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Current Pharmaceutical Design, 2013, 19, 687-701
687
Fibroblast Growth Factor Receptor Inhibitors
Suneel Kumar B.V.Sa,*, Lakshmi Narasub, Rambabu Gundlaa, Raveendra Dayama and Sarma J.A.R.Pa
a
GVK Biosciences Pvt. Ltd., Phase-1, Technocrats Industrial Estate, Balanagar 500037, Andhra Pradesh, India; bSchool of
Biotechnology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500072, Andhra Pradesh, India
Abstract: Fibroblast growth factor receptors (FGFRs) play an important role in embryonic development, angiogenesis, wound healing,
cell proliferation and differentiation. The fibroblast growth factor receptor (FGFR) isoforms have been under intense scrutiny for effective anticancer drug candidates. The fibroblast growth factor (FGF) and its receptor (FGFR) provide another pathway that seems critical
to monitoring angiogenesis. Recent findings suggest that FGFR mediates signaling, regulates the PKM2 activity, and plays a crucial role
in cancer metabolism. The current review also covers the recent findings on the role of FGFR1 in cancer metabolism. This paper reviews
the progress, mechanism, and binding modes of recently known kinase inhibitors such as PD173074, SU series and other inhibitors still
under clinical development. Some of the structural classes that will be highlighted in this review include Pyrido[2,3-d]pyrimidines, Indolin-2-one, Pyrrolo[2,1-f][1,2,4]triazine, Pyrido[2,3-d]pyrimidin-7(8H)-one, and 1,6- Naphthyridin-2(1H)-ones.
Keywords: FGFR receptor, Cancer metabolism, FGFR1 inhibitors, FGFR mediated signaling, cancer.
INTRODUCTION
The growth factor and its receptors play a crucial role in the
control of cell growth, differentiation, metabolism, and oncogenesis
[1]. The fibroblast growth factor receptor (FGFr) is a receptor tyrosine kinase (RTK) involved in many biological processes like Angiogenesis, embryo development, and homeostasis of adult body
tissues. The fibroblast growth factor receptor (FGFR) family consists of five highly related genes (FGFR1-4) that share 55% to 72%
identity in their amino acid sequence, whereas FGFR5 is the most
distant related member, with an approximate showing of only 30%
amino acid identity to other FGFR proteins [2-4].
FGFRs AND SIGNALING
The FGF family consists of 22 ligands that are bound to four
homologous high-affinity FGFRs (FGFR1–FGFR4) [5]. The FGFs
are secreted polypeptidic growth factors that bind to its receptors
being expressed at the cell surface of target cells [6]. They are single-pass transmembrane proteins, consisting of an extracellular
domain which binds FGF ligands, a transmembrane domain, and an
intracellular tyrosine kinase domain that transmits the signal to the
interior of the cell.
The general structure of FGFR1 (shown in (Fig. 1)) consists of
an extra cellular domain [Ig-like 1, 2, 3], a transmembrane domain,
followed by an intracellular domain. The intracellular region consists of the juxtamembrane region and the Kinase domain (split
kinase consists of 14 amino acids long, non-catalytic interkinase
domain), followed by a short C-terminal tail [7]. The FGF binding
leads to FGFR dimerization, followed by receptor auto phosphorylation and the activation of downstream signaling pathways and
subsequent trans-autophosphorylation on tyrosine residues in the
cytoplasmic domains (shown in (Fig. 2)) [8].
The seven potential tyrosine residues (Y766, Y463, Y583,
Y585, Y653, Y654, and Y730) were identified in the kinase domain
as key substrates for phosphorylation and activation of a number of
signaling molecules: Shc, PI3K, Src, PLC, Crk, SH2 domain containing phosphatase-2 (SHP-2), p38, STAT1/3, and FGFR substrate
2 (FRS2). These are involved in various cell signalling pathways
such as the Ras/MEK/MAPK Pathway, PLC and PI3K pathways
*Address correspondence to this author at the GVK Biosciences Pvt. Ltd.,
Phase-1, Technocrats Industrial Estate, Balanagar 500037, Andhra Pradesh,
India; Tel/Fax: +91 8886206206; E-mail: [email protected]
1873-4286/13 $58.00+.00
Fig. (1). The schematic structure of a fibroblast growth factor receptor. Ig I,
Ig II, and Ig III are the extracellular immunoglobin-like domains connected
with disulfide bridges. The intracellular tyrosine kinase domain has two
parts: a catalytical site and an ATP binding site. AB: acid box, TM: transmembrane5.
which promote cell growth, epithelial-mesenchyme transition, and
survival [9-11]. Phosphorylated tyrosine Y766 plays a crucial role
in the binding of phospholipase C- and activates the calciumdependent proteins [12-13]. Disruption of normal FGFR functions
has led to pathological conditions such as diabetic retinopathy,
rheumatoid arthritis, atherosclerosis and tumor neo vascularization,
breast cancer, human pancreatic cancer, astrocytomas, and Kaposi’s
sarcoma [14-24].
