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. 2022 Dec 15;14(1):83–91. doi: 10.1021/acsmedchemlett.2c00442

Using Imidazo[2,1-b][1,3,4]thiadiazol Skeleton to Design and Synthesize Novel MNK Inhibitors

Xin Jin †,‡,∥, Tingting Qiu †, Jianling Xie ‡, Xianfeng Wei †, Xuemin Wang ‡,§, Rilei Yu †, Christopher Proud ‡,§,*, Tao Jiang †,*
PMCID: PMC9841594  PMID: 36655132

Abstract

graphic file with name ml2c00442_0010.jpg

Mitogen-activated protein kinase-interacting protein kinases (MNKs) phosphorylate eukaryotic initiation factor 4E (eIF4E) and regulate the processes of cell proliferation, cell cycle, and migration and invasion of cancer cells. Selectively inhibiting the activity of MNKs could be effective in treating cancers. In this study, we report a series of novel MNK inhibitors with an imidazo[2,1-b][1,3,4]thiadiazol scaffold, from which, compound 18 inhibited the phosphorylation of eIF4E in various cancer cell lines potently. Compound 18 was more potent against MNK2 than MNK1, and decreased the levels of cyclin-B1, cyclin-D3, and MMP-3 in A549 and MDA-MB-231 cells, impaired cell growth and colony formation, arrested the cell cycle in the G0/G1 phase, and inhibited cell migration and the secretion of TNF-α, MCP-1, and IL-8 from A549 cells. It represents a starting compound to design further inhibitors that selectively target MNKs and apply in other diseases.

Keywords: MNK, eIF4E, Cell cycle, Migration, MMP-3

The mitogen-activated protein kinase-interacting protein kinases (MNKs) comprise MNK1 and MNK2. They are activated and regulated by Erk (extracellular regulated protein kinases) and, for MNK1, also by p38 MAP kinase.1,2 It has been shown that MNKs can phosphorylate hnRNPA1 (heterogeneous nuclear RNA-binding protein A1), PSF (polypyrimidine-tract binding protein-associated splicing factor), cPLA2 (cytoplasmic phospholipase A2), hSPRY2 (Sprouty2), and eIF4E in vitro, but only phosphorylate eIF4E at Ser209 in vivo.3,4 eIF4E binds to the 5′ cap of the mRNA structure (which contains m7GTP) and controls the translation of certain mRNAs.5 The activity of eIF4E can be regulated by the PI3K/Akt/mTORC1 and Ras/Raf/MAPK signaling pathways.1,3,6 Overexpression of MNKs and eIF4E, and elevated phosphorylation of eIF4E, show a positive relationship with various cancers, e.g., nonsmall cell lung cancer (NSCLC), melanoma, acute myeloid leukemia (AML).5,7−11 MNKs can modulate the processes of cancer cell proliferation, migration and metastasis by regulating the translation of specific mRNAs and thus the levels of the corresponding proteins, including cyclins, Snail, matrix metalloprotease 3 (MMP-3) and Bcl-2.3

Phosphorylation of eIF4E is essential in tumor development, at least in some settings,12 but is not necessary for normal conditions.13,14 MNKs may therefore be safe targets for the treatment of human diseases. MNK-1/2 double knockout (DKO) prevents mice from insulin resistance and obesity induced by high-fat-diet15 and enhance energy expenditure.16,17 Furthermore, MNKs regulate the immune system by impairing Toll-like receptor (TLR) signaling pathways and also modulate the tumor microenvironment (TME) to regulate proinflammatory cytokine production.18−20 Inhibition of MNKs (perhaps combined with other approaches) may be effective in the therapy of cancer or metabolic disease, with a low risk of on-target toxicity.4

Several MNK inhibitors have already been developed and studied as therapeutic agents for solid cancers, leukemia, and obesity, sometimes as a combination therapy with other agents.3 For several years, our group has been developing MNK selective inhibitors, of which, 7g (Figure 1), an MNK2 inhibitor, showed potent inhibition of cell migration without “off-target” effects or affecting cell cycle.21 Currently three compounds (BAY1143269,22 eFT508,23 and ETC-20624) have been studied in clinical trials for treating solid cancers and leukemia; their structures are shown in Figure 1. Of these compounds, only eFT508 is still in phase II (see clinicaltrials.gov).3,4 Therefore, novel and selective inhibitors of MNKs are still required to provide pharmacological agents to study the pathological roles of the MNKs, especially in preclinical models of human disease.

