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. 2023 Aug 1;14(8):1113–1121. doi: 10.1021/acsmedchemlett.3c00251

Discovery of N-(4-(Aminomethyl)phenyl)-5-methylpyrimidin-2-amine Derivatives as Potent and Selective JAK2 Inhibitors

Yang Tian †,‡, Songhui Qin ∥, Fang Zhang †, Jing Luo †, Xi He †, Yi Sun †, Tao Yang ∥,*
PMCID: PMC10424325  PMID: 37583815

Abstract

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The JAK2V617F mutation leads to JAK2 autophosphorylation and activation of downstream pathways, eventually resulting in myeloproliferative neoplasms (MPNs). Selective inhibitors showed advantages in terms of side effects; therefore, there is an urgent need to develop novel selective JAK2 inhibitors for treating MPNs. In this study, we described a series of N-(4-(aminomethyl)phenyl)pyrimidin-2-amine derivatives as selective JAK2 inhibitors. Systematic exploration through opening the tetrahydroisoquinoline based on the previous lead compound 13ac led to the discovery of the optimal compound A8. Compound A8 showed excellent potency on JAK2 kinase, with an IC50 value of 5 nM, and inhibited the phosphorylation of JAK2 and its downstream signaling pathway. Moreover, A8 exhibited 38.6-, 54.6-, and 41.2-fold selectivity for JAK1, JAK3, and TYK2, respectively. Compared to the lead compound, A8 demonstrated much better metabolic stabilities, with a bioavailability of 41.1%. These findings suggest that A8 is a relatively selective JAK2 inhibitor, deserving to be developed for treating MPNs.

Keywords: JAK2, Selectivity, Inhibitors, Myeloproliferative neoplasms, Pharmacokinetics

Myeloproliferative neoplasms (MPNs) are hematological disorders characterized by the overproduction of one or more mature myeloid blood cell lineages.1 MPNs are mainly divided into three categories: essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). As the illness progresses, both ET and PV may potentially convert to the more severe MF.2,3 Clinical studies on MPNs show that about 90% of patients carry mutations in Janus kinase 2 (JAK2), calreticulin (CALR), or thrombopoietin receptor (MPL).4−6 Among them, the JAK2V617F mutation plays a key role; in PV patients, this mutation accounts for 95%, while in ET and MF patients, it accounts for 50%, respectively.4,7,8 Therefore, JAK2 is an essential target for the treatment of MPNs.9

The JAK family consists of four subtypes, namely JAK1, JAK2, JAK3, and TYK2. This family plays a function in the cell through a variety of cytokines, such as interleukin, interferon, erythropoietin, thrombopoietin, and growth hormone.10−12 Among them, JAK2 participates in the growth and development of bone marrow cells through IL-3, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), and thrombopoietin (TPO).13 Since the discovery of the JAK2V617F mutation in MPNs in 2005, there has been considerable development of JAK2 inhibitors. A large number of JAK2 drugs targeting MPNs are in the clinical research stage, such as Lestaurtinib (CEP701), Momelotinib (CYT-387), Gandotinib (LY2784544), BMS-911543, Ilginatinib, and Zotiraciclib.14−23 Ruxolitinib, Fedratinib, and Pacritinib (Figure 1) were approved by the FDA in 2011, 2019, and 2022, respectively.

Figure 1.

Figure 1

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Representative drugs in clinical trials or launched JAK2 inhibitors.

JAK1 is widely involved in various inflammatory pathways, while JAK3 is only expressed in hematopoietic cells, bone marrow, and lymphocytes, and targeting JAK1/3 in MPNs leads to a series of side effects. The main target of Ruxolitinib is JAK1/2, which exhibited severe platelet abnormalities and immune system suppression in long-term follow-up.24,25 Fedratinib, inhibiting both JAK2 and FLT3, has the risk of causing Wernicke’s encephalopathy (WE), which was given a black box warning by the FDA.26 Similarly, the nonselective JAK2 inhibitor Pacritinib caused intracranial hemorrhage, heart failure, and cardiac arrest, which led to limited clinical application.27 Except for BMS-911543 and Ilginatinib, other clinical or research drugs have varying inhibitory activities on other subtypes of the JAK family. Therefore, developing highly selective JAK2 inhibitors is the trend to achieve low toxicity and high-efficiency therapeutic effects.