FGFR AND MUTATIONS
The FGFRs may be deregulated by amplification, mutation, or
translocation (Table 1). Amplification of the 8p11-12 is reported in
10% - 15% of breast cancers, particularly estrogen receptor (ER)
positive cancers [25, 26]. FGFR1 amplification was established as
an independent prognostic factor for the survival of patients with
oestrogen-receptor-positive tumours (Elsheikh et al., 2007). FGFR1
© 2013 Bentham Science Publishers
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Current Pharmaceutical Design, 2013, Vol. 19, No. 4
Table 1.
Kumar et al.
FGFR Aberrations Identified in Human Cancer
Cancer
Receptor
Abberation
Association with Other Syndromes
Molecular Consequence
Breast
FGFR1
8p11-12 amp
Not known
Amplification of FGFR1
Bladder
FGFR3
R248C
TDI
Enhanced kinase activity
FGFR3
S249C
TDI
Enhanced kinase activity
FGFR3
G370/372C
TDI
Enhanced kinase activity
FGFR3
S371/373C
TDI
Enhanced kinase activity
FGFR3
Y373/375C
TDI
Enhanced kinase activity
FGFR3
G380/382R
ACH
Enhanced kinase activity
FGFR3
A391/393E
CS
Enhanced kinase activity
FGFR3
K650/652E/Q/M/T
TDI, TDII, HCH, SADDAN, AN
Enhanced kinase activity
FGFR3
S249C
TDI
Enhanced kinase activity
FGFR3
A391E
CS
Enhanced kinase activity
FGFR2
S252W
AS
Alter ligand specificity
FGFR2
P253R
AS
Alter ligand specificity
FGFR2
N549K
Not known
Enhanced kinase activity
FGFR2
K659N
CR
Enhanced kinase activity
FGFR1
8p12 amp
Not known
Amplification of FGFR1
FGFR2
W290C
PS
Not known
FGFR4
N535K
Not known
Enhanced kinase activity
FGFR4
V550E
Not known
Enhanced kinase activity
FGFR3
t(4:14) trans
Not known
Overexpression of FGFR3
FGFR3
R248C
TDI
Enhanced kinase activity
FGFR3
K650/652M
TDI, SADDAN
Enhanced kinase activity
FGFR1
N546K
Not known
Enhanced kinase activity
FGFR2
K656E
Not known
Enhanced kinase activity
Prostate
Endometrial
Lung
RMS
MM
Brain
amplification is also defined in oral [26, 27], ovarian [28], non–
small cell lung (NSCLC) [29, 30], prostate [31], and bladder [32,
33] cancers, astrocytoma [34], and rhabdomyosarcoma [34].
FGFR2 is amplified in 10% of gastric cancers where it is associated
with a poor diagnosis [35], and is also reported in some triplenegative breast cancers. SNPs (single nucleotide polymorphisms) of
FGFR2 are linked to a greater risk of breast cancer [36]. FGFR3
amplifications have not been extensively explored and are rarely
discussed in cancer studies [37]. Oncogenic rearrangements of
FGFR3 [t(4:14)] have been described in 15% of multiple myelomas
(MM) where they are associated with a poor prognosis [38]. A
single mutation (P252R) in the IgII-III linker region of the FGFR1
leads to the Pfeiffer syndrome. FGFR3 mutations were observed in
60%–70% of non–muscle invasive tumours and 16%–20% of
muscle-invasive tumours . They are also reported in cervical and
prostate cancers. [39, 40]. Most of these FGFR3 mutations are
located in the extracellular domain of the ligand-binding region,
leading to a constitutively activated receptor [41]. FGFR2 is
mutated in ~12% of endometrial cancers, and mutated endometrial
cells are highly sensitive to FGFR inhibitors [42]. FGFR4
mutations are also referred to in 7%-8% of rhabdomyosarcomas and
are associated with a more aggressive phenotype [43].
RECENT FINDINGS OF FGFR1 ROLE IN CANCER METABOLISM
Metabolism refers to all chemical and life-sustaining reactions
taking place in the cells of living organisms and these processes
permit organisms to develop, reproduce, and maintain their structures. These metabolic pathways are classified into two categories.
A catabolic pathway breaks down organic matter and is transformed
into another chemical by a sequence of enzymes (glycolysis), while
anabolism uses that energy to build components of living cells
(macromolecules). Enzymes act as catalysts and allow these chemical reactions to proceed rapidly and efficiently as well as regulating
the metabolic pathways in response to changes in the cell's environment or through cell signaling. Cancer cells show increased
aerobic glycolysis and improved lactate production compared to
normal healthy cells, an occurrence known as “Warburg effect” or
“aerobic glycolysis”. Moreover, tumor tissues gather glucose in
Fibroblast Growth Factor Receptor Inhibitors
Current Pharmaceutical Design, 2013, Vol. 19, No. 4
689
Fig. (2). Intracellular signaling pathways mediated by FGFR1. The positions of the potential phosphotyrosine sites in human FGFR1 are indicated.
excess levels compared to the healthy tissue, as a large amount of
glucose is required for its anabolic reactions [44-46].
The pyruvate kinase isoenzyme M2 (PKM2 or M2-PK) is a key
regulator of the Warburg effect and plays a key role in tumor cells.
