allosteric EGFRi have recently been described and are currently being considered as
the new promises for a short future in the fight against NSCLC [94–96]. Since the
approval of the first EGFR inhibitor, gefitinib (1; ZD1819; Iressa™; AstraZeneca),
in 2003, time has shown that the therapeutic challenges for EGFR inhibition keep
changing and pushing the drug discovery process into a new direction.
3 Vascular Endothelial Growth Factor Receptors
(VEGFRs)
Vascular endothelial growth factor receptors (VEGFRs) are RTKs implicated in
vascular development, angiogenesis, and lymphangiogenesis, which are activated by
their natural ligands, i.e., the vascular endothelial growth factors (VEGFs). VEGFRs
are classified as VEGFR-1, VEGFR-2, and VEGFR-3, differing from each other in
their cellular roles, distribution, and ligand-specific recognition [6].
VEGFR-1, also known as FMS-like tyrosine kinase 1 (Flt-1), is expressed in the
cell surface of blood endothelial cells, as well as in monocytes and hematopoietic
and smooth muscle cells. VEGFR-1 activation mediates hematopoietic precursors’
recruitment and monocytes’ and macrophages’ migration, playing an important role
in early inflammation. For this reason, VEGFR-1 signaling is considered as crucial
for rheumatoid arthritis progression [6, 97].
Subtype VEGFR-2, also known as kinase insert domain receptor (KDR) or fetal
liver kinase (Flk-1), is expressed in vascular endothelial cells, megakaryocytes, and
neuronal and hematopoietic stem cells. VEGFR-2 is a key regulator of
vasculogenesis during embryonic development and of angiogenic processes during
adult life, participating in wound healing, diabetic retinopathy, rheumatoid arthritis,
psoriasis, inflammatory disorders, tumor growth, and metastasis [6, 97].
Fig. 12 ErbB covalent inhibitor afatinib (5) and the corresponding analogue (41) without the
crotonamide double bond. The covalent binding moiety is highlighted in purple and the solubilizing
basic substituent in green
Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
171
the new promises for a short future in the fight against NSCLC [94–96]. Since the
approval of the first EGFR inhibitor, gefitinib (1; ZD1819; Iressa™; AstraZeneca),
in 2003, time has shown that the therapeutic challenges for EGFR inhibition keep
changing and pushing the drug discovery process into a new direction.
3 Vascular Endothelial Growth Factor Receptors
(VEGFRs)
Vascular endothelial growth factor receptors (VEGFRs) are RTKs implicated in
vascular development, angiogenesis, and lymphangiogenesis, which are activated by
their natural ligands, i.e., the vascular endothelial growth factors (VEGFs). VEGFRs
are classified as VEGFR-1, VEGFR-2, and VEGFR-3, differing from each other in
their cellular roles, distribution, and ligand-specific recognition [6].
VEGFR-1, also known as FMS-like tyrosine kinase 1 (Flt-1), is expressed in the
cell surface of blood endothelial cells, as well as in monocytes and hematopoietic
and smooth muscle cells. VEGFR-1 activation mediates hematopoietic precursors’
recruitment and monocytes’ and macrophages’ migration, playing an important role
in early inflammation. For this reason, VEGFR-1 signaling is considered as crucial
for rheumatoid arthritis progression [6, 97].
Subtype VEGFR-2, also known as kinase insert domain receptor (KDR) or fetal
liver kinase (Flk-1), is expressed in vascular endothelial cells, megakaryocytes, and
neuronal and hematopoietic stem cells. VEGFR-2 is a key regulator of
vasculogenesis during embryonic development and of angiogenic processes during
adult life, participating in wound healing, diabetic retinopathy, rheumatoid arthritis,
psoriasis, inflammatory disorders, tumor growth, and metastasis [6, 97].
Fig. 12 ErbB covalent inhibitor afatinib (5) and the corresponding analogue (41) without the
crotonamide double bond. The covalent binding moiety is highlighted in purple and the solubilizing
basic substituent in green
Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
171