Our previous study identified a class of N-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine derivatives as selective JAK2 inhibitors.28 Although the preferred compound 13ac showed good selectivity within the human kinome, there is still room for improvement in the selectivity of JAK1, JAK3, and TYK2 due to the high homology of the catalytic domain JH1 among JAK families. Besides, compound 13ac demonstrated poor pharmacokinetic properties. Therefore, based on compound 13ac, we tried to optimize for a better JAK2 inhibitor. During the previous research on JAK2 inhibitors, we found that the hydrophilic end of compound 13ac is located in the solvent exposure region, where it has a significant impact on the selectivity.28 In addition, the terminally saturated isoquinoline structure might be one of the reasons for poor metabolism in vivo. Therefore, we tried to destroy the tetrahydroisoquinoline to change the spatial conformation of the terminal substituents and finally improve the family selectivity and metabolic stability. As shown in Figure S1, compared with 13ac, the key hydrogen bonds between the ring-opened compound and the binding pocket remain unchanged. However, the conformation of the hydrophilic end changed direction, and the pyrazole formed a water bridge hydrogen bond with a protein residue (ASN981). These phenomena suggest that the above modification strategy is feasible. Herein, we describe the design, synthesis, and biological evaluation of a series of N-(4-(aminomethyl)phenyl)pyrimidin-2-amine derivatives, leading to the discovery of potential selective JAK2 inhibitors.

The syntheses of the N-(4-(aminomethyl)phenyl)pyrimidin-2-amine derivatives A1–A18 are described in Scheme 1. The commercially available compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1 was used as the starting material. Under potassium carbonate, intermediate 1 is subjected to isopropyl substitution to afford intermediate 2. Subsequently, the boronate 2 and 2,4-dichloro-5-methylpyrimidine were coupled to obtain intermediate 3 via a Suzuki coupling reaction. Pyrimidine intermediate 3 and aniline were coupled by Buchwald–Hartwing reaction to give intermediate 4. Next, the Boc protecting group was removed by TFA to afford the desired intermediate 5. Finally, derivatives A1–A18 were synthesized by amidation or sulfonylation.

Scheme 1. Preparation of A1–A18.

Scheme 1

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Reagents and conditions: (a) 2-iodopropane, K2CO3, acetonitrile, reflux; (b) 2,4-dichloro-5-methylpyrimidine, PdCl2(dppf)2, K2CO3, dioxane/EtOH/water (v/v/v, 7/3/4), 80 °C, 2 h; (c) aniline derivatives, dioxane, reflux, 4 h, N2 atmosphere; (d) TFA, DCM; (e) appropriate acid, DIEA, HATU, DCM, rt; (f) appropriate acid chloride, DIEA, DCM, 0 °C–rt; (g) appropriate sulfonyl chloride, DIEA, DCM, rt.

According to the previous research, to explore the activity of compounds against JAK2V617F, we selected SET-2 cells with high expression of JAK2V617F and Ba/F3 JAK2V617F cells. Considering that 13ac had a certain inhibitory activity on FLT3, MOLM-13 cells were used for preliminary selectivity exploration. Improving metabolic stability is one of the purposes of this research; therefore, in the initial screening, the activity against liver microsomes in vitro was investigated. First, we obtained compounds A1 and A2 by opening the tetrahydroisoquinoline ring and retaining the original substituents. Table 1 summarizes the results: compared with compound 13ac, the activities of A1 and A2 on SET-2 and Ba/F3 JAK2V617F decreased to varying degrees but did not disappear completely. Surprisingly, the kinase activity screen indicated that the ring-opening strategy retained the activity on JAK2. In addition, in terms of metabolic stability, A1 and A2 were similar to 13ac, suggesting that these substituents might be unsuitable. To investigate the effect of the double bond, we introduced a saturated substituent to obtain compound A3. Although the metabolic stability of A3 was slightly increased, its activity on Ba/F3 JAK2V617F cells and JAK2 disappointingly decreased significantly. The tails of A1 and A3 belong to long-chain substituents, and the fixed conformational effects of unsaturated structures might cause the difference in activity. This result also suggested that unsaturated bonds were vital in maintaining the activity; therefore, we introduced different short-chain unsaturated substituents and their isosteres. According to the above ideas, compounds A4–A7 were synthesized, among which A4 and A7 demonstrated the best cell and kinase activities. In addition, compounds A4–A7 all showed more than 10-fold selectivity to MOLM-13, suggesting that short-chain substituents might have good selectivity for FLT3. Due to the instability of the terminal halogen, compounds A4 and A5 showed poor metabolic stability, and their half-life in liver microsomes was no more than 1 h. Surprisingly, the double bond substituent (A6) and cyclopropyl group (A7) performed well, with t1/2 > 100 min, which was significantly improved compared to compound 13ac.

