to moderate selectivity among VEGFR subtypes (VEGFR-1, VEGFR-2, and
VEGFR-3), with exception of cabozantinib (46, Fig. 14), a potent and selective
inhibitor of VEGFR-2 (Table 3) [7, 10, 118, 119]. Nevertheless, VEGFR subtype
selectivity is not considered an essential requirement for clinical efficacy and safety.
In fact, VEGFR-2 and VEGFR-3 dual inhibition is considered strategic to prevent
blood and lymphangiogenesis, respectively. Furthermore, known VEGFR TKIs are
usually not selective against other tyrosine kinases closely related to VEGFR-2, such
as PDGFRs, CSF1R, and c-KIT receptors (Table 3), and are commonly referred to as
multi-kinase inhibitors.
As can be noted from structures depicted in Figs. 14 and 15, different heterocyclic
scaffolds are employed in the development of new VEGFR TKI drug candidates,
including quinazolines, quinolines, pyrimidines, pyridines, indolinones, indazoles,
pyrrolo-triazines, pyridazines, and quinolinones, and these rings are usually
involved in the hydrogen bond interaction with the hinge amino acid residue.
These scaffolds are properly decorated with the introduction of substituents able to
perform complementary interactions with specific amino acid residues in the
ATP-binding site of VEGFRs, exploring the hinge region (adenine pocket), the
DFG sequence, the hydrophobic adjacent pockets, and the solvent-exposed region.
Table 3 Small-molecule VEGFR TKIs approved by FDA and their IC 50 values against VEGFR
subtypes
Drug
Company
Main targets
Inhibitory profile against
VEGFR subtypes (IC 50 in nM)
VEGFR1
VEGFR2
VEGFR3
Sorafenib
Bayer/Onyx VEGFR, c-KIT, Raf,
PDGFR-β
26
90
20
Sunitinib
Pfizer
VEGFR, c-KIT, Raf, PDGFR,
Flt3, CSR-1F
15
38
30
Pazopanib
GSK
VEGFR, c-KIT, PDGFR,
FGFR, c-Fms
10
30
47
Vandetanib
AstraZeneca VEGFR, EGFR
1,600
40
100
Nintedanib
Boehringer
Ingelheim
VEGFR, FGFR PDGFR
34
21
13
Axitinib
Pfizer
VEGFR, c-KIT, PDGFR-β
1.2
0.25
0.29
Cabozantinib Exelixis
VEGFR-2, Met, Ret, c-KIT
Flt-3, Tie2
N.D.
0.035
N.D.
Regorafenib
Bayer
VEGFR, c-KIT, RET, Raf-1
PDGFRβ
13
4.2
46
Lenvatinib
Eisai
VEGFR, RET, PDGFR,
FGFR, c-KIT
22
4
5.2
176
L. M. Lima et al.
VEGFR-3), with exception of cabozantinib (46, Fig. 14), a potent and selective
inhibitor of VEGFR-2 (Table 3) [7, 10, 118, 119]. Nevertheless, VEGFR subtype
selectivity is not considered an essential requirement for clinical efficacy and safety.
In fact, VEGFR-2 and VEGFR-3 dual inhibition is considered strategic to prevent
blood and lymphangiogenesis, respectively. Furthermore, known VEGFR TKIs are
usually not selective against other tyrosine kinases closely related to VEGFR-2, such
as PDGFRs, CSF1R, and c-KIT receptors (Table 3), and are commonly referred to as
multi-kinase inhibitors.
As can be noted from structures depicted in Figs. 14 and 15, different heterocyclic
scaffolds are employed in the development of new VEGFR TKI drug candidates,
including quinazolines, quinolines, pyrimidines, pyridines, indolinones, indazoles,
pyrrolo-triazines, pyridazines, and quinolinones, and these rings are usually
involved in the hydrogen bond interaction with the hinge amino acid residue.
These scaffolds are properly decorated with the introduction of substituents able to
perform complementary interactions with specific amino acid residues in the
ATP-binding site of VEGFRs, exploring the hinge region (adenine pocket), the
DFG sequence, the hydrophobic adjacent pockets, and the solvent-exposed region.
Table 3 Small-molecule VEGFR TKIs approved by FDA and their IC 50 values against VEGFR
subtypes
Drug
Company
Main targets
Inhibitory profile against
VEGFR subtypes (IC 50 in nM)
VEGFR1
VEGFR2
VEGFR3
Sorafenib
Bayer/Onyx VEGFR, c-KIT, Raf,
PDGFR-β
26
90
20
Sunitinib
Pfizer
VEGFR, c-KIT, Raf, PDGFR,
Flt3, CSR-1F
15
38
30
Pazopanib
GSK
VEGFR, c-KIT, PDGFR,
FGFR, c-Fms
10
30
47
Vandetanib
AstraZeneca VEGFR, EGFR
1,600
40
100
Nintedanib
Boehringer
Ingelheim
VEGFR, FGFR PDGFR
34
21
13
Axitinib
Pfizer
VEGFR, c-KIT, PDGFR-β
1.2
0.25
0.29
Cabozantinib Exelixis
VEGFR-2, Met, Ret, c-KIT
Flt-3, Tie2
N.D.
0.035
N.D.
Regorafenib
Bayer
VEGFR, c-KIT, RET, Raf-1
PDGFRβ
13
4.2
46
Lenvatinib
Eisai
VEGFR, RET, PDGFR,
FGFR, c-KIT
22
4
5.2
176
L. M. Lima et al.