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. 2019 Nov 26;10(12):1680–1685. doi: 10.1021/acsmedchemlett.9b00474

Pharmacokinetics-Driven Optimization of 7-Methylimidazo[1,5-a]pyrazin-8(7H)-one as Novel BRD4 Inhibitors

Yifei Yang †,‡, Pan Chen †, Leilei Zhao §, Fangqing Zhang §, Huibin Zhang §,*, Jinpei Zhou †,*
PMCID: PMC6912876  PMID: 31857846

Abstract

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The BET bromodomain containing protein (BRD4) plays a key role in transcription regulation. Therefore, efforts to generate BRD4 inhibitors with excellent potency and DMPK properties are of clinical value. As a continuing work to improve the stability in in vitro metabolic experiments of liver microsomes of our previously reported 7-methylimidazo[1,5-a]pyrazin-8(7H)-one, our optimization of this poor pharmacokinetics focusing on the phenyl substituent is performed. Fortunately, compound 17 displayed subnanomolar potency (IC50 = 30 nM) against BRD4(1), and its liver microsome stability in human, rat, and mouse are more favorable than previously reported inhibitor 28. Compound 17 exhibited antitumor efficacy with no significant toxicity in xenograft models of pancreatic cancer. In addition, fluorescent probe and nuclei-specific dye were utilized to verify apoptosis-inducing of compound 17 via intranuclear potency in BXPC-3 cell line.

Keywords: BRD4 inhibitors, pharmacokinetics, pancreatic cancer, fluorescent probe

Acetylation of lysine residues is a widespread protein post-translational modification (PTM)1 and extensively relevant to modulation of cellular processes, including protein conformation and interaction.2 Acetylation of histones in chromatin is associated with the regulation of gene transcription and chromatin remodeling.3 Deregulation of histone acetylation expression has been strongly linked to regulation of a broad range of genes, in particular primary response genes.4,5

Bromodomain-containing proteins principally mediate recognition of Kac and regulate gene transcription.6,7 Bromodomain is a conserved protein modular domain and approximately 110 amino acids in length. The three-dimensional structures were composed of four antiparallel a-helices (aZ, aA, aB, aC) arranged in a left-handed twist and two loops, linking aZ and aA (ZA loop) and aB and aC (BC loop).8,9 Despite the sequence diversity in ZA and BC loop regions, several conserved amino acid residues surround a central acetylated lysine binding site.10−13

The mammalian BET (bromodomain and extraterminal domain-containing) protein family is made up of four members (BRD2, BRD3, BRD4, and testis-specific BRDT) and all BET proteins contain two tandem N-terminal BRD modules (BD1 and BD2). BET protein binds to histone Kac motifs to active transcription through a hydrophobic pocket at one end of the helical bundle.14 The BET family has been reported by interacting with acetylated histone tails to recruit the positive transcription elongation factor complex (pTEFb) that is essential for RNA polymerase II-dependent transcription elongation.15,16 BRD4 also can activate pTEFb by directly phosphorylating CDK9 or its associated factors via an atypical kinase activity.17 In addition, BET proteins structurally alter or remove the nucleosomal barrier to allow passage of elongating RNA polymerase II.18

Targeting a bromodomain recognizing Kac was thought to be challenging because protein–protein interactions were difficult to modulate.19 This has changed when the first inhibitors of bromodomains, MS417(1) disclosed by Mitsubishi shown in Figure 1, were shown to bind in the KAc binding pocket. JQ1(2) with the similar structure to MS417 and I-BET762(3) discovered by GlaxoSmithKline (GSK) was also disclosed in late 2010.20,21 Several different binding moieties have also been discovered, such as 3, 5-dimethylisoxazoles, which is the component of I-BET151(5).22ABBV-075 disclosed by AbbVie has been advanced into clinical development focusing on advanced cancer, breast cancer, or hematologic malignancies.23−26 These inhibitors have raised much interest to understand the role of BET proteins as potential therapeutic targets in diverse diseases, such as oncology,27 inflammation,28 immunology,29 and cardiovascular disease.30

Figure 1.

Figure 1

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Structures of known BET inhibitors.

We previously published that structure activity relationship (SAR) was performed to develop imidazolopyridone derivate 28, a novel binding moiety as BRD4 bromodomain inhibitors.31 Therefore, the SAR development of the imidazolopyridone core resulting in developing novel BRD4 inhibitor 17, which showed the most potency and advantageous pharmacokinetic properties, was investigated further with regard to its potency in in vivo mouse xenograft models.

