Integrin targeted therapeutics

Abstract

Integrins are heterodimeric, transmembrane receptors that function as mechanosensors, adhesion molecules and signal transduction platforms in a multitude of biological processes. As such, integrins are central to the etiology and pathology of many disease states. Therefore, pharmacological inhibition of integrins is of great interest for the treatment and prevention of disease. In the last two decades several integrin-targeted drugs have made their way into clinical use, many others are in clinical trials and still more are showing promise as they advance through preclinical development. Herein, this review examines and evaluates the various drugs and compounds targeting integrins and the disease states in which they are implicated.

Keywords: Crohn's Disease; Integrin-targeted therapeutics; Multiple Sclerosis; abciximab; abegrin; acute coronary syndromes; age related macular degeneration; angiogenesis; cancer; cilengitide; eptifibatide; integrin-targeted peptides; integrin-targeted small molecules; integrin-targeted therapeutic antibodies; natalizumab; osteoporosis; tirofiban.

Figure 1

Integrin “Inside-out” signaling promotes integrin activation and heightens ligand affinity. External activating stimuli such as integrin or selectin ligation or cytokine binding to G-protein coupled receptors triggers intracellular signaling cascades that converge on integrin β-subunit tails. The activating signals induce conformational changes in the integrin tails that facilitate the docking of focal adhesion components such as Talin. The conformational changes in the tail region are transduced to the extracellular domain where structural rearrangments promote activation and increased affinity for ligand.

Figure 2

Integrin “Outside-in” signaling governs cellular processes. Ligand binding serves as the initiation point for transduction of intracellular signaling cascades that regulate a multitude of biological processes. Figure adapted from reference 5 with permission.

Figure 3

Integrins are the site of focal adhesions. Integrin ligation promotes receptor clustering and the formation of focal adhesions. Talin forms the initial contacts between integrin β-tails and the actin cytoskeleton. Vinculin crosslinks with Talin and actin to strengthen focal adhesions promoting focal adhesion growth. α-actinin can interact with integrin β-tails, vinculin, talin and actin to further reinforce crosslinking of the cytoskeleton. ILK associates with actin through its binding partner parvin creating a core scaffold for focal adhesion formation. Focal adhesion kinase (FAK) is involved in focal adhesion stabilization and turnover likely through post-translational modification of focal adhesion components.

Figure 4

CycloRGDFV bound to αvβ3 (RCSB code: 1L5G). Metal ions Mn²⁺ are depicted as spheres.

Figure 5

Ligand binding site of αvβ3 integrin (RCSB code: 1L5G) in complex with RGD peptide showing close contact residues of cycloRGDFV at the integrin dimer interface.

Figure 6

Examples of integrin antagonists (A) therapeutic antibody (B) cyclic peptide (C) small molecule antagonist.

Figure 7

Mechanisms of platelet activation. Binding of secreted factors to cognate ligands promotes platelet activation leading to αIIbβ3 activation. Activation of αIIbβ3 promotes integrin clustering and binding of fibrinogen and von Willebrand Factor leading to platelet aggregation and thrombus formation.

Figure 8

Structures of αIIbβ3 antagonists Eptifibatide and Tirofiban.

Figure 9

Structures of orally active, small molecule αIIbβ3 antagonists.

Figure 10

Mechanism of immune-cell mediated inflammation and its inhibition by α4 antagonists. Left Panel- α4 integrins are up-regulated on the surface of activated immune cells. Through contacts with endothelial cell adhesion molecules such as selectins and glycoproteins, these cells are captured from the circulation. The intial contacts are strengthened when α4 integrins make contact with MAdCAM and VCAM on endothelial cells. Extravasation and migration to sites of inflammation are mediated in part through α4 integrins. Right Panel- In the presence of α4 antagonists such as natalizumab, firm adhesion and subsequent migration are inhibited preventing immune cell infiltration within tissue.

Figure 11

Small molecule α4 antagonists vary in their propensity for teratogenic effects. IVL984 (potent teratogen), HMR1031 (mild teratogen) and IVL745 (non-teratogenic) are structurally similar yet have different teratogenicity profiles. The difference is attributed to their affinity for non-activated α4 integrin. Compounds that bind α4 in both activated and resting states appear to be more teratogenic.

Figure 12

Structures of αvβ3 antagonists in clinical development.