Identification of (S)-1-(2-(2,4-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)urea as a potential anti-colorectal cancer agent
Graphical abstract
Introduction
It was estimated that approximate 19.3 million new cancer cases and almost 10.0 million cancer deaths occurred in 2020 worldwide, and lung cancer still remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers [1]. In the past two decades, targeted therapy focused on receptor tyrosine kinases (RTKs) has become critically imperative among all cancer treatment approaches [2,3]. As the second leading cause of cancer death, there is still a great demand for the efficacious drugs for the treatment of colorectal cancers.
c-Mesenchymal epithelial transition factor (c-Met), which belongs to a member of RTK family, plays a significant role in regulating a large number of critical physiological processes, such as embryogenesis, tissue repair and organ development [4,5]. Upon binding to its only natural ligand, hepatocyte growth factor (HGF), c-Met phosphorylates, homodimerizes and triggers the stimulation of several intracellular signaling pathways including Ras/MAPK, PI3K/AKT, STAT3 and Rac1-Cdc42 pathways, etc [6,7]. Aberrant c-Met signaling is implicated in the development and progression of numerous human solid cancers, such as lung cancers, colorectal cancers, thyroid cancers, and gastric cancers [8]. Moreover, dysregulation of the c-Met is frequently associated with aggressive cancer phenotypes, poor prognosis and drug resistance in targeted therapies [9,10]. Thus, c-Met has attracted considerable attention as an effective target for the treatment of solid cancers, with a great many of small-molecule c-Met inhibitors having been assessed in preclinical or clinical study [[11], [12], [13]].
According to the binding modes with DFG motif of c-Met kinase, these inhibitors are mainly categorized into three types, as follows: type I, type 1.5 and type Ⅱ [[14], [15], [16]]. Type I inhibitors, such as JNJ-38877605, Crizotinib and Capmatinib (Fig. 1), localized to the ATP-binding site adopting a U-shaped conformation and typically exploited interactions with key A-loop residues [17,18]. H-bonds between potent type I inhibitors and the residues (Pro1158, Tyr1159 and Met1160) in the hinge region are formed. In most cases, type I inhibitors showed better selectivity than that of type II inhibitors; however, type I inhibitors have been shown to suffer from the emergence of acquired resistance in the clinic [19,20]. Type II inhibitors, represented by Foretinib, Cabozantinib, BPI-9016 M and Tepotinib (Fig. 1), bind at the deep hydrophobic back pocket between the hinge residue and the solvent-accessible area [[21], [22], [23], [24]]. In most cases, the multi-binding modes of type II inhibitors have a broader inhibition spectrum which could help in overcoming acquired resistance to type I inhibitors, but they also have tolerability issues in clinical settings [25]. To our knowledge, jm8006189-62 is the only reported type 1.5 c-Met inhibitor which also bind to ATP-binding site and extend into the kinase back-pocket [14,26]. Being different from Type II inhibitors, Type 1.5 inhibitors targeted c-Met with a folded P-loop and displayed both favorable potency and selectivity for c-Met kinase.
Recepteur d'origine nantais (Ron), also known as macrophage stimulating 1 receptor MST1R, is a receptor tyrosine kinase encoded by the MST1R gene that shares 34% homology with c-Met. As two members of MET family, the tyrosine kinase region of c-Met and Ron is quite similar at 80% homology [27,28]. Ron could interact with a variety of cytoplasmic effectors, such as Src, Hsp70, PLCγ, PI3K, and integrin-β4, etc [29]. Moreover, abnormal Ron expression leads to hyperphosphorylation of Ron kinase, which activates various intracellular signaling cascades downstream which mainly includes Ras/MAPK and PI3K/AKT [30,31]. Thus, dysregulation of Ron has also been proved to be associated with the progression, metastasis, survival and prognosis of various types of cancers [[32], [33], [34]]. Due to the homology of c-Met and Ron, only few c-Met/Ron dual inhibitors have been discovered until now, such as BMS-777607 and MK-8033 (Fig. 1) [35,36].
Given the above role of the overexpression and/or aberrant activation of c-Met and Ron in cancer pathogenesis, targeting them represents a promising cancer therapy strategy, especially colorectal cancers. However, no c-Met/Ron dual inhibitors are validated in clinic for the treatment of colorectal cancers [37,38]. Taking Cabozantinib as lead compound, we discovered a series of novel quinoline analogues bearing thiazolidinone fragments as potent c-Met/Ron dual inhibitors in our previous endeavor (Fig. 2) [39,40]. Among them, compound 1 was confirmed as a potent inhibitor with excellent kinase inhibitory activity and in vitro anticancer activity, especially against colorectal cancer cell lines (Fig. 2). Further modification was carried out in the present work, and the optimal compound (S)-8m was obtained. To be specific, the synthesis of novel compounds, kinase inhibitory activity, anticancer activity against different types of human cancer cell lines, the study of SARs, in vitro stability, docking study and anticancer mechanism were all included in our current research.
Section snippets
The design of novel compounds
In our previous research, we discovered 1-(4-((7-(3-(diethylamino)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)-3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)urea (1) as a c-Met/Ron dual inhibitor [39,40]. Biological evaluation indicated that it exhibited potent anticancer activity against various types of cancer cell lines, especially against colorectal cancer cell line HT-29 cell (IC50 = 0.091 μM). Meanwhile, preliminary SARs of Moieties I to V were also summarized based on the
Conclusions
Following our reported kinase inhibitor 1, a comprehensive series of quinoline derivates were designed, synthesized and evaluated for their biological activity. The kinase inhibition profile study revealed that compound 8m was a multikinase inhibitor that potently inhibited c-Met and Ron. It also exhibited moderate to excellent cytotoxic activity against different types of human cancer cell lines, especially against COLO 205 cells (IC50 = 0.035 μM) which was remarkably superior to that of
Chemistry
Unless otherwise noted, all chemicals were obtained from commercial vendors and used directly without further purification. Analytical reagent (AR) grade solvents were used for all reactions. Reaction progress was monitored by TLC on pre-coated silica plates (Huanghai HSGF254, 0.20 mm, pH 6.2–6.8) and spots were visualized by UV (254 nm). Flash column chromatography was done using silica gel (Qingdao Ocean Chemical Company, 200–300 mesh). 1H NMR and 13C NMR spectra were recorded on a Bruker
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This work was supported by Science and Technology Projects of Guizhou Province (Qian Ke He Foundation-ZK[2021]key project 015).
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These authors contributed equally to this work.