The synthesis of BRD4 inhibitors 16–27 is described in Scheme 1. The starting material 9 was converted to compound 10 via diazotization and hydrolysis. Compound 10 was reacted with dimethyl sulfate to produce intermediate 11. Then compound 12 was prepared from 11 using tosylmethyl isocyanide. Intermediate 12 was coupled with 2-bromo-1-fluoro-4-nitrobenzene via Suzuki coupling reaction to produce vital intermediate 13. Nucleophilic substitution reaction and reduction reaction were utilized to obtain compounds 15a–h. Lastly, the target compounds 16–27 were prepared by using diverse sulfonyl chloride.

Scheme 1.

Scheme 1

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Reagents and conditions: (a) sodium nitrite, conc. H2SO4, −5 to 60 °C, 82%; (b) dimethyl sulfate, Cs2CO3, CH3CN, 58 °C, 74%; (c) tosylmethyl isocyanide, sodium hydrogen, THF, −5 to 25 °C; (d) tetrakis(triphenylphosphine) palladium, Na2CO3, toluol, 80 °C, 71%; (e) phenol, K2CO3, N,N -dimethylformamide, 75°C, 81%; (f) iron powder, NH4Cl, H2O/MeOH, 90 °C, 77%; (g) RSO2Cl, triethylamine, CH2Cl2, −5 °C, sodium hydroxide, diethylene dioxide, 66 °C, 72%.

As in our previous report, AlphaScreen assay was used to evaluate the binding activities with BRD4 protein. Initial medicinal chemistry efforts led to discovery of compound 28, a moderately potent, selective inhibitor against BRD4 protein with IC50 = 33 nM. And compound 28 with notable antiproliferative potency (IC50 = 110 nM) was identified in HL-60 (human promyelocytic leukemia) cancer cell lines.32 However, the pharmacokinetics experiment exhibited that the BRD4 inhibitor 28 showed poor in vitro microsomal stability in human, rat, and mouse (MF% = 21.2, 17.6, 13.2, respectively). These results mean that 28 cannot be a potent candidate for further research.

As we began to focus on improving the pharmacokinetics properties, docking study and SAR evaluation were utilized to generate novel analogues of compound 28. Our previous reports have showed that 7-methylimidazo[1,5-a]pyrazin-8(7H)-one of 28 exhibited the strong inhibition potency, acting as KAc mimic.31−33 The docking process was utilized to elaborate the interaction between the moiety and BRD4 protein. The pyridone carbonyl of the compound forms a hydrogen bond with the NH2 of Asn140 and the N-methyl moiety occupies a small hydrophobic pocket, which is vital to stabilize the complexes. Moreover, the phenyl ether moiety of inhibitor 28 occupies a hydrophobic pocket formed by the side chains W81, P82, and F83 (WPF) while the ethylsulfonyl stretched into the ZA loop regions. The binding mode of compound 28 in the Kac pocket of BRD4(1) (PDB id: 3P5O) was exhibited in Figure 2. Based on the information, we explore improvement of the pharmacokinetics properties of inhibitor 28 by focusing on modifications of the phenyl ether and ethylsulfonyl moiety for keeping binding potency with BRD4 protein.

Figure 2.

Figure 2

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Molecular mimic docking conformation. (A) Docking mode of inhibitor 28 (purple). (B) Docking mode of inhibitor ABBV-075 (blue). (C) Superimposition docking mode of inihibitor 28 (purple) and Abbv-075 (blue).

To test our conjecture, compounds 16–20 (Table 1) containing differently substituted phenyl groups that stretched into the WPF pocket, were designed and synthesized to improve pharmacokinetics properties. Gratifyingly, compounds 16–20 exhibited similar BRD4 binding potency to compound 28. Based on the encouraging results, the metabolic stability of these compounds was evaluated in a liver microsome assay. The data indicated that 3,4,5-the trifluorophenyl substituent (16) provided moderate stability in rat (MF% = 55.8) and human (MF% = 54.3) liver microsomes, although in the 3,4,5-trifluorophenyl substituent exhibited poor stability in mouse (MF% = 36.0). Introducing methyl (18, 19) and isopropyl (20) groups both failed to provide an improvement in metabolic stability. Maintaining mono fluoro substituent in the site of phenyl led to markedly improved liver microsome stability (compound 17 and 21). Especially, compound 17 with para-fluorophenyl substituent showed more excellent liver microsome stability in human (MF% = 95.2) than the lead compound 28 (MF% = 21.2) in vitro.

Table 1. BRD4 Binding Activities and Pharmaceutical Properties of Compounds 16–28.