It also determines the glucose conversion rate and arranges the
active tetrameric form during this process. It forms an inactive dimeric shape while developing new building blocks. Pyruvate kinase
type M2 works as a switch between an active tetrameric form and
an inactive dimeric form, which is a metabolic sensor as shown in
(Fig. 3). Recent studies by Christofk et al. [47] have found that
PKM2 is crucial for aerobic glycolysis and provides a growth advantage to tumours. They also demonstrated that the pyruvate
kinase M2 isoform (PKM2) enzymatic activity is inhibited by direct
phosphorylation at tyrosine residue 105 (Y105) of PKM2, and disrupts the formation of active tetrameric PKM2 by releasing cofactor
fructose-1,6-bisphosphate [48,49]. This leads to the inhibition of
active tetrameric PKM2 formation through disturbance of the cofactor fructose-1,6-bisphosphate binding. Christofk et al. also found
that PKM2 Y105 phosphorylation is common in cancers. Further
mutation studies of the Tyr105 to Phe in PKM2 proved that it was
associated with decreased cellular lactate production and increased
oxygen consumption relative to wild-type PKM2. These findings
suggest that FGFR1 mediates growth signaling through Tyr105
phosphorylation, which decreases PKM2 activity and regulates
PKM2 to provide a metabolic advantage to tumor cells, thereby
promoting tumor growth [50,51].
FGFR INHIBITORS AND CLINICAL TRAILS
Many pharmaceutical companies are currently investigating
FGFR1 inhibitors that target cancer. Most of these reported FGFR
inhibitors are ATP-competitive and non-selective inhibitors that
also inhibit VEGFRs and/or PDGFRs (Table 2, (Fig. 4)). Ponatinib
(AP24534) is an oral multi-targeted tyrosine kinase inhibitor that is
currently being evaluated in a phase II trial of patients with chronic
myelogenous leukemia. Ponatinib (AP24534) is a multi-targeted
kinase inhibitor that shows similar potency against pan-FGFR and
Fig. (3). Glycolysis with debranching synthetic processes. HK: hexokinase,
PFK: 6-phosphofructo 1-kinase, GAPDH: glyceraldehyde 3-P dehydrogenase, LDH: lactate dehydrogenase, PPP: pentose-P-pathway, M2-PK or
PKM2: pyruvate kinase isoenzyme M2. The figure reproduced with permission from Elsevier.
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Current Pharmaceutical Design, 2013, Vol. 19, No. 4
Table 2.
Kumar et al.
Drugs Targeting FGFR in Clinical Development
Drug
Target IC50 [nM]
FGFR1
FGFR2
FGFR3
FGFR4
VEGFR1
PDGFR
Phase
BIBF1120 (vargatef)
69
37
108
-
34
60
I–III
TKI258 (dovotinib)
8
-
9
-
10
27
I–III
E7080 (lenvantinib)
46
-
-
-
22
39
I–II
TSU-68 (orantinib)
1200
-
-
-
-
8
I–II
AZD4547
0.2
2.5
1.8
164.8
-
-
I–II
BGJ398
0.9
1.4
1
60
I
O
N
N
N
N
N
NH2
N
O
N
H
N
N
NH
H
N
N
O
F
F
F
O
O
O
N
N
Dovitinib (TKI-258)
BIBF1120 (Vargatef)
Ponatinib (AP24534)
N
F
N
H
O
O
O
NH2
OH
O
O
O
O
N
HN
N
Cl
N
H
N
H
N
H
O
O
N
N
H
E7080 (Lenvatinib)
N
H
HN
AZD-4547
TSU-68 (SU6668)
O
Cl
O
Cl
OH
O
N
H
O
O
N
N
N
N
N
N
O
N
N
H
N
H
O
N
H
BGJ398 (NVP-BGJ398)
SU5402
O
O
N
N
N
H
N
N
N
H
NH
O
SU4984
NH
PD173074
Fig. (4). The list of FGFR1 inhibitors in clinical trials.
also selectively inhibits the panel of FGFR-expressed cell lines
(endometrial, bladder, gastric, breast, lung, and colon) [53]. Ponatinib potently inhibits FGFR-mediated signaling and viability in
Ba/F3 cells, which is engineered to express activated FGFR1-4 with
IC50 values <40 nmol/L. Reduced tumor growth was observed in
mice upon oral dosage of ponatinib (10–30 mg/kg) and also inhibited signaling in all three tumor models examined.
BIBF1120 (Vargatef) is another potent and multi targeted
small-molecule inhibitor that could potently block the VEGF
receptor (VEGFR), PDGFR and FGFR kinase activity with an IC50
range of 20-100 nmol/L [54]. Further encouraging phase II clinical
trial data in chemotherapy combination regimes involving patients
with NSCLC and ovarian cancers have resulted in BIBF1120 being
evaluated in phase III trials of these tumor types.
