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ACS Medicinal Chemistry Letters logoLink to ACS Medicinal Chemistry Letters
. 2019 Feb 25;10(4):601–605. doi: 10.1021/acsmedchemlett.8b00589

Identification of the 2-Benzoxazol-2-yl-phenol Scaffold as New Hit for JMJD3 Inhibition

Assunta Giordano †,, Giovanni Forte , Stefania Terracciano , Alessandra Russo , Marina Sala , Maria C Scala , Catrine Johansson §, Udo Oppermann §, Raffaele Riccio , Ines Bruno , Simone Di Micco ‡,*
PMCID: PMC6466828  PMID: 30996803

Abstract

graphic file with name ml-2018-00589j_0006.jpg

JMJD3 is a member of the KDM6 subfamily and catalyzes the demethylation of lysine 27 on histone H3 (H3K27). This protein was identified as a useful tool in understanding the role of epigenetics in inflammatory conditions and in cancer as well. Guided by a virtual fragment screening approach, we identified the benzoxazole scaffold as a new hit suitable for the development of tighter JMJD3 inhibitors. Compounds were synthesized by a microwave-assisted one-pot reaction under catalyst and solvent-free conditions. Among these, compound 8 presented the highest inhibitory activity (IC50 = 1.22 ± 0.22 μM) in accordance with molecular modeling calculations. Moreover, 8 induced the cycle arrest in S-phase on A375 melanoma cells.

Keywords: Fragment-based approach, anticancer agent, one-pot microwave reaction, JMJD3 inhibitor, melanoma


JMJD3, along with tetratricopeptide repeat X-linked protein (UTX), constitutes the KDM6 subfamily, which catalyzes the demethylation of lysine 27 on histone H3 (H3K27). Both proteins share a highly homologous Jumonji C domain, endowed with Fe2+ and α-ketoglutarate,1 which recognizes the trimethylated (H3K27me3) and dimethylated (H3K27me2) lysine 27 of H3 as substrate regulating the lysine methylation state. UTX is ubiquitously expressed,2,3 and it controls the basal levels of H3K27me3 and the induction of ectoderm and mesoderm differentiation.4 JMJD3 is highly expressed in the embryonic stem cells where it regulates neuronal and epidermal differentiation; its expression is induced by inflammation5 and viral and oncogenic stimuli.6 Moreover, JMJD3 inhibits cell reprogramming,7 whereas UTX is fundamental for it.

JMJD3 has been shown to be correlated to inflammatory pathologies8,9 and neurological disorders.10,11 Different studies have also reported the key role of JMJD3 in cancers12 such as initiation and maintenance of T-cell acute lymphoblastic leukemia;13 overexpression of JMJD3 associated with the pathogenesis of Hodgkin’s lymphoma,14 metastatic prostate cancer,15 and pediatric brainstem glioma;16 promoter role in epithelial–mesenchymal transition and cell invasion.17 The reported data suggest JMDJ3 as therapeutic target both in inflammatory diseases and in cancer disorders. However, despite the great potential as therapeutic target, the specific biological function of JMJ enzymes in regulating cellular processes is still poorly understood due to the absence of selective inhibitors. Indeed, concerning JMJD3, up to date, only one JMJD3/UTX binder has been reported, GSK-J1,1 along with a series of its derivatives showing a similar or lower activity.18 Recently, we identified the quinoline-5,8 dicarboxylic acid scaffold as new potential lead compound for the development of JMJD3 inhibitors, using a fragment-based approach.19 This chemical core is endowed with an unprecedented selectivity toward the proposed biological target and a relevant inhibition potency in the micromolar range. Our successful strategy was based on in silico screening of a metal chelator fragment library (Figure S1), which was previously proposed to develop metalloprotein inhibitors.20,21 The results obtained by our investigations validated the computer-aided strategy followed, consisting in molecular docking studies against two JMJD3 conformations with catalytic charge center refined at DFT theory and integrated by molecular dynamics simulations.19 In details, we used two available X-ray structures of JMJD3 as protein models (PDB IDs: 4ASK as Model A and 2XXZ as Model B) because their structural comparison revealed different spatial rearrangements of some amino acids and of Fe2+ upon GSK-J1 binding.1

In order to further explore other chelating fragments here we report the design of new and potent binders of this attractive biological target.

