Discovery of antiproliferative and anti-FAK inhibitory activity of 1,2,4-triazole derivatives containing acetamido carboxylic acid skeleton

Article abstract of DOI:10.1016/j.bmcl.2021.127965

Small molecule inhibitors of the focal adhesion kinase are regarded as promising tools in our armamentarium for treating cancer. Here, we identified four 1,2,4-triazole derivatives that inhibit FAK kinase significantly and evaluated their therapeutic pote

Full text of DOI:10.1016/j.bmcl.2021.127965

Bioorg. Med. Chem. Lett. 40 (2021) 127965
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of antiproliferative and anti-FAK inhibitory activity of 1,2,4-tri-
azole derivatives containing acetamido carboxylic acid skeleton
,
,
b
,
,
,d
Muhamad Mustafaa b, Gamal El-Din A. Abuo-Rahmaa *, Amer Ali Abd El-Hafeezc
,
Esam R. Ahmede, Dalia Abdelhamidb, Pradipta Ghoshd h, Alaa M. Hayallaha
f
,
g,
,i,j
a Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, Egypt
b Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
c Pharmacology and Experimental Oncology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
d Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
e VACSERA, Cairo, Egypt
f Department of Medicine, University of California San Diego, La Jolla, CA, USA
g Rebecca and John Moore Comprehensive Cancer Center, University of California San Diego, La Jolla, CA, USA
h Veterans Affairs Medical Center, La Jolla, CA, USA
i Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, 71526, Egypt
j Pharmaceutical Chemistry Department, Faculty of Pharmacy, Sphinx University, New Assiut, Egypt
A R T I C L E I N F O
A B S T R A C T
Keywords:
Small molecule inhibitors of the focal adhesion kinase are regarded as promising tools in our armamentarium for
treating cancer. Here, we identified four 1,2,4-triazole derivatives that inhibit FAK kinase significantly and
evaluated their therapeutic potential. Most tested compounds revealed potent antiproliferative activity in HepG2
and Hep3B liver cancer cells, in which 3c and 3d were the most potent (IC50 range; 2.88 ~ 4.83 µM). Compound
3d possessed significant FAK inhibitory activity with IC50 value of 18.10 nM better than the reference GSK-
2256098 (IC50 = 22.14 nM). The preliminary mechanism investigation by Western blot analysis showed that
both 3c and 3d repressed FAK phosphorylation comparable to GSK-2256098 in HepG2 cells. As a result of FAK
inhibition, 3c and 3d inhibited the pro-survival pathways by decreasing the phosphorylation levels of PI3K, Akt,
JNK, and STAT3 proteins. This effect led to apoptosis induction and cell cycle arrest. Taken together, these results
indicate that 3d could serve as a potent preclinical candidate for the treatment of cancers.
FAK inhibitors
Synthesis
5-Pyridinyl-1,2,4-triazoles
Anticancer activity
Docking study
Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is a
critical enzyme in the signaling pathway and is overexpressed in
different solid tumors such as liver cancer, breast cancer, colon cancer,
etc.1 FAK plays a prominent role in cell survival, migration, adhesion,
and proliferation.2 Also, FAK consists of three different domains,
including an N terminal FERM (four-point-one, ezrin, radixin, moesin)
domain, a catalytic kinase domain (central), and a C-terminal focal
adhesion targeting (FAT) domain. These domains contain tyrosine
phosphorylation sites that regulate the molecular functions and the
catalytic activity of FAK.3 Ample evidence indicates that FAK potenti-
ates cancer progression and that inhibiting the kinase is a promising
therapeutic strategy.3,4 Consequently, FAK is recognized as an important
therapeutic target for the treatment of cancer.
fundamental role in regulating numerous cellular functions such as
proliferation, survival, metabolism, and growth, while STAT3 is crucial
for cell growth and is activated mostly in solid tumors (the same as FAK).
In this respect, the inhibition of Akt and STAT3 phosphorylation leads to
remarkable anticancer activity. Interestingly, the FAK inhibition results
in suppressing the phosphorylation of both Akt and STAT3.5,7,8
Recently, numerous efforts devoted to developing potent FAK in-
hibitors to treat cancers.4,9,10 Most of the developed inhibitors targeted
the ATP binding site of FAK and were designed to bind to the essential
amino acids in the active site, such as Cys502 in the kinase hinge and
Asp564 of the DFG motif. TAE226 is one of the earliest discovered FAK
inhibitors with potent antiproliferative activity (Fig. 1).11 Despite its
superior potency, TAE226 did not enter clinical trials due to its effect on
glucose metabolism.12 Four FAK inhibitors; PND-1186, PF-562271,
CEP37440, and GSK-2256098, finished phase І clinical trials, whereas
FAK inhibition influences other essential proteins such as Akt and
Signal transducer and activator of transcription 3 (STAT3).5,6 Akt plays a
* Corresponding authors at: Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
E-mail address: gamal.aborahma@mu.edu.eg (G.E.-D.A. Abuo-Rahma).
https://doi.org/10.1016/j.bmcl.2021.127965
Received 26 December 2020; Received in revised form 9 March 2021; Accepted 11 March 2021
Available online 17 March 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