TKI258 (dovotinib) is an orally available ATP-competitive
inhibitor that is currently under evaluation in phase II and III trials
in breast, bladder, and renal cancers [55]. TKI258 demonstrated a
similar potency against FGFR, PDGFR, and VEGFR. E7080 (lenvantinib) is a triple angiokinase that has a higher affinity towards
VEGFR compared to FGFR. E7080 showed positive results from a
phase II trials in thyroid cancer which have led to the launch of a
phase III study in this tumor type [56, 57]. AZD4547 is an oral,
potent, and selective inhibitor of the FGFR 1, 2, and 3 tyrosine
kinases [58]. AZD4547 is currently in phase I/II testing in gastric
and breast cancer, and BGJ398 is also in phase I trials. TSU-68
Current Pharmaceutical Design, 2013, Vol. 19, No. 4
Fibroblast Growth Factor Receptor Inhibitors
Various halogens and small alkyl substituents were explored at
2’, 6’ and 3’, 5’ positions in the phenyl group of the core. Disubstitution at the 2’, 6’-positions of the phenyl group with halogens or
small alkyl groups generally increased the potency. In a similar
manner, disubstitution at the 3’,5’-positions with small aliphatic
groups were increased selectivity towards FGFR1.
In summary, Pyrido[2,3-d]pyrimidine derivatives are proved to
be selective FGFR1 inhibitor and SAR studies imply that 3,5disubstutients are more potent and selective than other substituents
[3,5-diOMe (9)> 2,6-diCl (11) > H (8)].Further modifications of the
active compound (2), yielded a highly potent and selective inhibitor
of FGFR1 (8), which exhibits the nanomolar potency, high selectivity towards FGFR1,and showed little effect against EGFR, InsR,
MEK, and cPKC.
(orantinib) is another orally available and triple angiokinase inhibitor that targets PDGFR, FGFR1, and VEGFR1-2, and is currently
evaluated in phase II trials [59]. In addition, PD173074, SU5402,
and SU4984 are currently being evaluated in a discovery stage. In
addition, several antibodies are being developed to target selective
FGFR family members so as to reduce the toxicity effects. These
include PRO-001 (FGFR3-specific), IMCA1 (FGFR1-IIIc–
specific), and R3Mab (FGFR3- specific), all of which are currently
being evaluated in a preclinical stage [60-62].
FGFR1 INHIBITORS AND SAR
Several series of small molecule inhibitors targeting FGFR1
kinase activity are currently being pursued as potential therapeutics
for cancer, such as 3-substituted indolin-2-ones, Pyrido[2,3-d]pyrimidine, Pyrrolo[2,1-f][1,2,4]triazine, and Pyrido[2,3-d]pyrimidin7(8H)-one etc.,
Indolin-2-one Derivatives
A series of novel Indolinone derivatives were discovered as a
result of random-screening approach towards a small molecule
library against various RTKs [67-72]. Using random screening approach, 3-substituted indolin-2-ones (9) were discovered as novel
and selective VEGFR inhibitors (Table 4).
Initial SAR studies suggest that proton at the N-1 position of
the indolin-2-ones are required for the inhibitory activity against the
PDGFR and VEGFR and electron-donating substitution groups the
C-3 position of indolin-2-ones are required to achieve the selectivity. The selectivity was achieved through substitution of the indolin-2-one core, especially at the C-3 position. Extensive SAR study
on 3-substituted indolin-2-ones resulted in significant improvement
in potency and selectivity towards FGFR1, VEGFR2, and PDGFR
and some of the analogues were reported in Table 4. A variety of
heterocycles were replaced at the C-3 position, such as thiophenes,
Pyrido[2,3-d]pyrimidines Derivatives
Pyrido[2,3-d]pyrimidine derivatives were discovered as novel
tyrosine kinase inhibitors through compound library screening by
the Parke-Davis group.[63-66] Initial screening led to the identification of a novel pyrido[2,3-d]pyrimidine derivative (1) showing
similar potency against FGFR1, PDGFR1 and c-Src. Exhaustive
SAR studies were carried out at 2’, 6’, and7’ positions of the core to
improve potency and selectivity. FGFR1 selectivity was achieved
through addition of the phenyl group to the 6th position of the
pyrido[2,3-d]pyrimidine core (Table 3). PD166866 (2) was found to
be one of the selective inhibitor of FGFR1 [IC50 0.06 M] and
showing weak inhibitory activity against PDGFR (IC50>50 M) and
c-Src (IC50 > 50 M).
Table 3.
Representatives of Pyrido[2,3-d]pyrimidines Derivatives
R2
N
R1
N
N
N
O
H
N
H
IC50 uM
Compound
R1
R2
1 (PD089828)
H
2 (PD166866)
691
Reference
PDGFR1
FGFR1
C-Src
Ph
13.24
8
19.33
30
H
3,5-(MeO)2
>50
0.06
>50
30
3
H
2,6-(CI)2
1.25
0.14
0.22
30
4
-NH(CH2) 4NMe2
2,6-(CI)2
0.68
0.075
0.12
31
5
-NH(CH2) 4NEt2
2,6-(CI)2
0.36
0.048
0.0074
31
6
-NH2
2,3,5,6-(Me)4Ph
>50
0.71
>50
31
7
-NH(CH2) 3NEt2
2,6-(CI)2
0.66
0.082
0.073
31
8 (PD173074)
-NH(CH2) 4NEt2
3,5-(MeO)2
17.6
0.0215
>50
27
692
Current Pharmaceutical Design, 2013, Vol. 19, No. 4
Table 4.
Kumar et al.