From the inspection of the docked chelator library on both protein conformations (Models A and B), we selected the 2-(benzo[d]oxazol-2-yl)phenol and 2-(benzo[d]thiazol-2-yl)phenol fragments (1 and 2, Scheme 1), which were properly lodged into α-ketoglutarate cavity.

Scheme 1. Synthetic Scheme and Chemical Structures of 1, 2, and 811.

Scheme 1

See experimental details in the Supporting Information.

The selected fragments do not present any carboxylic group, despite the previously selected scaffold B11 (Figure S1).19 Their binding mode, especially with Model B, suggests that they could fill the cavity devoted to host the methylated lysine (Figure S2). Thus, we evaluated the ability of 1 and 2 to inhibit JMJD3 by AlphaScreen protocol (Figure 1).

Figure 1.

Figure 1

Effect of compounds 1, 2, 811 (25 μM), and GSK-J1 (10 μM, reference compound) on JMJD3 activity. Data are given as the means ± SEM, n = 3.

The experiments highlighted that 1 inhibits the enzymatic activity of 40%, whereas 2 was inactive (Figure 1). Hence, we selected 1 as starting scaffold for the synthetic modification in order to improve the affinity toward JMJD3. The docked pose of 1 suggested a modification of phenol moiety to increase the interaction network with α-ketoglutarate pocket of JMJD3, with surrounding residues: T1387, K1381, N1400, W1410, V1472 (Figure S2). Thus, we screened on both protein conformations (Models A and B) a small library of 52 chemical-diverse substituents endowed with H-bond acceptor/donors (Figure S3), considering the synthetic feasibility and commercial availability of reactives. Our analysis was based on the docked energy and visual inspection. In particular, in our growing fragment strategy, we paid attention on the influence of the inserted substituents to preserve the original docked pose of parent scaffold and the favorable interactions with α-ketoglutarate cavity, as well as maintaining the bidentate coordination manner with Fe2+ ion.1,19,22,23 The docking outcomes of all generated compounds (859, Scheme 1, Table S1, and Figure S3) lead to a focused collection of benzoxazole derivatives (811, Scheme 1), selected for the synthesis and useful to provide preliminary information for structure–activity relationship.

The results obtained on Model A revealed that 811 fill equivalent spaces. Compounds 811 (Figures 2 and S4–S6) coordinate in bidentate manner the Fe2+ ion as observed by cocrystallized GSK-J1 (Figure 2C).1 The benzoxazole portion of 811 makes π–π interactions with the side chain of H1390, as observed for GSK-J1, and is H-bonded to Y1379. A π–π interaction is also observed for the phenol moiety of 810 and the methoxybenzodioxole of 11 with Y1381. The hydroxyl group of phenolic ring of 810 is further H-bonded to H1470. Actually, 811 differ for the interaction given by the different substituents of the R aromatic ring (Scheme 1). Indeed, the hydroxyl group at C-4 of phenol ring of 8 establishes H-bond with K1381, T1387, and N1400 (Figure 2A). The carboxylic groups of 9 gives a salt bridge with K1381 and hydrogen bonds with T1387 and N1400 (Figure S4). The fluorine at C-4 of 10 points toward the K1381 (Figure S5).24 Finally, the methoxybenzodioxole of 11 interacts with K1381 and T1387 (Figure S6).

Figure 2.

Figure 2

Three-dimensional model of the interactions of 8-Model A (A), 8-Model B (B), and GSK-J1-Model A (C) (PDB ID 4ASK). JMJD3 is represented by molecular surface and tube, 8 (cyan) and GSK-J1 (black) by sticks and balls. The atom color codes are C (8), cyan; C (GSK-J1), black; C (JMJD3), gray; polar H, white; N, dark blue; O, red. The dashed black lines indicate the H-bonds between ligand and protein.

The docked poses of 811 into Model B showed a similar pattern of interactions established by the common structural portion (Figures 2 and S4–S6). Indeed, the Fe2+ ion is coordinated in a bidentate manner by the nitrogen and the hydroxyl group of 810, whereas the oxygen of the five-membered ring is H-bonded to Y1379. The OH group is also H-bonded to H1470. The compound 11 structurally differs from its congeners also for a methoxy group instead of a hydroxyl group, which is able to coordinate the Fe2+. The phenol ring of 810 and the methoxybenzodioxole of 11 establish π–π interactions with Y1379. The substituents, introduced to get 811, basically give the same pattern of interactions observed into Model A.