M. Mustafa et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127965
defactinib is the only compound that completed phase ІІ clinical trials
(Fig. 1).4 The main pharmacophore of FAK inhibitors comprises
diphenyl five/six-membered nitrogenous heterocyclic rings. Several
five-membered heterocyclic FAK inhibitors, such as oxadiazoles (VІІ,
VІІІ),13,14 triazoles (ІX, X),15,16 and thiadiazoles (XІ, XІІ)17,18 revealed
potent FAK inhibitory and antiproliferative activity (Fig. 2). The struc-
tural features analysis displayed that the diphenyl substitution at ring A
and ring B on the five-membered heterocyclic ring is fundamental for the
activity. Several compounds bearing diphenyl dioxine, substituted
phenyl, or pyridinyl in ring A possessed significant anti-FAK and anti-
proliferative activity, whereas ring B was separated from the heterocy-
acid with bromoacetylbromide. The target compounds 3a-d were ob-
tained through reacting 1a-d with 2 in the presence of triethylamine in
93–96% yield at 70 ◦C. The structures of the target compounds were
checked by 1HNMR, 13CNMR, mass spectroscopy, and further confirmed
by elemental analyses. The purity of compound 3d was fatherly checked
by HPLC analysis using a linear gradient of methanol: water mixture at a
rate of 1.0 mL/min leading to elution of hybrid 3d as a single peak after
4.79 min at λmax of 220 nm (Supporting information).23
The synthesized carboxylic acid derivatives 3a-d were evaluated for
their antiproliferative activity on HepG2 and Hep3B liver cancer cell
lines. These cells were selected deliberately because they profoundly
express FAK protein.24,25 Doxorubicin and GSK2256098 were used as a
positive control. As illustrated in Table 1, the derivatives 3a-d possessed
a distinctive potency on both tested cells; compounds 3c and 3d showed
potent antiproliferative activity in HepG2 cells with IC50 values of 4.72
and 3.78 µM, respectively. Besides, 3a revealed moderate anti-
proliferative activity in HepG2 cells (IC50 = 8.83 µM). Despite this
promising activity of the prepared compounds on HepG2 cells, the de-
rivative 3b did not possess notable activity and showed 20-folds lower
antiproliferative activity than Doxorubicin. On Hep3B cells, compounds
3a, 3c, and 3d showed more potent antiproliferative activity than
Doxorubicin and GSK2256098. The most active derivatives 3c and 3d
were tested for their FAK inhibitory activity, using GSK2256098 as a
positive control. Interestingly, both tested compounds revealed strong
FAK inhibitory activity in low nanomolar concentrations (Table 1). It is
worth mentioning that 3d possessed comparable FAK inhibitory activity
to the reference GSK2256098 with IC50 value of 18.10 nM.
clic ring by
a
linker containing thioacetamide, butanamide,
thioacetohydrazide, or amide.
The 1,2,4-triazole and pyridine rings are well-known moieties pre-
sent in several anticancer agents.13,19–21 The 1,2,4-triazole is an
important bioisostere to various bonds and heterocyclic ring and pos-
sesses H-bond accepting properties, strong dipole moment, and pi
electron-deficient aromaticity.22 Besides, both 1,2,4-triazole and pyri-
dine moieties display considerable stability towards chemical and
metabolic degradation.
Based on the abovementioned findings and as a probe for the
investigation of more potent FAK inhibitors, we report herein the syn-
thesis and biological investigation of 5-pyridinyl-1,2,4-triazole de-
rivatives as potential FAK inhibitors. Pyridine and benzoic acid were
investigated as ring A and ring B, respectively. The 1,2,4-triazole (five-
membered ring) was connected to ring B via thioacetamide moiety.
The synthesis of derivatives 3a-d was accomplished by treating iso-
nicotinic acid hydrazide with the appropriate isothiocyanate (methyl,
ethyl, allyl, or phenyl) at 70 ◦C (Scheme 1). The resulting thio-
semicarbazide was then reacted with 2 N NaOH and acidified with HCl
to yield the 1,2,4-triazole-3-thiol derivatives 1a-d, whereas 4-(2-bro-
moacetamido) benzoic acid 2 was obtained by reacting p-aminobenzoic
Moreover, the immunoblotting analysis was performed in HepG2
cells for compounds 3c and 3d, whereas GSK-2256098 was used as a
positive control. The obtained results revealed that both 3c and 3d
displayed a substantial ability to repress FAK phosphorylation compa-
rable to the reference GSK-2256098 at 4 µM concentration (Fig. 3A and
Fig. 1. Chemical structures of different six-membered FAK inhibitors.
2

