217
AMD Future Perspectives: New promising drugs
cellular activities including growth, differentiation, metabo-
lism, 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 intra-
cellular 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 endo-
thelial 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.
5.2 Fibroblast growth factor receptor (FGFR) family
– Class IV
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 prop-
erties and kinase domains, however all share a common
extracellular region composed of three immunoglobu-
lin (Ig) like domains (D1-D3), and thus belong to the
immunoglobulin superfamily
(18)
.
5.3 Vascular endothelial growth factor receptor
(VEGFR) family – Class V
Vascular endothelial growth factor (VEGF) is one of the
main inducers of endothelial cell proliferation and perme-
ability 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 sig-
naling appears to be effective in the pharmacological
treatment of neovascularization
(20)
.
5.4 Intracellular inhibition of the tyrosine kinase
cascade:
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.
5.5 Vatalanib - Wet AMD
Oral
Oral administration of PTK787 (Vatalanib), a tyrosine
kinase inhibitor that blocks phosphorylation of VEGF
and PDGF receptors, provides inhibition of retinal neo-
vascularization. The development of new vessels are pre-
vented 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 adminis-
trated inhibits angiogenesis. It is being studied as a pos-
sible treatment for several types of cancer.
Vatalanib is being developed by Bayer Schering and
Novartis. It inhibits all knownVEGF 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)
.