We further investigated the stability of 811–JMJD3 complexes by molecular dynamics simulations (50 ns, 310 K, see experimental details in the Supporting Information).19,25,26 The trajectory analysis revealed that 8 makes different contacts with protein residues, and it keeps most of all interactions observed from the docked pose during the entire simulation (>50%) with both protein models (Figure 3B). The backbone-positional RMSD of Model A bound to 8 shows a better stability during molecular dynamics simulations with respect to the reference structure, with a comparable behavior on both protein models (Figure 3A). The atom relative orientation of 8 is kept during the simulation with Models A and B as highlighted by the RMSD of heavy atoms (Figure 3A, right plot). The trajectory of 9-Model A showed oscillations (Figure S7), and fluctuations are observed for 9 atom relative orientation. Indeed, at the end of simulation, 9 moved away from α-ketoglutarate pocket of Model A. Lower oscillations are observed with Model B (Figure S7) with respect to the simulation with Model A. The 10-Model A trajectory is rather constant, whereas for 10-Model B a larger deviation from the initial position is observed especially in the first 5 ns of the simulation (Figure S8). Very few contacts with the surrounding amino acids are observed during the simulation for 10 with Models A and B. Fluctuations of the trajectory are found for 11 with both Models (Figure S9). In particular, 11 keeps the bidentate coordination of the Fe2+ with Model A for the whole trajectory, whereas with Model B, just for 75% of the simulation time the nitrogen is involved in coordination of the metal ion (Figure S9). Compound 11 gives H-bonds with K1381, T1387, and N1440 for ≤10% of simulation time (Figure S9). Collectively, the integrated analysis of docking results and molecular dynamics on both models suggested a higher activity of 8 compared to 911 as experimentally confirmed by AlphaScreen analysis.

Figure 3.

Figure 3

(A) Heavy atom-positional RMSD (Å) as function of simulation time (ns): on the left Models A (blue line) and Model B plot; on the right 8 plot. (B) Protein–ligand contact histograms during the simulation of 8-Model A (left) and 8-Model B (right).

For the synthesis of compounds 811, classical approaches to benzoxazole derivatives involve cyclocondensation of carboxylic acid derivatives such as esters and acyl chlorides with o-aminophenols through initial nucleophilic attack at an activated carbonyl group by the aniline moiety or through oxidative cyclocondensation with aldehydes.27 However, these methodologies suffer from several limitations in the preparation of the starting materials and the use of oxidizing agents, which are not compatible with the presence of para-hydroxyl groups in the molecule. Hence, we opted for a microwave-assisted coupling between the carboxylic acid and 2-hydroxyaminophenol under catalyst and solvent-free conditions (Scheme 1).28

The reaction mixture was irradiated in a microwave oven. After several attempts to determine the optimum reaction conditions, we obtained the best result setting the reaction temperature at 250 °C for 2 min. Following this procedure, the desired products were obtained in good yields, after extraction and purification by semipreparative RP-HPLC chromatography on C18 column (see experimental details in Supporting Information). The structures of the synthesized compounds 811 were fully characterized by MS and NMR spectra (Figures S11–S22).

The synthesized compounds 811 were investigated for inhibition of JMJD3 (at 25 μM) by means of AlphaScreen (Figure 1). The experimental tests revealed that 8 exhibited the highest inhibitory activity (90%). Compounds 9 and 10 also moderately decreased the enzyme activity by 27% and 20%, respectively. The analogue 11 did not show any inhibitory activity. It is noteworthy that these experimental data are in good qualitative agreement with the theoretical outcomes, highlighting the structural features of modified phenolic portion as responsible for the binding affinity toward the macromolecule. Compound 8 showed an IC50 value of 1.22 ± 0.22 μM against JMJD3 by AlphaScreen assay. We also evaluated the inhibition activity of 8 against UTX, the highly structural related isoform of JMJD3. Unlike GSK-J1, 8 showed an interesting selectivity (about 21-fold, Table 1) toward JMJD3. Then, we calculated the ligand efficiency (LE) of 8. This parameter, taking into account the ligand size and potency, is useful to evaluate the quality of a disclosed hit.29,30 Indeed, a LE > 0.3 kcal/mol is usually considered promising for a fragment hit. Since for 8, we obtained a LE = 0.48 kcal/mol, this fragment was confirmed to be a good structural seed to develop new JMJD3 inhibitors. On a side note, the LE value of 8 is even better than our proposed quinoline-5,8 dicarboxylic acid scaffold, previously identified by the same fragment-based strategy.19

Table 1. IC50 ± SEM and LE Value of 8.

