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.

Fig. 1

Classification of protein kinases of the human kinome. Protein kinases can be divided into tyrosine kinases and serine/threonine kinases. Tyrosine kinases can be subdivided into approximately 30 families, which mediate a variety of biological responses. The kinases in six other groups mostly phosphorylate serine/threonine residues. These groups include AGC-containing protein kinase A (PKA)/protein kinase G (PKG)/protein kinase C (PKC) families; CAMK calcium/calmodulin-dependent kinase; CK1 casein kinase 1; CMGC-containing cyclin-dependent kinase (CDK)/mitogen-activated protein kinase (MAPK)/glycogen synthase kinase (GSK)/CDK-like kinase (CLK) families; STE homologues of yeast sterile 7, sterile 11, sterile 20 kinases; TKL tyrosine kinase-like kinase. Each of these groups can also be classified into families, of which at least one example per group is shown. ABL Abelson kinase; Akt Akt/protein kinase B (PKB); EGFR epidermal growth factor receptor; FGFR fibroblast growth factor receptor; MLK mixed-lineage kinase; PDGFR platelet-derived growth factor receptor; TIE tyrosine kinase with immunoglobulin-like and EGF-like domain; VEGFR vascular endothelial growth factor receptor

Fig. 2

Structure of a receptor tyrosine kinase. The extracellular domain of a receptor tyrosine kinase can bind specific ligands such as growth factors, while the intracellular domain achieves (auto)phosphorylation of the kinase. The extra- and intracellular domain are parted by the transmembrane region that is anchored in the cell membrane. The ATP-binding cleft is located between the two lobes of the intracellular domain. A schematic representation of the ATP-binding cleft, with its different regions, is shown on the right side of the figure. The binding regions of type I and type II tyrosine kinase inhibitors are indicated

Fig. 3

Signal transduction pathways and biological processes mediated by receptor tyrosine kinases focused on angiogenesis. a A selection of pathways activated by receptor tyrosine kinase involved in angiogenesis is shown. Pathway activation, for example by VEGFR or PDGFR, can result in a variety of angiogenic processes, such as cell proliferation, migration, survival, and vascular permeability. b The phosphatidylinositol 3′-kinase (PI3K) pathway is an important downstream pathway of diverse receptor tyrosine kinases and is involved in various cellular processes in angiogenesis. Akt/protein kinase B (PKB) is activated downstream of PI3K. BAD Bcl-2-associated death promoter; eNOS endothelial nitric oxide synthase; FAK focal adhesion kinase; Grb2 growth factor receptor-bound protein 2; GSK3 glycogen synthase kinase 3; MAPK mitogen-activated protein kinase; MEK MAPK and extracellular-signal-regulated kinase (ERK) kinase; mTOR mammalian target of rapamycin; NF-κB nuclear factor-κB; PIP3 phosphatidylinositol 3,4,5-triphosphate; PKC protein kinase C; PLCγ phospholipase C-γ; p70S6K p70S6 kinase; Shb SH2 and β-cells; TSAd T-cell specific adaptor

Fig. 4

Chemical structures of ATP and anti-angiogenic tyrosine kinase inhibitors. a Chemical structure of ATP. ATP consists of an adenine ring, a ribose sugar, and three phosphate groups. The adenine ring, which forms hydrogen bonds with the ATP-binding site of its target kinase, is encircled in this figure. b Chemical structures of the anti-angiogenic tyrosine kinase inhibitors sunitinib, sorafenib, pazopanib, vandetanib, axitinib, cediranib, vatalanib, and motesanib. The targets of these inhibitors, their clinical activity, and their phase of development are listed in Table 1