Representatives of Indolin-2-one Derivatives
H
O
O
H O
O
R
N
H
O
5
6
N
H
R
N
H
O
5
6
N
H
R
N
H
O
5
6
N
H
6
1b
1a
R
N
H
O
5
N
H
1d
1c
IC50 uM
Compound
Scaffold
R
9
1b
10
Reference
VEGFR2
FGFR1
PDGFR
H
0.02
0.03
0.51
33
1b
4-CH3
0.2
0.03
2.11
33
11
1b
5-Br
0.35
0.08
0.62
33
12 (SU6668)
1c
H
2.14
3.68
0.14
33
13
1c
6-(3-OCH3phenyl)
0.09
0.36
0.17
33
14
1c
6-OCH3
1.35
3.89
0.14
33
15 (SU5416)
1a
H
43
10000
2220
38
16
1d
5-Br
0.07
13.3
0.92
35
17
1d
5-COOH
0.02
0.31
1.03
35
18
1d
6-(4-OCH3phenyl)
>20
>20
94.01
35
pyrazoles, pyrroles and furan and predominantly, the Z-isomeric
form of this series was the most active.
Most of indolin-2-one derivative were proved to be most potent
and triple angiokinase inhibitor, for example, SU5402, andSU4984are shown to be specific inhibitors of FGFR, VEGFR and
currently being evaluated in discovery stage. SU5416 (15) is shown
to be as selective inhibitor of VEGFR, and whereas SU6668 (12)
showed similar inhibitory activity against FGFR, VEGFR, and
PDGFR.
Pyrrolo[2,1-f][1,2,4]triazine Derivatives
A series of pyrrolo[2,1-f][1,2,4]-triazine derivatives were developed as dual kinase (VEGFR and FGFR1) inhibitor by BristolMyers Squibb.[73-74]Compound 20was identified from mass
screening and showed modest inhibition against VEGFR2 (IC50130
M) (Table 5).
Further modifications on the active compound (20) lead to the
identification of compound 22, which is more potent in the kinase
assay and also displayed excellent cellular potency (IC5013 nM)
was selected as the preferred C4-substituent for subsequent SAR
studies. Additional SAR studies were carried out at the 6’-position
of the pyrrolo[2,1-f][1,2,4]triazine nucleus of compound 22. Five
membered hetero aromatic rings were used as C6-ester replacements. Oxazole(23) and 1,3,4-oxadiazole replacements(26)showed
good inhibitory activity against dual kinases (VEGFR2 and FGFR1
(IC50 20 nM)) and HUVEC proliferation employed (IC50< 10 nM).
Further modifications were carried out on substituted C6oxadiazole analogue (compound 26) and difluoro sulfone oxadiazole analogue (28) showed comparable VEGFR2 and FGFR1
kinase activity with IC50 values of 53 and 220 nM, respectively. In
summary, pyrrolo[2,1-f][1,2,4]-triazine derivatives are another dual
kinase series (VEGFR and FGFR1). Extensive SAR studies carried
out at 4’ and 6’ position of the pyrrolo[2,1-f][1,2,4]triazine nucleus,
led to active against dual kinases.
Pyrido[2,3-d]pyrimidin-7(8H)-one
Pyrido[2,3-d]pyrimidin-7(8H)-ones are also dual kinase inhibitors series developed by the Parke-Davis group [75-77]. Compound
(29) was identified from mass screening with a similar profile towards the PDGFR,FGFR1and c-Src TKs. Further SAR modifications were carried out at the C-2 and N-8 positions of pyrido[2,3d]pyrimidin-7(8H)-one (Table 6).
The neutral substituents at the C2 position showed very poor
potency against the TKs, 2-hydroxy, methyl and 2-dimethylamino
are inactive. These analogues revealed the importance of secondary
amine at this position which is required for binding. Further modifications were carried out at a 2-NHR substitution pattern. A wide
range of C-2 substituent modifications, starting with small neutral
moieties, aliphatic and aryl cationic moieties, aliphatic anionic
moieties and aromatic neutral moieties (anilines) were investigated
and some of these analogues are listed in Table 6.
These modifications lead to identification of the most potent
aniline derivative (33), which showed nanomolar potency towards
Current Pharmaceutical Design, 2013, Vol. 19, No. 4
Fibroblast Growth Factor Receptor Inhibitors
Table 5.
Representatives of Pyrrolo[2,1-f][1,2,4]triazine Derivatives
R1
R2
N
X
O
N
Ar
N
H
O
R3
N
Compound
X
R1
R2
R3
Ar
19
O
H
H
Me
20
NH
H
H
21
NH
F
22
NH
F
IC50 nM
Reference
VEGFR2
FGFR1
-CO2Et
270
-
39
Me
-CO2Et
130
-
39
H
Me
-CO2Et
34
-
39
F
Me
-CO2Et
13
-
40
8
20
40
49
110
40
110
140
40
18
19
40
17
28
40
53
220
40
N
23
NH
F
F
Me
O
24
NH
25
NH
F
F
F
N
Me
F
N
O
Me
O
N
N
26
NH
F
F
N N
Me
O
N
27
NH
F
F
Me
N
O
N N
28
NH
F
F
Me
O
F
O
S F
O
Table 6.