M. Mustafa et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127965
Fig. 2. Chemical structures of various five-membered FAK inhibitors.
Scheme 1. Synthetic approach of the target 1,2,4-triazole derivatives 3a-d. a) (i) RNCS, EtOH, 70 ◦C, 4 h, (ii) 2 N NaOH, 3 h, (iii) HCl; b) K2CO3, 24 h; c) TEA, DMF,
70 ◦C, 10 h.
B). As FAK plays an important role in the activation of different pro-
survival mechanisms, including PI3K/Akt and JNK/STAT3 in the liver
cancer cells, we tested the effect of 3c and 3d on the PI3K/Akt and JNK/
STAT3 pathways using western blotting.26 We found that 3c and 3d
significantly repressed the phosphorylated PI3K, Akt, JNK, and STAT3
(Fig. 3A, C–F) in HepG2 cell line. These degrees of suppression of the
signaling pathways were positively correlated with the observed anti-
proliferative activity. We hypothesized that such suppression of the
3

M. Mustafa et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127965
Gly563 amino acids. The sulfur atom formed a hydrogen bond with
Glu506 amino acid and the 1,2,4-triazole-3-thiol moiety pointed toward
Table 1
Concentration producing 50% growth inhibition (IC50, µM ± SEM) of the car-
boxylic acid derivatives 3a-d on HepG2 and Hep3B liver cancer cells.
the gatekeeper amino acid Met499. Also, the pyridine ring formed H…
π
interaction with Ile428 amino acid. On the other hand, the 2nd mode
revealed an essential hydrogen bond between the nitrogen of the pyri-
dine moiety and Cys502 of the kinase hinge (Fig. 6B). Also, both pyri-
Cpd
R
Antiproliferative activity,
FAK inhibitory activity,
nM
µM
HepG2
Hep3B
dine and 1,2,4-triazole rings formed H…
π contacts with Leu501 and
3a
Methyl
Ethyl
Allyl
Phenyl
–
8.83 ±
0.52
3.87 ± 0.23
N.T.
Leu567 amino acids, respectively, whereas N2 of the latter ring showed
a hydrogen bond with Gly429 amino acid. The presence of the phenyl
3b
40.97 ±
2.4
17.94 ±
1.05
N.T.
group helped in the formation of several
π interactions and was in high
3c
4.72 ±
0.28
2.88 ± 0.17
36.37 ± 1.8
18.10 ± 0.92
N.T.
proximity to Asp564 of the DFG motif. Moreover, the carboxylic acid
formed a hydrogen bond with Ser568. Both obtained poses are reason-
able and showed several essential interactions. However, the 2nd pose
might be more realistic because it rationalized the role of both the ni-
trogen in the pyridine moiety and the phenyl group through the for-
mation of different electrostatic interactions.
3d
3.78 ±
0.22
4.83 ± 0.28
7.21 ± 0.42
6.91 ± 1.02
Doxorubicin
GSK2256098
1.99 ±
0.12
–
3.24 ±
0.57
22.14 ± 1.12
The prediction of Lipinski and ADME properties is one of the sig-
nificant and widely identified parameters used to predict the oral
bioavailability of active therapeutics.27,28 Compounds that obey all or
three of these parameters: molecular weight (MW) ≤ 500, number of
hydrogen bond acceptors (HBA) ≤ 10, number of hydrogen bond donors
(HBD) ≤ 5, and octanol–water partition coefficient (iLogP) ≤ 5, will
most probably have acceptable oral bioavailability. Therefore, Lipinski
violations and drug-likeness properties of the synthesized 1,2,4-triazoles
were calculated using the SwissADME online predictor. All the prepared
derivatives showed no Lipinski violations and showed acceptable to-
pological polar surface area (TPSA) and bioavailability scores (F).
Fortunately, none of the prepared derivatives was classified as Pan-
Assay Interference Compounds (PAINS). In other words, these com-
pounds are predicted to interact specifically with the ATP binding site of
FAK instead of binding to random targets, and hence, likely to have
fewer off-target effects.
PI3K/Akt and JNK/STAT3 signaling pathways might alter cell survival
and lead to apoptosis. Therefore, we examined the effect of 3d on cell
cycle progression in HepG2 cells using its IC50 concentration (3.78 µM),
we observed that compound 3d was able to arrest the cell cycle at sub G1
and S phases (41.61% and 54.11%, respectively), (Fig. 4). Meanwhile,
3d revealed a substantial ability to induce apoptosis by dissipating and
dispersing cellular integrity leading to increasing the early and late
apoptotic cells by 4.98% and 23.62%, respectively (Fig. 5).
Compound 3d was docked into the ATP binding site of FAK kinase
(PDB code: 2JKK) to elucidate its binding mode.11 The native ligand
(TAE226) was re-docked into the active site to validate the docking
study (RMDS = 1.3813). Compound 3d showed two possible binding
modes inside the ATP binding site of FAK, and both modes revealed
essential interactions inside the active site. Regarding the 1st mode, N1
of the 1,2,4-triazole made a hydrogen bond with Cys502 of the kinase
hinge (Fig. 6A). Meanwhile, the oxygen of the amide group showed two
hydrogen bonds with Asp564 of the DFG motif of the activation loop and
In conclusion, the 5-pyridinyl-1,2,4-triazole derivatives 3a-d were
synthesized and evaluated for their antiproliferative activity in two
hepatic cancer cell lines (HepG2 and Hep3B). Compounds 3c and 3d
Fig. 3. The 1,2,4-triazole derivatives 3c and 3d inhibited FAK phosphorylation and its downstream cascades. A) Western blotting analysis showed that levels of p-
FAK, p-PI3K, p-Akt, p-JNK, and p-STAT3 were downregulated in HepG2 cells treated with 3c and 3d, DMSO served as a negative control, and GAPDH served as a
loading control; B-F) The relative protein expression levels of p-FAK, p-PI3K, p-Akt, p-JNK, and p-STAT3, compared to their total form FAK, PI3K, Akt, JNK, and
STAT3, respectively, were quantified by Image J. The values are the means ± SEM of three different experiments. *, P < 0.05, ** and P < 0.01 indicate a significant
difference compared with DMSO negative control treatment.
4