Figure 1.

Figure 1

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Structures of MNK inhibitors discussed in this paper.

Herein, we designed and synthesized a series of novel MNK inhibitors with scaffold of imidazo[2,1-b][1,3,4]thiadiazol. Among these compounds, 18 showed strong inhibition to MNKs and inhibited cancer cell proliferation by arresting cell cycle. Additionally, compound 18 inhibited cell migration and regulated TME by decreasing the secretion of proinflammatory cytokines.

Julen Oyarzabal., e.g., have reported some fragments through virtual screening for designing MNKs inhibitors.25 Among them, the structure of imidazo[2,1-b][1,3,4]thiadiazol (hit core) attracted our attention, which has been used in many cancer drugs or antiviral drugs.26 Software of MOE (molecular operating environment) was used to determine the interaction between the MNK2 protein and hit core. Results showed that it shared the same combination mode with ligand (staurosporine) (Figure 2). Moreover, compound ETC-206 also comprises a bicyclic core. Through scaffold hopping, we designed two series of compounds based on hit core and added substituents at C-1 and at C-7 or C-6; see Scheme 1, Scheme 2.

Figure 2.

Figure 2

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Design illustration of imidazo[2,1-b][1,3,4]thiadiazol and overlay of hit core (pink stick) and staurosporine (yellow stick) with the MNK2 ATP docking pocket (PDB: 2hw7). Amino acid atoms are shown with gray lines. Hydrogen bonds are shown with yellow dashed lines.

Scheme 1. Synthesis of Compounds 8–13.

Scheme 1

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Reagents and conditions: (i) EtOH, methyl 4-formylbenzoate, reflux, FeCl3·6H2O; (ii) 2-bromo-1-phenylethan-1-one or 2-bromo-1-(4-fluorophenyl)ethan-1-one or 2-bromo-1-(4-cyanophenyl)ethan-1-one, acetonitrile; CH3COOH, reflux; (iii) LiOH·H2O, THF/H2O; then HCl, pH 2–3; (iv) NHS, EDCI, amines, DMF.

Scheme 2. Synthesis of Compounds 18–20, 23–30a.

Scheme 2

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Reagents and conditions: (i) EtOH, bromoacetaldehyde diethyl acetal, reflux; NaOH; (ii) NBS, DCM; (iii) LiOH·H2O, THF/H2O; then HCl, pH 2–3, (iv) NHS, EDCI, DMF, N-methyl piperazine; (v) (4-cyanophenyl)boronic acid, or pyridine-4-boronic acid, or methyl 4-boronobenzoate, Pd(PPh3)4, CsF, dioxane/H2O; (vi) (4-cyanophenyl)boronic acid, Pd(PPh3)4, CsF, dioxane/H2O.(vii) LiOH·H2O, THF/H2O; then HCl, pH 2–3; (viii) NHS, EDCI, DMF, related amines.

Thiosemicarbazide reacted with methyl 4-formylbenzoate in the presence of ferric trichloride hexahydrate (FeCl3·6H2O) to yield compound 1, which was converted to 2, 3, and 4 by performing cycloaddition reaction with 2-bromo-1-phenylethan-1-one, 2-bromo-1-(4-fluorophenyl)ethan-1-one and 2-bromo-1-(4-cyanophenyl)ethan-1-one, respectively. Hydrolysis of the methyl ester group of 2, 3, and 4 was carried out using LiOH·H2O in a mixture of tetrahydrofuran (THF) and water (1:1) to produce 5, 6 and 7 respectively. Subsequent treatment of the carboxylic acids 5, 6, and 7 with N-hydroxysuccinimide (NHS), 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDCI), and corresponding amines in DMF to obtain amides 8–13.

Starting from compound 1, which cyclized with bromoacetaldehyde diethyl acetal to get compound 14. Then compound 14 was brominated using N-bromosuccinimide (NBS) to give methyl 4-(5-bromoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoate 15, which subjected ester hydrolysis and amide formation to afford compound 17. At last, compounds 18, 19, and 20 were prepared in one Suzuki coupling step as depicted in Scheme 2. Moreover, compound 15 was subject to the Suzuki coupling reaction to form compound 21, followed by ester hydrolysis and amide formation to afford compounds 23–30 (see Scheme 2).