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ID R1 R2 BRD4/BD1(IC50nM)a BRD4/BD2 (IC50nM) HL60b IC50 (μM) RajiInh%(2 μM) BxPC3Inh%(2 μM) MF%c
Hum Rat Mouse
16 3,4,5-tri-F-phenyl Et 46 140 0.59 46.0 28.7 55.8 54.3 36.0
17 p-F-phenyl Et 30 29 0.045 39.5 38.4 95.2 76.2 65.6
18 2-Me-5-F- phenyl Et 22 34 0.44 33.8 2.9 13.2 7.6 11.2
19 2-F-5-Me- phenyl Et 46 21 0.27 49.9 28.8 14.1 5.7 4.6
20 p-isopropylphenyl Et 49 36 0.11 50.4 35.4 13.1 3.9 17.2
21 p-F-phenyl Me 44 NT 0.37 24.2 25.3 100 78.0 75.9
22 p-Br-pheny Me 37 44 0.23 33.1 34.8 66.7 54.2 61.2
23 m-Br-pheny Me 57 61 0.45 29.4 36.1 45.9 34.9 67.2
24 p-3,5-Dimethy lisoxazole-pheny Et 64 50 0.51 22.9 23.2 54.3 59.1 48.2
25 m-3,5-Dimethy lisoxazole-pheny Et 92 81 0.53 19.7 25.1 NT NT NT
26 p-3,5-Dimethy lisoxazole-pheny Me 141 153 1.12 23.7 26.4 NT NT NT
27 p-3,5-Dimethy lisoxazole-pheny Me 162 179 1.23 28.9 31.7 NT NT NT
28 2,4-di-F-phenyl Et 33 25 0.11 46.23 33.2 21.2 17.6 13.2
JQ1     87 79 0.87 47.9 31.1      
Abbv-075     39 47 0.12 51.2 42.7 60.8 69 60.9
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a

Data are expressed as the mean ± SD from the dose–response curves of at least three independent experiments.

b

IC50 values are shown as mean values of at least three determinations unless specified otherwise.

c

The percent of residue via liver microsomes and each experiment was performed at at least three times.

Unexpectedly, triple fluoro substituents (compound 16) were pleasingly potent and selective for BRD4(1) due to a significant reduction in BD2. 3,5-Dimethy lisoxazole substituent (compounds 24–27) was further utilized to reduce lipophilicity and improve physicochemical property, which led to the decrease of potency for BRD4(1) protein. The docking models showed that large volume of substituents at phenyl ether moiety of compounds 24–27 cannot occupy a hydrophobic part of the WPF (Figure 3). However, the mono bromo substituted derivatives (22 and 23) did not show more potent BRD4 binding activities than compound 28. Based on the information, diverse substituents on the phenyl ether moiety of inhibitor 28 play vital roles in binding into BRD4 protein. Interestingly, we discovered that ethyl sulfonamide (17, 24, 25) exhibited more potent activities than methyl sulfonamide (21, 26, 27), which interacted with the conserved residue at the ZA loop.

Figure 3.

Figure 3

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Molecular mimic docking conformation (PDB id: 3P5O). (A) Docking mimic mode of inhibitor 24 (yellow). (B) Superimposition mimic docking mode of inhibitor 24 (yellow) and 28 (purple).

Previously, we reported that BRD4 inhibitors exhibited significantly potent antiproliferation activities in hematologic malignancies such as MV4-11, Human myeloid monocyte leukemia cell.33 Herein, the antiproliferation potency of these compounds was evaluated in the hematologic malignancies (HL-60 (promyelocytic cell line), Raji (lymphoblast-like cell line)) and solid tumor (BxPC-3 (human pancreatic cancer cell line)). Especially, compounds 17 and 28 showed robust antiproliferation potency in HL-60 cell lines (IC50 = 45 and 11 nM, respectively). Meanwhile, compound 17 showed antiproliferation Inh% of 38.4 in the BxPC-3 cell line with 2 μM (Table 1). In addition to the MTT assay, the inhibitory effects of compound 17 on the tumorigenicity of cells in vitro were evaluated with plate clone-forming tests (Figure 4). Compound 17 exhibited prominent drug potency in BxPC-3 cells (2 μM compound 17 reduced plate colony growth by more than 50%).

Figure 4.

Figure 4

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Plate clone-forming potency of inhibitor 17 in BxPC-3 cell lines.