Table 1. Structures and Bioactivities of Compounds A1–A18.

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graphic file with name ml3c00251_0009.jpg

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a

IC50 = compound concentration required to inhibit tumor cell proliferation by 50%; data are expressed as the mean ± SEM from the dose–response curves of at least three independent experiments.

b

% control = remaining active kinase percentage.

c

Human liver microsomal metabolism.

Considering the metabolic instability of amide bonds in vivo, we tried to replace them with sulfonamides and finally obtained compounds A8–A12. This series of compounds exhibited excellent activity on SET-2, BaF3 JAK2V617F, and JAK2; some were even better than 13ac. The unsaturated structure of short-chain compounds demonstrated a weak influence: for A8 and A9, the IC50 values on Ba/F3 JAK2V617F cells are 25.3 and 69 nM, and the potencies on JAK2 are −1 and 0, respectively. In this series, comparing the results of compounds A9, A10, and A11, short-chain substituents showed certain advantages in activity and selectivity. In addition, as we speculated, the metabolic stability of compounds A8–A12 was significantly improved after replacing the amide bond. The design strategy of this study involved opening the ring of saturated tetrahydroisoquinoline. The substituent and the benzene ring were connected through methylene; therefore, the number of methylenes was explored. Based on the substituent structure with good activity above, compounds A13–A18 were synthesized. Disappointingly, the inhibitory activities on cells and JAK2 kinase were significantly reduced. We speculated that the increased linker might affect the conformation of substituents in the hydrophilic pocket, thereby affecting the activity. In addition, comparing compounds A3 and A14, A8 and A18, the long chain reduced the metabolic stability.

After the above optimization, compounds A2, A4, A6, A7, A8, A9, and A12 were comparable or even superior to 13ac in cell activity and selectivity, so the kinase selectivity of these compounds was tested. It can be seen from Table 2 that, compared with 13ac, the JAK subtype selectivity of compounds A2, A4, and A6 decreased significantly. The selectivity of compound A7 against JAK1 and JAK3 was enhanced significantly, while the selectivity on TYK2 was somewhat reduced. All compounds except A2 showed increased selectivity for FLT3, suggesting a potential safety improvement. It was worth mentioning that the selectivity of the sulfonamide derivatives was greatly improved, indicating the essential function of the sulfonamide structure in the selectivity. In addition, the kinase assay in this study targets the JAK2-JH1 domain; considering that there is a cysteine residue in the JH2 pseudokinase domain, compound A8 with potentially the covalent warhead might bond to JAK2 covalently. We then expressed the JAK2-JH2 protein and measured the affinity of A8 to JAK2-JH2 through fluorescence polarization assay. The results in Figure S2 show that A8, the same as 13ac, exhibited an affinity to JAK2-JH2 with an IC50 value of more than 10 μM. This result proved that A8 was an ATP-competitive inhibitor.

Table 2. Kinase Selectivity of the Preferred Compounds.

  Kinase IC50a (nM)(Selectivity (fold vs JAK2))
Compd JAK1 JAK2 JAK3 TYK2 FLT3
A2 43 (6.1) 7 54 (7.7) 43 (6.1) 108 (15.4)
A4 73 (24.3) 3 166 (55.3) 33 (10) 206 (68.7)
A6 106 (21.6) 8 208 (41.6) 77 (9.6) 320 (40)
A7 87 (21.7) 4 156 (39) 62 (15.5) 311 (77.7)
A8 193 (38.6) 5 273 (54.6) 206 (41.2) 467 (93.4)
A9 142 (23.7) 6 287 (47.8) 192 (32) 412 (68.7)
A12 178 (35.6) 5 265 (53) 204 (40.8) 297 (59.4)
13ac 42 (14) 3 94 (31) 75 (25) 62 (20.7)
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a

IC50 data are detected by Eurofins Discovery.