We tested the activity against MNKs of these compounds by assessing the level of phosphorylation of eIF4E, which is the best-characterized and only in vivo validated substrate for the MNKs. Compounds were treated in 3T3-L1 cells at 5 μM for 2 h and cell lysates were analyzed by sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) (Figure S1). Compound MNK-I1 (its structure is shown in Figure 1) was used as a positive control at 1 μM as previous reported.21 The results showed that compounds 8–13 did not show any activity against MNKs; compounds 18, 19, 20, and 29 showed moderate or strong MNKs inhibition activity at 5 μM, which indicated introducing substituent at the C-5 position was better than at the C-6 position.

We then tested the IC50 values for MNK1/2 of compounds 18–20, 23–30in vitro (Table 1). The results showed that compound 18 exerted strong inhibition to MNK1 and MNK2 with IC50 values of 11.5 and 8.6 nM, respectively. Introducing different groups with hydrogen bond acceptor at R1 (e.g., compound 18–20) showed different inhibitory activity to MNKs. Compounds 18–20 were docked into the protein MNK2 (2hw7) to identify their interaction maps. We found that compound 19, 20 can not form the hydrogen bond with Lys113 (see Figure S2) and then the inhibitory activity to MNKs was decreased. Moreover, the length of alkylamine at R2 affected the inhibition to MNK1 and MNK2. With the increasing of length, the activity of compounds showed variable results. When the length of carbon chain was two, compounds showed best inhibition to MNK1/2 (i.e., compound 26 was more potent than compound 23, and compound 28 showed high potency against MNK1 and MNK2 with a respective IC50 values of 11.58 and 8.81 nM, which was better than compound 27 and 30 showed). Therefore, the formation of hydrogen bond between the R1 group and Lys113 (MNK2 protein), and an appropriate linker (the length of two carbon atom would be the best) at R2 would increase the inhibitory activity to MNKs.

Table 1. IC50 Values for MNK1 and MNK2 of Indicated Compounds.

  IC50 (nM)
  
Compound MNK1 MNK2 alog P
18 11.5 8.6 2.34
19 375.5 104.6 2.89
20 210.2 169.7 1.63
23 27.8 20.83 2.86
24 25.04 33.44 2.91
25 31.13 21.6 2.83
26 10.02 10.4 3.16
27 21.6 16.69 2.44
28 13.58 8.81 2.36
29 36.91 5.33 3.92
30 42.93 57.75 2.97
Staurosporine 44.17 8.85 –
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a

log P was calculated by ACD/Laboratories software. IC50 values are the average of two determinations.

Compound 18 showed the best inhibition to MNKs, and we evaluated its ability of intracellular MNK activity in several cancer cell lines. It inhibited the phosphorylation of eIF4E completely but did not affect the phosphorylation of S6K (Thr389), rpS6 (Ser240/244), or AKT (Ser473) in C4–2B cells (Figure S3), which showed 18 inhibited the activity of MNKs without affecting the mTORC1 or mTORC2 pathways. We then tested the effects of 18 in other tumor cell lines, such as PC-3, MDA-MB-231, A549, H446, H1299, and three AML cell lines. It showed moderate inhibition of p-eIF4E at 3 μM (Figure S3), but only at higher concentrations (10 μM) in U937 and SKM-1 cell lines (Figure S4).

We then used MEF cells in which MNK1 or MNK2 had been knocked out to assess the relative efficacy of compound 18 against MNK1 and MNK2 in cells (Figure 3), monitoring the effects of 18 on the phosphorylation of eIF4E in these cell lines specifically reflects the activity of the remaining MNK isoform. In wild-type MEFs, both ETC-206 and 18 inhibited the phosphorylation of eIF4E moderately at 3 μM (Figure 3C). In MNK1-KO cells, both compounds exerted potent inhibition to p-eIF4E levels, with almost complete inhibition at 1 μM (Figure 3B). In contrast, ETC-206 and 18 only caused about 50% inhibition of p-eIF4E even at 3 μM in MNK2-KO MEF cells (Figure 3A). This indicates that ETC-206 and compound 18 inhibit MNK2 considerably more potently than MNK1.

Figure 3.

Figure 3

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Comparison of the effects of ETC-206 and 18 on eIF4E phosphorylation in wild-type and MNK knockout MEFs. (A, B, C) MEFs (MNK2-KO, MNK1-KO, wild-type) were treated with ETC-206 or 18 at indicated concentrations for 2 h. Cells were then lysed and lysates were analyzed by SDS-PAGE and Western blot using the indicated antibodies. (D, E, F) Quantification of data from three independent experiments for p-eIF4E. Error bars are SEM *, p < 0.05; **, p < 0.005, ***, p < 0.0005, ****, p < 0.0001.