Representatives of Pyrido[2,3-d]pyrimidin-7(8H)-one Derivatives
Cl
N
R1
N
Compound
R1
R2
29
NH2
30
N
R2
O
Cl
IC50 nM
Reference
PDGFR
FGFR1
c-Src
EGFr
Me
4.9
1.3
0.26
5.6
41
Me
Me
>50
>50
>50
N.T*
41
31
OH
Me
>50
>50
>50
N.T*
41
32
NH(CH2)5 CO2H
Me
0.73
0.58
0.37
1
41
Me
0.40
0.46
0.02
0.26
41
33
H
N
693
694
Current Pharmaceutical Design, 2013, Vol. 19, No. 4
Kumar et al.
(Table 6) Contd….
R1
Compound
H
N
34
O
35
H
36
O
O
H
37
O
IC50 nM
R2
H
N
H
N
H
N
Reference
PDGFR
FGFR1
c-Src
EGFr
Et
0.80
0.21
0.053
0.20
41
Me
0.53
0.37
0.05
0.03
41
Me
0.13
0.11
0.009
0.19
41
Me
0.072
0.061
0.010
0.22
41
Me
0.12
0.11
0.032
0.08
41
O
O
38
H
N
O
H
•
N.T denotes not tested
Table 7a. Representatives of 7-Substituted Naphthyridin-2(1H)-one Derivatives
Cl
N
R
Compound
R
39
N
O
Cl
IC50 uM
Reference
c-Src
PDGFR
FGFR1
NH2
0.35
3.6
0.38
43
40
NHMe
0.42
8.0
0.21
43
41
NMe2
>50
>50
>50
43
42
NH(CH2)2 NEt2
13
>50
33
43
43
NH(CH2)3 (1-imidazole)
0.54
3.2
0.21
43
44
NHPh(4-Me-piparazine)
0.023
0.26
0.042
43
45
NH(CH2)5 NET2
0.024
0.74
0.08
43
all four kinases PDGFR (IC50 0.40 nM), FGFR1 (IC50 0.46 nM),
and c-Src (IC50 0.02 nM) TKs. They also showed good potency
(IC50 0.26 nM) toward the EGFr TK.A series of substituents around
the anilino ring of compound (35) were explored to improve activity and selectivity. Carboxylic acid moiety analogues (36-38)
showed excellent potency towards all three kinases and especially
the 4-substitutedacetic acid analogue (37).
1,6 and 1,8-Naphthyridin-2(1H)-one
7-Substituted 1,6- and 1,8-Naphthyridin-2(1H)-ones [78], is
another dual kinase inhibitor series from Parke-Davis. The 1,6naphthyridin-2(1H)-ones showed broadly similar activity to the
analogous pyrido[2,3-d]-pyrimidin-7(8H)-ones, whereas the 1,8naphthyridin-2(1H)-ones were at least 103-fold less potent. Further
Current Pharmaceutical Design, 2013, Vol. 19, No. 4
Fibroblast Growth Factor Receptor Inhibitors
695
Table 7b. Representatives of 1’,6’-Naphthyridine Derivatives
Cl
O
N
N
N
R1
N
R2
O
N
R1
A
R2
Cl
R1
Scaffold
R1
R2
43
A
NH(CH2)3morph
44
A
45
R2
C
B
Compound
N
IC50 uM
Reference
FGFR1
VEGFR
PDGFR
NHCONHtBu
0.031
0.009
45
43
NH(CH2)34-Mepip
NHCONHEt
0.021
0.051
30
43
A
NH(CH2)-4morph
NHCONHtBu
0.007
0.006
15
43
46
B
NH(CH2)34-Mepip
NH2
4.6
2.9
8.8
43
47
B
NH(CH2)34-Mepip
NHCONHtBu
0.14
0.054
1.2
43
48
B
NH(CH2)34-Mepip
NH(CH2)34-Mep
23
8.7
>50
43
49
C
NH(CH2)34-Mepip
NH2
0.22
1.8
4.7
43
50
C
NH(CH2)34-Mepip
NHCONHEt
0.016
0.11
0.54
43
51
C
NH(CH2)34-Mepip
NHCONHtBu
0.026
0.007
0.014
43
modifications were carried out on 1,6-naphthyridin-2(1H)-ones and
some of these analogues were reported in Table 7a & 7b.
The parent 7-NH2 (39) and 7-NHMe compounds (40) showed
moderate inhibitory potency (IC50 300-400 nM) against c-Src and
FGFR1. 2-dimethylamino analogue (41) was inactive against all
kinases (IC50 50 nM), which indicates the importance of the donor.
Further modifications were carried out as 2-NHR substitution pattern. A number of NH-aryl analogues were used to improve potency
and selectivity. The shortest chain NH(CH2)2NEt2 analogue (42) is
less effective inhibitor against all three enzymes than the NHMe
derivative, although activity improves steadily as the chain is
lengthened. Overall, the longer chain cationic derivatives proved to
be the most potent c-Src and FGFR inhibitors, with good selectivity
(43-45).
1’,6’-Naphthyridines is another similar series reported by
Parke-Davis. Extensive SAR studies were carried out on 2’ and 3’
as well as 7’-position of the 1,6- Naphthyridine core. SAR studies
of 1,6-naphthyridines, demonstrated that the nature of the substituents on the 3-phenyl ring is critically important for determining the
pattern of kinase activity while potency depends on substituents
present on the phenyl ring (3,5-diOMe > 2,6-diCl >> H in potency)
and on the nature of the 2-substituent (tBu urea > Et urea > NH2in
selectivity).