M. Mustafa et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127965
Fig. 4. Compound 3d arrested the cell cycle at sub G1 and S phases in HepG2 cells. Representative cell cycle distribution data are shown by flow cytometric analysis
upon incubation with 3d or DMSO as a negative control for 24 h.
Fig. 5. Apoptotic effect of compound 3d on HepG2 cells. Representative cytograms of apoptotic HepG2 cells stimulated with 3d or DMSO as a negative control for
24 h.
emerged as potent antiproliferative agents against both cell lines tested.
The top potent derivatives 3c and 3d were assessed for their anti-FAK
activity and revealed remarkable potency at nanomolar concentra-
tions. Furthermore, the study of FAK phosphorylation inhibition in
HepG2 cells revealed that both 3c and 3d repress the phosphorylation of
FAK significantly. Preferably, compound 3d decreased the phosphory-
lation of PI3K, Akt, JNK, and STAT3. Moreover, 3d induced apoptosis
and arrested preG1 and S phases of the cell cycle. In support of this
study, molecular docking analysis revealed that 3d showed good fitting
within the ATP binding site of FAK. Also, the obtained ADME properties
were in an acceptable range. From the above data, it could be assumed
that the synthesized 5-pyridinyl-1,2,4-triazole carboxylic acid de-
rivatives (3a-d) are a set of promising compounds for the development
of potent antiproliferative agents as well as FAK inhibitors.
Declaration of Competing Interest
The authors declare that they have no known competing financial
5

M. Mustafa et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127965
Fig. 6. 3D representation of 3d B (cyan) within the ATP binding site of FAK. A) Proposed binding mode 1; B) Proposed binding mode 2 (PDB code: 2JKK).
12 Hao H-f, Takaoka M, Bao X-h, et al. Oral administration of FAK inhibitor TAE226
interests or personal relationships that could have influenced the work
inhibits the progression of peritoneal dissemination of colorectal cancer. Biochem
reported in this paper.
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13 Zhang L-R, Liu Z-J, Zhang H, et al. Synthesis, biological evaluation and molecular
docking studies of novel 2-(1, 3, 4-oxadiazol-2-ylthio)-1-phenylethanone derivatives.
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14 Altıntop MD, Sever B, Çiftçi GA, Turan-Zitouni G, Kaplancıklı ZA, Ozdemir A. Design,
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organic chemistry, Faculty of Dentistry, Deraya University) for their
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