Furthermore, to further examine the metabolic stability of these compounds, we conducted in vivo pharmacokinetic studies on compounds A8, A9, and A12; the results are shown in Table 3. Compared with 13ac, the pharmacokinetic properties of the three compounds exhibited significant promotion, and they were more suitable for oral administration in future in vivo experiments. Among the three compounds, A8 had the highest exposure, with a Cmax of 121.4 ng/mL and an AUC0-t of 3517.8 ng·h/mL, about 13 times that of 13ac. In summary, compound A8 was preferred, and further research was conducted on A8.

Table 3. In Vivo Pharmacokinetic Properties of the Preferred Compounds.

  ADME Parametera
Compd Cmax(ng/mL) tmax(h) T1/2(h) Clz(L/h/kg) AUC0-t(ng·h/mL) F (%)
A8 121.4 ± 23.2 1.4 ± 0.5 5.2 ± 1.0 17.7 ± 8.6 3517.9 ± 129.4 41.1
A9 77.8 ± 12.5 1.0 ± 0.2 6.3 ± 2.0 20.4 ± 9.8 1556.8 ± 210.3 35.7
A12 89.3 ± 21.1 1.6 ± 0.3 3.5 ± 1.1 21.3 ± 10.4 2011.6 ± 189.4 40.5
13ac 51.1 ± 26.5 0.9 ± 0.4 1.8 ± 0.5 28.8 ± 9.5 253.6 ± 24.1 25.7
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a

Sprague–Dawley rats (n = 5) were treated at a dose of 5 mg/kg as a solution (2% ethanol and 1% Tween 80, pH 5).

In the previous study, 13ac was screened within the human kinome. Therefore, to study the selectivity of A8, the top 50 kinases with potential activity were selected for screening, and the results are shown in Figure 2. In addition to the potency of the JAK family, A8 demonstrated inhibitory effects on kinases such as LCK, LYN, and FAK. According to Table S1 in the Supporting Information, A8 exhibited 50-fold or higher selectivity compared to these kinases. In general, A8 was a potential candidate with good selectivity.

Figure 2.

Figure 2

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Kinome-wide selectivity profiling of compound A8 with KinaseProfile assay by Eurofins Discovery. Measurements were performed at a concentration of 1 μM of the inhibitor in duplicate. The % percent control means remaining active kinase percentage, and DMSO was used as a control. TREEspot image was mapped with the KinMap software tool provided by Cell Signaling Technology, Inc. (www.cellsignal.com).

To further explore the function of A8 on the JAK2-STAT signaling pathway, we investigated the phosphorylation levels of JAK2 and its related proteins in Ba/F3 JAK2V617F cells by Western-blot experiments. As shown in Figure 3, A8 inhibited JAK2, STAT3, and STAT5 phosphorylation in a dose-dependent manner, consistent with the reported type I JAK2 inhibitor 13ac. Besides, A8 exhibited inhibition of AKT phosphorylation. The above results indicated that A8 inhibited the activation of the JAK2-STAT signaling pathway by blocking the phosphorylation of JAK2 and its downstream substrates in Ba/F3 JAK2V617F cells. As mentioned above, the JAK2 signaling pathway is widely involved in cell proliferation, growth, differentiation, and other processes, so we explored the effect of compound A8 on cycle and apoptosis in Ba/F3 JAK2V617F cells. As shown in Figure 4, compared with the positive compound 13ac, A8 arrested the cell cycle in the G0/G1 phase at a concentration of 16 nM, and this effect was concentration-dependent. In terms of apoptosis, similar to 13ac, A8 significantly induced apoptosis at a concentration of 40 nM (Figure 5). The above results indicated that A8 exerted antitumor activity by inducing apoptosis.

Figure 3.