  IC50 (μM)
 
  JMJD3 UTX LEa (kcal/mol)
8 1.2 ± 0.2 25.7 ± 2.3 0.48
a

Calculated at 25 °C by using the equation: LE = (1.37/HA) × pIC50, where HA is number of non-hydrogen atoms.

Recently, the JMJD3 promoting role in progression and metastasis of melanoma has been reported.31 These studies also suggest a contrasting role of UTX and JMJD3 in melanoma, with UTX working as tumor suppressor. Thus, we decide to investigate the ability of 8 to affect cell cycle progression and/or induced cell death of A375 cells. First, we evaluated the cell permeability of 8 with the well-validated parallel artificial membrane permeability assay (PAMPA) technique, obtaining an acceptable apparent permeability value (Papp) of 9.12 × 10–7 ± 1.67 × 10–8 cm/s. Then, the A375 melanoma cells were incubated with compound 8 at different concentrations (1–5–10–20–40–80–100 μM). After 24 h the cells were collected, incubated with iced ethanol 70% for 2 h, and stained with propidium iodide for flow cytometer analysis. Compound 8 showed to affect melanoma cell proliferation in a concentration-dependent manner, with a significant effect at 20 μM. The higher effect was reached at 100 μM by arresting cell cycle in S phase (Figure 4 and Table S2). Moreover, we obtained the IC50 (24.7 ± 1.1 μM) of 8 through the FACS titration, to avoid interference in MTT assays being a colored compound. These results are in agreement with the previous studies showing that JMJD3 can also gather at DNA double-strand break sites (DSBs) to facilitate the expression of specific genes, such as Ku80, which is a key mediator protein in NHEJ pathway (nonhomologous end-joining).32 In particular, Ku proteins are essential for the S-phase cycle transition and Ku80–/– cells present a stronger S checkpoint response33 after a DNA damage.

Figure 4.

Figure 4

Flow cytometer analysis of representative cell cycle of A375, treated with 8 (n = 3).

A375 melanoma cell lines were incubated by 100 μM 8 for 4 and 24 h and lysed for SDS-PAGE for a Western blot assay and the nitrocellulose membrane was blotted with an anti-H3K27me2 antibody. After 24 h of treatment with 8, a slight decrease of the H3K27me2 level was observed (Figure S10). The absence of a clear result is probably due to the low inhibitor activity of 8 against UTX, which continues exerting the demethylase activity.

In conclusion, by a fragment-based approach we have identified a novel promising hit to develop new JMJD3 inhibitors. Indeed, the identified benzoxazole derivative 8 inhibits the protein in the low micromolar range and is able to induce cell cycle arrest of A375 cancer cells. Furthermore, the low molecular weight and the remarkable LE value of 8 promote this chemical core for the hit to lead optimization step for the development of new benzoxazole-based JMJD3 inhibitors for melanoma treatment.

Acknowledgments

We thank Dr. Eduardo M. Sommella (Department of Pharmacy, University of Salerno, Italy) for HR mass spectra.

Glossary

ABBREVIATIONS

JMJD3

Jumonji domain-containing protein 3

UTX

ubiquitously transcribed X chromosome tetratricopeptide repeat protein

H3K27

lysine 27 on histone H3

H3K27me3

trimethylated lysine 27 on H3

H3K27me2

dimethylated lysine 27 on H3

NHEJ

nonhomologous end-joining

DFT

density functional theory

RMSD

root-mean-square deviation

MW

microwave

LE

ligand efficiency

DSBs

DNA double-strand break sites

NMR

nuclear magnetic resonance

MS

mass spectroscopy

SEM

standard error of the mean

FACS

fluorescence assisted cell sorting

PAMPA

parallel artificial membrane permeability assay

Papp

apparent permeability

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.8b00589.

  • Computational details, synthetic procedures, AlphaScreen method, characterization data, NMR and mass spectra, cell assay, PAMPA test, Western blot (PDF)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) and Fondazione Cariplo (grant TRIDEO Id. 17099 to S.D.M.).

The authors declare no competing financial interest.

Supplementary Material

ml8b00589_si_001.pdf (6.4MB, pdf)

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Supplementary Materials

ml8b00589_si_001.pdf (6.4MB, pdf)

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