Drug metabolism and pharmacokinetics (DMPK) properties are vital for the development of candidates in clinical trials. Compounds 16–24 and 28 have excellent protein binding activities and potency of antiproliferation in cell lines, the DMPK properties of which were evaluated in in vitro microsomal stability (Table 1). The data indicated that the 3,4,5-tri-F-phenyl substituent (16) provided moderate stability in rat (MF% = 55.8) and human (MF% = 54.3) liver microsomes. However, the mono fluoro substituent in the site of phenyl led to markedly improved liver microsome stability. Compounds 17 and 21 showed excellent liver microsome stability in human (MF% = 95.2 and 100, respectively), and compound 17 exhibited higher potency for BRD4(1) with IC50 = 30 nM. Therefore, molecular 17 was further used to explore the mechanism of inducing apoptosis and anticancer potency in vivo.

Based on the in vitro results, we carried out in vivo studies to investigate the efficacy of compound 17 in xenograft models of pancreatic cancer. All treatment groups had no significant impact on animal body weight throughout the study (Figure 5A). It is intriguing that single agent treatment of compound 17 exhibited splendid cancer regression potency and reduced the tumor volume to almost 65% with 50 mkd (Figure 5B and S1). Immunohistochemical (IHC) analyses demonstrated that 17 downregulated c-Myc, up-regulated the hexamethylene bisacetamide inducible protein 1 (HEXIM1), and suppressed cell proliferation (Ki-67 stain) in the tumor tissues compared with normal saline (Figure 5C). Collectively, these findings elucidated that compound 17 was worthy for further investigation as BET inhibitor in preclinical trials.

Figure 5.

Figure 5

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Effects of compound 17 on Pan02 tumor xenografts growth. (A) Average weight of each daily dosing group of 17 and 5-fluorouracil (30 mg/kg/2 day via i.p.) and con. (B) Tumor growth inhibition rate of compound 17 in vivo by weight. (C) Immunohistochemistry for c-Myc, HEXIM1, Ki-67 and hematoxylin and eosin (HE) staining of tumor tissues with 17 treatment groups compared with the normal saline treatment group.

Molecular 17 has exhibited robust antiproliferation in cancer line and cancer regression potency in vivo. Nevertheless, the localization of the sites recognized by the ligands in cells was further explored via fluorescent probe. Next, we designed and synthesized the fluorescent ligand 31 (Figure S2) based on compound 17. Spectroscopic properties of fluorescent ligand 31 were assessed, including the ultraviolet absorption and the emission spectra. The absorption spectrum of compound 31 is characterized by absorption maxima at 480 nm (Figure 6A). The data of emission spectra showed that the increase in polarity of the solutions (from 80% dioxane to the aqueous buffer in PBS) led to around 10-fold increase in the quantum yield (Figure 6B). Then the specific localization was assessed in the human pancreatic cancer cell line BxPC-3. The data indicated that our BET inhibitor 17 exhibited specific nuclei localization by the colocalization with the nuclei-specific dye Hoechst33242. The merged figures uncovered a clear superimposition between the Hoechst33242 signal and the green signal of compound 31 (Figure 7).

Figure 6.

Figure 6

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Spectroscopic properties of fluorescent ligand 31. (A) Absorption spectra of compound 31 in solutions varying from aqueous to 80% dioxane/water (v/v) PBS. (B) Influence of the polarity of the medium on the fluorescence of compound 31 investigated by the addition of dioxane (indicated in % v/v) in PBS measured at a λmax of 480 nm.

Figure 7.

Figure 7

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Specific localization in BxPC-3. (A) Compound 31 exhibited specific nuclei localization in the human pancreatic cancer cell line BxPC-3. (B) Nuclei-specific dye Hoechst33342. (C) Merged images of panels A and B.

In summary, the pharmaceutical properties of initial compound 28 were directed by structure-based drug design to improve liver microsome stability. Compound 17 with nanomolar BRD4 potency is soluble, permeable, and reduced the tumor volume in xenograft models of pancreatic cancer in mice. In addition, fluorescent probe and nuclei-specific dye were performed to evaluate apoptosis-inducing of compound 17 via intranuclear potency in BXPC-3 cell line. Our results showed that compound 17 exhibited significant druglike properties and developability, and further preclinical evaluation of compound 17 is currently underway.

Glossary

Abbreviations

BRD4

bromodomain-containing protein4

IHC

immunohistochemical

PTM

post-translational modification

CDK9

Cyclin-dependent kinase 9

SAR

structure activity relationship.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00474.

  • Compound synthesis, spectroscopic characterization, and biology experimental procedures (PDF)

This study was supported by the Natural Science Foundation of Jiangsu Province (No. BK 20141349), the China National Key HiTech Innovation Project for the R&D of Novel Drugs (No. 2013ZX09301303-002), and China Scholarship Council.

The authors declare no competing financial interest.

Supplementary Material

ml9b00474_si_001.pdf (593.8KB, pdf)

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Supplementary Materials

ml9b00474_si_001.pdf (593.8KB, pdf)

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