Figure 3

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(A) Inhibition of JAK2 signaling pathway by A8 in Ba/F3 JAK2V617F cells. (B) Data was statistically analyzed, Dunnett’s t test vs control: *, P < 0.05; **, P < 0.01; ***, P < 0.001.

Figure 4.

Figure 4

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(A) Cell cycle effects of A8 on Ba/F3JAK2V617F cells. Cells were treated with increasing concentrations of A8 and 13ac for 24 h, harvested, fixed, and stained with propidium iodide prior to flow cytometric analysis. (B) Data was statistically analyzed, Dunnett’s t test vs control: *, P < 0.05.

Figure 5.

Figure 5

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(A) Effects of A8 and 13ac on the induction of apoptosis. Ba/F3JAK2V617F cells were treated with A8 and 13ac for 2 h at 20, 40, 80, 160, and 320 nM, respectively. (B) Data was statistically analyzed by Prism, Dunnett’s t test vs control: *, P < 0.05; **, P < 0.01; ***, P < 0.001.

Compound A8 enhanced the selectivity and pharmacokinetic properties by opening the ring of lead compound 13ac and innovatively introducing a sulfonamide structure. In the previous structure–activity relationship discussion, sulfonamide played a vital function in activity and selectivity; therefore, we tried to explore the mode of action of A8 and the JAK2 protein through molecular docking. It could be seen from Figure 6 that the structure with pyrimidin-2-amine still formed hydrogen bonds with the corresponding amino acids (TYR931 and LEU932), which was also a vital skeleton to maintain the activity of JAK2. In addition, the sulfonamide amine also demonstrated an important interaction. Among them, the amino group formed a hydrogen bond with the carbonyl group of LEU855, one oxygen atom of the sulfonyl group formed a hydrogen bond with the amino group of GLN853, and the other oxygen atom maintained a water bridge hydrogen bond with the phenolic hydroxyl group of TYR931. These three effects fixed the conformation of sulfonamides, which contributed to the increased selectivity of the JAK subtypes.

Figure 6.

Figure 6

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Molecular docking of A8 in the cavity of JAK2 protein (PDB code: 2XA4).29

Based on compound 13ac, we designed a series of selective JAK2 inhibitors through ring opening and optimization of the kinase solvent region. After tests on cell activity, metabolic properties, kinase selectivity, and in vivo pharmacokinetic properties, compound A8 was finally selected for further studies. A8 exhibited excellent inhibitory activity on JAK2, with an IC50 of 5 nmol/L. In addition, A8 exhibited 38-fold, 54-fold, and 41-fold selectivity for JAK1, JAK3, and TYK2, respectively. In Ba/F3 JAK2V617F cells, A8 significantly blocked the G0/G1 phase and induced apoptosis. It was worth mentioning that A8 had much better in vivo metabolic properties than 13ac, which was expected to be developed as a selective JAK2 inhibitor. The research in this paper provides a reference for the future development of a new generation of selective JAK2 inhibitors.

Acknowledgments

The authors greatly appreciate the financial support from the National Natural Science Foundation of China (82204191), the Natural Science Foundation of Sichuan Province (no. 2022NSFSC1341), and the China Postdoctoral Science Foundation (no. 2022M712279).

Glossary

Abbreviations

FLT3

Fms-like tyrosine receptor kinase 3

JAK1

Janus kinase 1

JAK2

Janus kinase 2

JAK3

Janus kinase 3

TFA

trifluoroacetic acid

PE

petroleum ether

EA

ethyl acetate

DCM

dichloromethane

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.3c00251.

  • Table S1, binding affinities of A8 with 52 protein kinases; Figure S1, design strategy based on 13ac by molecular docking; synthesis and characterization of intermediates and compounds, 1H and 13C NMR spectra, and biological assay methods (PDF)

  • Structure of 13ac (PDB)

Author Contributions

§ Y.T. and S.Q. contributed equally.

The authors declare no competing financial interest.

Supplementary Material

ml3c00251_si_001.pdf (3.4MB, pdf)
ml3c00251_si_002.pdb (729.8KB, pdb)

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Supplementary Materials

ml3c00251_si_001.pdf (3.4MB, pdf)
ml3c00251_si_002.pdb (729.8KB, pdb)

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