To further understand the selectivity of compound 18 against kinases, we compared the inhibitory activity of 18 against 60 kinases from different families at 3 μM. The profiling results showed that 18 was a multikinase inhibitor (Figure 4, Table S1). Among the detected kinases, 18 has the highest inhibition rate of MNK1 and MNK2 up to 100%. Compound 18 also inhibited other kinases, in particular QIK (quiescence-induced kinase) and CLK1 (CDC2-like kinase 1), as well as the c-Jun N-terminal kinases JNK1 and JNK2. These four kinases belong to the CAMK and CMGC families (Figure S5) and regulate cancer cell proliferation and cancer progression.27−29 Caution must therefore be exerted in interpreting data obtained using 18, as they may, to some extent, reflect the ability of 18 to inhibit other kinases.

Figure 4.

Figure 4

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Heatmap of the inhibitory activity of compound 18 against a panel of 60 kinases at 3 μM.

Since elevated levels of the MNKs and p-eIF4E are found in many cancers, we analyzed the influence of 18 on the proliferation of cancer cells. When we treated A549 or MDA-MB-231 cells with compound 18 at 5 μM up to 6 days, we saw that 18 decreased the cell number for both lines (Figure S6A,C). It inhibited the phosphorylation of eIF4E up to 96 h which indicated that 18 was sufficiently stable in cell culture (Figure S6B,D). Additionally, 18 significantly decreased the colony-forming ability of A549 and MDA-MB-231 cells in line with dose-dependent suppression of phosphorylation of eIF4E (Figure 5).

Figure 5.

Figure 5

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Compound 18 suppresses clonogenicity. (A, C) Representative cell plate scan images from 10-day clonogenic assay: A549 and MDA-MB-231 cells were treated with DMSO or 18 at indicated concentrations. (B, D) Quantification of data from three independent experiments for (A, C). **, p < 0.005, ***, p < 0.0005.

To gain a better understanding of cell proliferation induced by compound 18, we analyzed A549 and MDA-MB-231 cells for their response to treatment with 18 (5 μM). We observed reduced expression of several cell cycle factors, the levels of cyclin B1 and cyclin D3 decreased (Figure 6A, S7). We also looked at all these proteins in three AML cell lines, and 18 decreased the levels of cyclin B1 and cyclin D3 in MV4-11 cells at 3 μM (Figure S8). Additionally, G0/G1 arrest was observed with 18 after 8 h treatment in A549 cells (Figure 6B).

Figure 6.

Figure 6

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Compound 18 affects the levels of proteins involved in the cell cycle and migration and inhibits the cell cycle. (A) A549 and MDA-MB-231 cells were treated with 18 (5 μM) for 24 h and then lysates were analyzed by Western blot for the indicated proteins. (B) A549 cells treated with 18 (5 μM) for indicated time was analyzed by flow cytometry-based propidium iodide staining.

The inhibitions of MNK and p-eIF4E have been found to impair the process of EMT (epithelial-to-mesenchymal transition) and metastasis in cancer cells.30 Therefore, we tested the influence of 18 on A549 and MDA-MB-231 cells. Cells were treated with 18 for 24 h and compound 18 caused a significant reduction of MMP-3 in both cell lines (Figure 6A). MMPs (e.g., MMP-3, MMP-9) affect many extracellular matrix (ECM) component proteins to promote migration and invasion and induce EMT.30 We then used “scratch wound healing assays” to analyze the effect of 18 on the migratory potential of A549 and MDA-MB-231 cells (Figure 7A,D). In line with the reduction of MMP-3, we observed significantly reduced migratory potential in cells with 18 compared with DMSO at 6 h after treatment (Figure 7B,E) and the effect was even more pronounced at 24 h (Figure 7C,F).

Figure 7.

Figure 7

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Compound 18 inhibits cell migration of A549 and MDA-MB-231 cells in “wound-healing” assays. (A, D) A549 and MDA-MB-231 cells were treated with 18 (5 μM) or DMSO for 6 and 24 h. Pictures were taken at the indicated time points. (B, E) Percentage change in wound area after 6 h was analyzed by ImageJ. (C, F) Percentage change in wound area after 24 h has analyzed by ImageJ.

