“At present, 58 receptor tyrosine kinases (RTKs) are known, grouped into 20 subfamilies.

They play pivotal roles in diverse cellular activities including growth, differentiation, metabolism, adhesion, motility and death.

RTKs are composed of an extracellular domain, which is able to bind a specific ligand, a transmembrane domain, and an intracellular catalytic domain, which is able to bind and phosphorylate selected substrates.

Binding of a ligand to the extracellular region causes a series of structural rearrangements in the RTK that lead to its enzymatic activation.

In particular, movement of some parts of the kinase domain gives free access to adenosine triphosphate (ATP) and the substrate to the active site.

This triggers a cascade of events through phosphorylation of intracellular proteins that ultimately transmit (“transduce”) the extracellular signal to the nucleus, causing changes in gene expression.

Many RTKs are involved in oncogenesis, either by gene mutation, or chromosome translocation, or simply by over-expression.

In every case, the result is a hyper-active kinase, that confers an aberrant, ligand-independent, non-regulated growth stimulus to the cancer cells.”⁽¹⁶⁾

From these 20 subfamilies of Receptor Tyrosine Kinases (RTK), seven families are promising field of investigation and only two families of RTK represent now the most promised field of drug development in AMD; fibroblast growth factor receptor (FGFR) family and vascular endothelial growth factor receptor (VEGFR) family.

RTK Class I Epidermal growth factor receptor family, RTK Class II Insulin receptor family RTK Class III Platelet-derived growth factor receptor RTK Class IV Fibroblast growth factor receptor (FGFR) family, RTK Class V Vascular endothelial growth factor receptor (VEGFR) family, RTK Class XII RET receptor family (RET proto-oncogene) RTK Class VIII Eph receptor family.

Fibroblast growth factors comprise the largest family of growth factor ligands⁽¹⁷⁾.

The natural alternate splicing of four fibroblast growth factor receptor (FGFR) genes results in the production of over 48 different isoforms of FGFR.

These isoforms vary in their ligand binding properties and kinase domains, however all share a common extracellular region composed of three immunoglobulin (Ig) like domains (D1-D3), and thus belong to the immunoglobulin superfamily⁽¹⁸⁾.

Vascular endothelial growth factor (VEGF) is one of the main inducers of endothelial cell proliferation and permeability of blood vessels.

Two RTKs bind to VEGF at the cell surface, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1)⁽¹⁹⁾.

The VEGF receptors have an extracellular portion consisting of seven Ig-like domains so, like FGFRs, belong to the immunoglobulin superfamily.

VEGFR-2 is the major mediator of endothelial cell proliferation, migration, survival, and permeability.

The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling.

The therapeutic strategy is the blockade of VEGF effects by inhibition of the tyrosine kinase cascade downstream from the VEGF receptor.

The concept of disrupted signaling appears to be effective in the pharmacological treatment of neovascularization⁽²⁰⁾.

This promising therapeutic strategy is the blockade of VEGF effects by inhibition of the tyrosine kinase cascade downstream from the VEGF receptor; such therapies currently in development include, Vatalanib, TG100801, Pazopanib, AG013958 and AL39324.

Oral administration of PTK787 (Vatalanib), a tyrosine kinase inhibitor that blocks phosphorylation of VEGF and PDGF receptors, provides inhibition of retinal neovascularization.

The development of new vessels are prevented while there is no effect on mature retinal vessels in murine⁽²¹⁾.

Vatalanib (PTK787 or PTK/ZK) is a small molecule protein kinase inhibitor that orally administrated inhibits angiogenesis.

It is being studied as a possible treatment for several types of cancer.

Vatalanib is being developed by Bayer Schering and Novartis.

It inhibits all known VEGF receptors (VEGFR1, VEGFR2, and VEGFR3) as well as platelet-derived growth factor receptor-beta and c-kit, but is most selective for VEGFR-2.

The “Safety and Efficacy of Oral PTK-787 in Patients With Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration” (ADVANCE) study evaluate the tolerability and safety of 3 months treatment with PTK-787 tablets given daily⁽²²⁾.

It is a topical tyrosine kinase inhibitor that specifically targets VEGFR, only tested in animal models.

JAK2 is a signalling kinase that acts downstream from erythropoietin, a glycoprotein hormone, which, along with VEGF, is involved in the pathogenesis of diabetic retinopathy.

The VEGF receptor and JAK2 inhibitor TG101095 dosed topically bid for two weeks significantly reduced CNV area in a laser-induced CNV mouse model⁽²³⁾.

Multi-targeted kinase inhibitors have been shown to be effective in oncology.

Newly developed small molecule kinase inhibitors (including TG100572 and the prodrug TG100801), which inhibits VEGF, PDGF, and FGF receptors in addition to Src family of kinases (sarcoma proto-oncogenic tyrosine kinases family).

They act in intracellular environment⁽²⁴⁾.

TG100801 a prodrug version of TG100572, is administered noninvasively as an eye drop and is designed to suppress VEGF mediated leakage and additionally the kinase targets associated with inflammation, edema, and angiogenesis which are the pathological hallmarks of AMD and of other back of the eye diseases including diabetic macular oedema and proliferative diabetic retinopathy⁽²⁵⁾.

It is synthesized at TargeGen (TargeGen inc San Diego).

Topical administration of TG100801 suppressed CNV in mice and reduced the retinal oedema induced by retinal vein occlusion in rats, without observable safety issues.

Data have suggested that the delivery of these agents occur by local penetration through sclera rather than by systemic absorption as neither compound was detectable in the plasma⁽²⁴⁾.

Therefore, TG100801 may offer equal efficacy to injectable agents, while offering the convenience and potential safety advantages due to a non-invasive route of delivery and eye penetration.

Currently a multicentric, open-label, randomized, phase II study is evaluating the effects of 30 days of dosing with two dose levels of TG100801, instilled twice a day, on central retinal/lesion thickness, as measured by optical coherence tomography (OCT).

The safety of TG100801 in patients with AMD will also be evaluated in this trial⁽²⁶⁾.

Pazopanib (GW786034), by GlaxoSmithKline, is a second-generation multi-targeted tyrosine kinase inhibitor against all VEGF receptors (VEGFR-1, VEGFR-2, VEGFR-3) PDGFR-a, PDGFRβ, and c-kit that blocks tumour growth & inhibits angiogenesis.

An early phase trial is evaluating the safety, and pharmacokinetics of Pazopanib eye drops in patients with neovascular AMD⁽²⁷⁾.

AGO013958 (Pfizer Inc.) is a subtenon injectable Tyrosine kinase inhibitor.

A phase I/II, randomised, masked, single and multiple dose, sequential dose-escalation study of the safety and efficacy of AG-013958 in subjects with subfoveal choroidal neovascularization associated with age-related macular degeneration has been completed⁽²⁸⁾.