FGFR1 and Crystal Structures
So far, 15 FGFR1 structures (including X-ray & NMR), reported in PDB, are described in Table 8. A total of 5 crystal structures of FGFR tyrosine kinase domain in complex with chemical
inhibitors have been reported and were shown in (Figs 4-8). Here,
we will start with a brief description of the ATP pocket of FGFR1
(PDB ID: 3GQI), which appears to be the binding site for all the
inhibitors complexes with FGFR1 crystal structures, as reported up
to now, followed by a description of the remaining FGFR1 crystal
structures and their limitations in structure-based drug designing
approaches.
Most of these small molecule kinase inhibitors have been developed so far by targeting the ATP binding site, and by mimicking
the active conformation of kinase that was used to bind with ATP.
The crystal structure of ATP bound to the FGFR1 kinase domain
(PDB ID: 3GQI [79]) revealed important interactions as well as
active conformation of kinase (as shown in (Fig. 5a)). The binding
site of the co-factor ATP is a cleft located at the interface of the two
domains and does not require the DFG motif in the activation loop
to adopt a ‘DFG-out’ conformation for binding. This cleft can be
divided into three regions, defined by reference to the chemical
moieties in ATP. The hydrophobic character comprises amino acids
Ile 545, Val561, Ala640, Val492, Val559, Leu630, and Leu484,
and forms the environment for the adenine moiety of ATP as shown
in (Fig. 5b). More precisely, the adenine ring is “sandwiched” between Ala512 and Leu630 with which it makes close hydrophobic
contacts. N6 and N1 atoms of the adenine ring form hydrogen bond
interactions with hinge region amino acids, with the backbone carbonyl of Glu562 and the backbone NH of Ala 564, respectively.
These residues belong to the amino acid stretch that connects the
two domains of the kinase. These are called a hinge segment. The
second region corresponds to the three amino acids that interact
with the ribose moiety of ATP. Val 18 of the glycine-rich loop is in
Van Der Waals contact with the ring, while Asp 568 makes hydrogen bonds with its hydroxyl substituents. Finally, polar amino acids
that fix the conformation of the triphosphate chain of ATP, either
by direct interaction (Lys 514) or by mediation of a magnesium
cation (Asp 641), constitute the third region.
The crystal structure FGFR1 kinase domain (PDB ID: 2FGI), in
complex with 8, revealed that the pyrido[2,3-d]pyrimidine ring
occupies the adenosine binding region and the hydrophobic cavity
includes Leu484, Ala512, Tyr563, Ala564, and Leu630.[66]
PD173074 forms two important H-bond interactions with the hinge
region aminoacids. The first hydrogen bond interaction was observed between N-3 of the pyrimidine ring and the amide nitrogen
of Ala564, and the second H-bond interaction was observed between nitrogen of the butylamino group and carbonyl oxygen of
696
Current Pharmaceutical Design, 2013, Vol. 19, No. 4
Table 8.
Kumar et al.
List of Crystal Structures Reported for FGFR1
Entry
Method
Resolution (Å)
Domain
Ligand
Breaks
1FGK
X-ray
2.0
Tyrosine kinase domain
Apo
464-763
3KY2
X-ray
2.7
Tyrosine kinase domain
Apo
no breaks
1AGW
X-ray
2.4
Tyrosine kinase domain
SU4984
463-763
1FGI
X-ray
2.5
Tyrosine kinase domain
SU5402
464-762
2FGI
X-ray
2.5
Tyrosine kinase domain
PD173074
486-490, 580593, 646, 658
3C4F
X-ray
2.07
Tyrosine kinase domain
3-(3-methoxybenzyl)-1H-pyrrolo[2,3b]pyridine
580-591
3GQI
X-ray
2.5
SH2 Domain
3-(3-methoxybenzyl)-7-azaindole
no breaks
3GQL
X-ray
2.8
Tyrosine kinase domain
AMP
580-592, 645658
3KXX
X-ray
3.2
Tyrosine kinase domain
Apo
no breaks
3JS2
X-ray
2.2
Tyrosine kinase domain
5-(2-thienyl)nicotinic acid
582-588
1XR0
NMR
-
Phosphotyrosine binding domain (ptb)
-
8-136
2CR3
NMR
-
Ig-like domain
-
1-99
1CVS
X-ray
2.8
Extracellular domain
-
16-144
1FQ9
X-ray
3
Extracellular domain
-
16-144
1EVT
X-ray
2.8
Extracellular domain
-
8-138
Lys514
HO
Phe489
Mg2+
OH
Asp641
P
O
O P
HO O
O
P
O
Ala640
O
HO
O
Asp568
Leu630
HO
N
N
N
Va492
N
NH2
Ala564
Glu562
5(A)
5(B)
Fig. (5). (A). The interaction diagram of AMP is shown beneath its co-structure with FGFR1 kinase. (B). The chemical structure of AMP is shown beneath its
co-crystal with FGFR1 (PDB: 3GQI)
Current Pharmaceutical Design, 2013, Vol. 19, No. 4
Fibroblast Growth Factor Receptor Inhibitors
697
O
N
N
N
H
O
N
N
NH
O
NH
PD173074
(A)
(B)
Fig. (6). (A). 2D Structure of co-ocrystal (PD173074) complexed with FGFR1 [PDB: 2FGI]. (B) The crystal conformation of PD173074 (Compound 3) is
shown beneath its co-crystal with FGFR1 (PDB: 2FGI).
