Bioorganic & Medicinal Chemistry Letters
Synthesis and biological evaluation of selenogefitinib for reducing
bleomycin-induced pulmonary fibrosis
,
,
Yue Baia 1, Yunhao Zhanga 1, Peng Chua, Changyuan Wanga, Lei Lia, Yan Qia, Xu Hana,
Baojing Zhanga, Huijun Suna, Yanxia Lib, Lixue Chena *, Xiaodong Maa
,
,*
a College of Pharmacy, Dalian Medical University, Dalian 116044, PR China
b Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Selenium has demonstrated effectiveness in the reduction of oxidative stress and inflammation in vitro and in vivo,
both of which are key indicators of the pathogenesis of pulmonary fibrosis. Gefitinib, an FDA-approved EGFR
inhibitor, effectively reverses the deterioration of bleomycin-induced pulmonary fibrosis. Based on this, we
proposed introducing a selenium atom into the structure of gefitinib, resulting in the generation of selenogefi-
tinib. Compared to gefitinib, selenogefitinib was significantly less hepatotoxic and cytotoxic in cells. The results
of the H&E staining of lung tissue validated that Selenogefitinib effectively protected the structure of the alveolar
tissue and mitigated the infiltration of inflammatory cells in bleomycin-induced pulmonary fibrosis models. The
reduction in the deposition of collagen fibers in lung tissue determined by Masson staining and hydroxyproline
(HYP) content also corroborated the efficacy of selenogefitinib in the treatment of pulmonary fibrosis.
IPF
Selenium
Gefitinib
EGFR inhibitor
Oxidative stress
Anti-inflammation
Furthermore, Selenogefitinib decreased the levels of pro-inflammatory markers IL-4, IL-6, and TNF-
α more
significantly than gefitinib, which indicated that it exhibited a higher anti-inflammatory activity. In addition, the
presence of selenium manifested a greater reduction in oxidative stress based on the decrease in the levels of
MDA in mice blood. These results suggested that Selenogefitinib may be a potential candidate for the treatment
of IPF.
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung
disease resulting from a variety of pathophysiological processes,
including excessive inflammation, oxidative stress, and abnormal
epithelial-mesenchymal transition (EMT).1,2 The sequela of IPF mainly
constitute dyspnea, dry cough, and general fatigue due to impaired gas
exchange caused by scarring of the lung tissue.3,4 It was previously re-
ported that IPF was associated with a numerical expansion of fibroblasts
and myofibroblasts, leading to the excessive production and deposition
of extracellular matrix (ECM) and the formation of fibroblastic foci.5,6 If
not effectively managed, lung function will continue to be impaired after
being diagnosed as pulmonary fibrosis, with approximately 50% of pa-
tients dying within 2–5 years.7 In 2014, Nintedanib (Fig. 1) and Pirfe-
nidone were approved by the Food and Drug Administration for the
treatment of IPF, both of which were shown to slow down the pro-
gression of the disease.8,9 As an TGF-β inhibitor, pirfenidone inhibits the
progression of pulmonary fibrosis by downregulating the levels of
vascular endothelial growth factor (VEGF) and procollagen I and II.10,11
VEGF, a powerful angiogenic factor, mediates fibrogenic responses in
myofibroblasts.12 Nintedanib is a multi-target protein tyrosine kinase
inhibitor that can block the autophosphorylation of VEGFR, FGFR, and
PDGF, thereby slowing down the progression of IPF.13–15 Although these
new therapies have manifested a better prognosis, IPF remains an
incurable disease, which is partly the result of its complex and poorly
understood etiology.16–18 A first-in-class selective autotaxin inhibitor,
GLPG1690.19, demonstrated superior efficacy compared to Pirfenidone
and similar efficacy to Nintedanib in reducing the Ashcroft fibrotic score
and collagen content in a mouse bleomycin-induced pulmonary fibrosis
model in preclinical studies. It is now currently being evaluated in phase
III clinical trials (NCT 02738801).
EGFR activation has been shown to stimulate fibroblast proliferation
in animal models. Therefore, inhibition of EGFR could be advantageous
in diminishing the progression of growth factor-α-induced pulmonary
fibrosis. The EGFR inhibitor Gefitinib has been shown to significantly
slow down the progression of IPF and partially reverses the fibrotic
* Corresponding authors.
1
These authors contributed equally to this work.
Received 27 April 2021; Received in revised form 23 June 2021; Accepted 27 June 2021
Available online 1 July 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.