Inhibition of MNKs and the p-eIF4E have been shown to regulate proinflammatory cytokine production.31−33 Cytokines are involved in oncogenesis, the progression of tumors, and the development of resistance to therapy.34 To explore the effect of 18 on cytokine release, proinflammatory cytokine concentrations were measured in cell supernatants from A549 cancer cells. Treatment with 18 for 48 h in A549 cells decreased the levels of tumor necrosis factor α (TNFα), interleukin (IL)-8 and monocyte chemotactic protein 1 (MCP-1) in a concentration-dependent manner (Figure S9). These results indicated compound 18 could regulate the release of pro-inflammatory cytokines by inhibiting the activity of MNKs.

We then assessed the pharmacokinetic (PK) profile of compound 18in vivo. As shown in Table 2, at a dose of 50 mg/kg, compound 18 reached the maximum concentration of 17161 ng/mL in 1 h. While bioavailability was decent at 60.9%, the concentration in serum decreased quickly in 8 h (Figure S10). Given the sensitivity of 18 to A549 cells in vitro, we examined the antitumor activity of 18 in an A549 xenograft model (Figure S11A,B). 18 was administered orally at 75 mg/kg or 150 mg/kg once daily in A549 xenograft model onto nude mice. Irinotecan, which inhibits topoisomerase activity, was selected as a positive control, as it has been approved for the treatment of NSCLC for many years.3518 was well tolerated over a treatment time of 14 days as indicated by a body weight loss of <10%, while the antitumor efficacy for the 18 group (150 mg/kg) that reached a T/C-ratio (relative tumor proliferation rate) of 0.5 was higher than the positive control group (Irinotican, 3 mg/kg) that showed a T/C ratio of 0.4. Compound 18 exerted antitumor activity in vivo that was clearly dose-dependent, although the extent was not significant.

Table 2. Mouse Pharmacokinetics Data for Compound 18.

Compound 18
Dose (mg/kg) 25 50
Route of administration i.v. p.o.
Vz (mL/kg) 1517 3155
Cmax (ng/mL) 32145 17161
Tmax (h) 0.08 1
t1/2 (h) 3.4 4.42
CL (mL/h/kg) 308 507
AUC0-t (ng·h/mL) 80937 98503
F (%)a – 60.9
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a

F (%) calculated after i.v. and p.o. administration at 25 mg/kg and 50 mg/kg respectively of 18.

In summary, we describe a novel MNK inhibitor, compound 18, that preferentially inhibits MNK2, which, importantly, is the constitutively active form of the MNKs maintaining basal levels of p-eIF4E. It inhibited the phosphorylation of eIF4E in certain cancer cell lines and impaired cell cycle progression and cell migration. Although compound 18 showed “off-target” effects in the kinase selectivity assay, it still provides a hit compound for further modification and investigation. Further work is needed to obtain selective MNK inhibitors based on this structure and explore other selectively MNK inhibitors in monotherapy or combined therapy for cancer.

Glossary

ABBREVIATIONS

AML

acute myeloid leukemia

MNKs

mitogen-activated protein kinase-interacting protein kinases

eIF4E

eukaryotic initiation factor 4E

TME

tumor microenvironment

MMP-3

metalloprotease 3

EMT

epithelial-to-mesenchymal transition

QIK

quiescence-induced kinase

CLK1

CDC2-like kinase 1

TNFα

tumor necrosis factor α

MCP-1

monocyte chemotactic protein 1

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00442.

  • Experimental details for in vitro and in vivo studies; synthetic procedures, and characterization of all compounds; biology experiments and kinase profiling of compound 18 (PDF)

Author Contributions

X.J. performed the experiments, analyzed the data, and wrote the paper. J.X., X.W., and T.Q. performed some of the experiments. X.J., R.Y., X.W., T.J. and C.P. contributed to the paper. T.J. and C.P. designed and supervised the research.

We are grateful to the Natural Science Foundation of China (Grant No. 82073759), National Science and Technology Major Project for Significant New Drugs Development: (2018ZX09735004), the Government of South Australia for funding to support research links between SAHMRI and Shandong and to the South Australian Health & Medical Research Institute for research support. This research was also supported by Qingdao Postdoctoral Science Foundation (862105040014).

The authors declare no competing financial interest.

Supplementary Material

ml2c00442_si_001.pdf (2.4MB, pdf)

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