OH
O
CH3
N
H
O
N
H
SU5402
(A)
(B)
N
N
O
O
N
H
SU4984
(C)
(D)
Fig. (7). (A) 2D Structure of co-crystal (SU5402) complexed with FGFR1 [PDB: 1FGI]. (B) The crystal conformation of [SU5402 (Compound 1)] is shown
beneath its co-crystal with FGFR1 (PDB: 1FGI). (C) 2D Structure of co-crystal (SU4984) complexed with FGFR1 [PDB: 1AGW]. (D) The crystal conformation of SU4984 is shown beneath its co-crystal with FGFR1 (PDB: 1AGW)
698
Current Pharmaceutical Design, 2013, Vol. 19, No. 4
Kumar et al.
O
O
N
H
(A)
(B)
Fig. (8). (A). 2D Structure of co-crystal (3-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine) complexed with FGFR1 [PDB: 3C4F]. (B). The crystal conformation of 3-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine is shown beneath its co-crystal with FGFR1 (PDB: 3C4F)
S
O
OH
N
(A)
(B)
Fig. (9). (A). 2D Structure of Cocrystal (5-(2-thienyl)nicotinic acid) complexed with FGFR1 [PDB: 3JS2]. (B). The crystal conformation of 5-(2thienyl)nicotinic acid is shown beneath its co-crystal with FGFR1 (PDB: 3JS2).
Ala564 (shown in (Fig. 6)). A third hydrogen bond was observed
between one of the dimethoxy groups of compound and the amide
nitrogen of Asp64. This crystal structure (2FGI) suffers with breaks
[five residues missing (from Glu486 to Gly490)] in active site region important for the ligand binding. But this crystal structure
(2FGI) resulted in higher enrichment factors for the screening of
known FGFR1 inhibitors compared to 1FGI and 1AGW. Obdulia
Rabal’s study also addresses similar issues and points to the importance of loop refinement for this crystal structure [78,79].
The two crystal structures of FGFR-inhibitor complex (PDB
ID: 1FGI and 1AGW) with SU5402 and SU4984 have been solved
by Humbert and associates [80,81]. These complexes (shown in
(Figs. 7a and 7b)) revealed that the oxindole ring of these two inhibitors occupies the same adenosine binding region and makes the
same hydrophobic region contacts which include Leu484, Ala512,
Tyr563, Ala564, and Leu630. The oxindole makes two hydrogen
bonds with hinge region amino acids, the first interaction was observed between N-1 of the oxindole and the carbonyl oxygen of
Glu562, and another interaction was between O-2 of the oxindole
and the amide nitrogen of Ala564 (shown in (Figs 7C and 7D)).
The C-3 phenyl ring of SU4984 makes an oxygen-aromatic contact
with the carbonyl oxygen of Ala564 while the piperazine ring outside of the cleft forms van der wall contact with a highly conserved
residue (Gly567). The remarkable feature observed in these two
complexes is the dramatic conformational change in the glycine
rich loop conformation. The difference in the position of Phe489 on
this loop folds 10 Å towards the inhibitor structures and caps the
active site. Because of induced fit conformation upon small ligand
binding, which would prevent larger compounds from accommodating the binding site of this structure, these two crystal structures
(PDB: 1FGI and 1AGW) failed to recognize the 6-membered ring
heterocyclics. Diller and Li [82] also reported similar issues with
1AGW due to a strong induced-fit generated by the small inhibitor,
SU4948.
Another FGFR tyrosine kinase domain (PDB ID: 3C4F, resolution 2.07 Å), first determined by Joseph Schlessinger and associates
[83-84]. in complex with [3-(3-methoxybenzyl)-7-azaindole], is
shown in (Fig. 8). 3-(3-methoxybenzyl)-7-azaindole is one of the BRaf kinase inhibitors, showing moderate inhibitory activity against
FGFR1 (IC501.9nM).
Current Pharmaceutical Design, 2013, Vol. 19, No. 4
Fibroblast Growth Factor Receptor Inhibitors
Recently, a crystal structure of FGFR1 kinase in complex with
5-thiophen-2-yl derivative of nicotinic acid was determined at a
resolution of 2.2 Å (PDB ID: 3JS2) [84]. Two conformations of this
complex were determined, the one with the nucleotide binding loop
down and the other with the loop extended, as shown in (Fig. 9). As
shown in that figure, this small inhibitor occupies the ATP binding
site and forms a hydrogen bond with the nitrogen of Ala564. These
two crystal structures also suffer from induced fit conformation
upon small ligand binding, and failed to recognize the 6-membered
ring heterocyclics.
CONCLUSION
The current review illustrates the numerous different structural
classes of FGFR1 selective and dual kinase inhibitors that have
been generated over the past several years. Also covers the brief
review on reported crystal structures of FGFR1 kinase and the limitations of these structures in structure based drug design.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflicts of
interest.
[18]
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ACKNOWLEDGEMENTS
Declared none.
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Received: July 12, 2012
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