the treatment of angiosarcoma

“…Protein kinases are enzymes that transfer a phosphate group from adenosine triphosphate (ATP) on to tyrosine, serine or threonine residues of substrate molecules, which are themselves often other protein kinases [37]. inducing endothelial cell proliferation [38].…”