Synthesis and biological evaluation of novel benzo[c][1,2,5]thiadiazol-5-yl and thieno[3,2-c]- pyridin-2-yl imidazole derivatives as ALK5 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2019.07.015

Transforming growth factor (TGF-β), a key mediator of tumor growth and metastasis, has been recognized as an important cancer drug target. A series of benzo[c][1,2,5]thiadiazol-5-yl imidazoles (14a–g) and thieno[3,2-c]-pyridin-2-yl imidazoles (20a–g) were

Full text of DOI:10.1016/j.bmcl.2019.07.015

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Accepted Manuscript
Synthesis and biological evaluation of novel benzo[c][1,2,5]thiadiazol-5-yl and
thieno[3,2-c]- pyridin-2-yl imidazole derivatives as ALK5 inhibitors
Zhen Guo, Xiaowei Song, Li-Min Zhao, Ming Guan Piao, Jishan Quan, Hu-Ri
Piao, Cheng Hua Jin
PII:
S0960-894X(19)30460-3
https://doi.org/10.1016/j.bmcl.2019.07.015
BMCL 26556
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 March 2019
3 July 2019
8 July 2019
Please cite this article as: Guo, Z., Song, X., Zhao, L-M., Piao, M.G., Quan, J., Piao, H-R., Jin, C.H., Synthesis and
biological evaluation of novel benzo[c][1,2,5]thiadiazol-5-yl and thieno[3,2-c]- pyridin-2-yl imidazole derivatives
as ALK5 inhibitors, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.
2019.07.015
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Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Synthesis and biological evaluation of novel
benzo[c][1,2,5]thiadiazol-5-yl and thieno[3,2-c]-
pyridin-2-yl imidazole derivatives as ALK5 inhibitors
Zhen Guoa,1, Xiaowei Songd,1, Li-Min Zhaoa, Ming Guan Piaoa, Jishan Quana,c,
Hu-Ri Piaoa, Cheng Hua Jina,b,
,
a College of Pharmacy, Yanbian University, Yanji 133002, PR China
bKey Laboratory of Natural Resources of Changbai Mountain and Functional Molecules, Ministry of
Education, Molecular Medicine Research Center, Yanbian University, Yanji 133002, PR China.
c Department of Pharmaceutics, College of Pharmacy, Yanbian University, Yanji 133002, PR China
d Department of Radiology, Yanbian University Hospital, Yanji 133002, PR China
 Corresponding authors.
E-mail addresses: jishanquan@sina.com (J. Quan), jinchenghua@ybu.edu.cn (C.H. Jin).
1 These authors contributed equally to this work.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Abstract
Transforming growth factor (TGF-β), a key mediator of tumor growth and
metastasis, has been recognized as an important cancer drug target. A series of
benzo[c][1,2,5]thiadiazol-5-yl imidazoles (14a–g) and thieno[3,2-c]-pyridin-2-yl
imidazoles (20a–g) were designed, synthesized, and evaluated for their activin
receptor-like kinase 5 (ALK5) activities. Among these compounds, 14c showed the
highest activity (IC50 = 0.008 μM) against ALK5 kinase, which was 16.1-fold and
1.8-fold higher than those of positive control compounds LY-2157299 (IC50 = 0.129
μM) and EW-7197 (IC50 = 0.014 μM), respectively. Compound 14g (350) showed the
highest selectivity index of ALK5 against p38α MAP kinase, which was significantly
higher than that of positive control compounds LY-2157299 (4) and EW-7197 (211).
The inhibitory effects of compound 14c on TGF-β-induced Smad signaling and cell
motility were studied in SPC-A1, HepG2 and HUVEC cells using western blot
analysis and wound healing assay. ADMET prediction analysis showed that
compounds 14c and 14g had good pharmacokinetics and drug-likeness behaviors.
Keywords: ALK5; TGF-β; imidazole; inhibitors; ADMET

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Transforming growth factor-β (TGF-β) is a cytokine found in various normal cells
and transformed cells, and has various biological functions, such as cell proliferation,
differentiation, migration, apoptosis, and adhesion.1 TGF-βs (TGF-β1, TGF-β2, TGF-
β3) play an important role in cancer biology, including all aspects of tumor inhibition
and tumor promotion. TGF-β can effectively inhibit the proliferation of epithelium,
endothelium, and hematopoietic cell lines, which is core to tumor inhibition
mechanisms.2 TGF-β-mediated growth inhibition and TGF-β overexpress are
conducive to tumor growth and metastasis.2 In particular, TGF-β overexpress occurs
at various stages of illness, including cancer, inflammation, and fibrosis.2
TGF-β adjusts signaling through a transmembrane receptor, which is a serine–
threonine complex composed of type-I (activin receptor-like kinase 5, ALK5) and
type-II receptor kinases.3 Initially ALK5 is phosphorylated by the combination of
TGF-βs and a type-II receptor in the juxtamembrane glycine-serine (GS) domain and
Smad proteins are produced simultaneously. The activated ALK5 phosphorylates
receptor-associated Smads, such as Smad2 and Smad3, bind with Smad4 to form
complexes. These Smad complexes are delivered into the nucleus, where they
regulate the expression of several hundred genes, including cell differentiation,
proliferation, apoptosis, migration, and extracellular matrix production.4 Through this
mechanism, TGF-β signals can be transmitted into the nucleus and regulate various
biological activities. As ALK5 is the key node of TGF-β signal transduction,
inhibiting ALK5 phosphorylation with substrate Smad2/Smad3 can block
transmission of the TGF-β signal to the nucleus.
Our group and others have previously reported the discovery and development of
small-molecule ALK5 inhibitors, such as compounds 1 (SB-505124),5 2,6 3 (LY-
2157299),7
4
(EW-7197),8,9 these inhibit ALK5 autophosphorylation at
submicromolar concentrations (Fig. 1). Among them, compound 3 has progressed to
phase-III trials for treatment of glioblastoma, glioma, hepatocellular carcinoma,10 and
pancreatic cancer.11–14