Biological Evaluations and Computer-Aided Approaches of Janus Kinases 2 and 3 Inhibitors for Cancer Treatment: A Review

Abstract

Cancer remains one of the leading diseases of mortality worldwide. Janus kinases 2/3 (JAK2/3) have been considered a drug target for the development of drugs to treat different types of cancer. JAK2/3 play a critical role in innate immunity, inflammation, and hematopoiesis by mediating the signaling of numerous cytokines, growth factors, and interferons. The current focus is to develop new selective inhibitors for each JAK type. In this review, the current strategies of computer-aided studies, and biological evaluations against JAK2/3 are addressed. We found that the new synthesized JAK2/3 inhibitors are prone to containing heterocyclic aromatic rings such as pyrimidine, pyridine, and pyrazolo [3,4-d]pyrimidine. Moreover, inhibitors of natural origin derived from plant extracts and insects have shown suitable inhibitory capacities. Computer-assisted studies have shown the important features of inhibitors for JAK2/3 binding. Biological evaluations showed that the inhibition of the JAK receptor affects its related signaling pathway. Although the reviewed compounds showed good inhibitory capacity in vitro and in vivo, more in-depth studies are needed to advance toward full approval of cancer treatments in humans.

Keywords: JAK2; JAK3; anticancer; compounds.

Figure 1

Structure of the JAK2 kinase domain (PDB ID: 8BM2, JH1; 7F7W, JH2) (A) and domain structure of JAK2 (B). Magenta color indicates the JH2 domain, and green color represents the JH1 of JAK2. The 3D structure image was generated with PyMOL software v. 3.0.3 (https://www.pymol.org/).

Figure 2

Cys909 residue (sticks) in the JAK3 structure (PDB ID: 5TTV).

Figure 3

Chemical structures of heterosteroid derivatives 1 and 2 described by Mohamed et al. [52]. In the figure, the numbers in bold refer to the compounds described in the text, indicating their inhibitory values in distinct cancer cell lines. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 4

Chemical structure of the lead 4-piperazinyl-2-aminopyrimidine derivative described by Li et al. [53]. In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory values in JAK2 and distinct cancer cell lines. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 5

Chemical structure of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives synthesized by Yin et al. [39]. In the figure, the numbers in bold refer to the compounds described in the text, indicating their inhibitory values in JAK2. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 6

Chemical structures of 2,4-disubstituted quinazoline derivatives synthesized by Jyothi-Buggana et al. [54]. In the figure, the numbers in bold refer to the compounds described in the text, indicating their inhibitory values in JAK2. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 7

Chemical structure of methylseleninic acid (10). In the figure, the number in bold refers to the compound described in the text. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 8

Chemical structure of the lead 2-aminopyridine derivative evaluated by Ma et al. [58]. In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory value in JAK2. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 9

Chemical structure of the 2-aminopyrimidine derivative analyzed by Li et al. [59]. In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory values in JAK2 and cancer cell lines. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 10

Chemical structure of S-adenosylmethionine (13). In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory values in distinct cancer cell lines over time. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 11

Chemical structure of 2-((5-nitrothiazol-2-yl)carbamoyl)phenyl acetate (14). In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory values in a cancer cell line. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 12

Chemical structure of the 2-amino-4-aryl-6-(quinolin-2-ylthio)pyridine-3,5-dicarbonitrile derivatives synthesized by Nafie et al. [70]. In the figure, the numbers in bold refers to the compound described in the text, indicating their inhibitory values in distinct cancer cell lines. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 13

Chemical structure of the compound 1-nitro-2-acetylanthraquinone glycine (18). In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory values in distinct cancer cell lines. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 14

Chemical structure of bufothionine (19). In the figure, the number in bold refers to the compound described in the text. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 15

Chemical structure of the lead imidazopyrrolopyridine derivative evaluated by Xu et al. [74]. In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory values in JAK2. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 16

Chemical structures of thiazole aromatic alkylamino analogs evaluated by Sanachai et al. [75]. In the figure, the numbers in bold refer to the compounds described in the text, indicating their inhibitory values in JAK2 and cancer cell lines. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 17

Chemical structure of compounds 23 and 24 analyzed by Newton et al. [76]. In the figure, the numbers in bold refer to the compounds described in the text, indicating their inhibitory values in JAK2. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 18

Chemical structure of the 3β-acetoxy-5α-androstane derivative evaluated by Tantawy et al. [77]. In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory values in a cancer cell line. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 19

Chemical structure of compound 26 identified by in silico methods as a potential JAK2 inhibitor by Singh et al. [78]. In the figure, the number in bold refers to the compound described in the text. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 20

Chemical structure of compounds 27, 28, and 29 identified by computational techniques as potential JAK2 inhibitors by He et al. [79]. In the figure, the numbers in bold refer to the compounds described in the text. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 21

Chemical structure of the leading 9H-purine-2,6-diamine derivative obtained by Guo et al. [80]. In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory values in BRD4 and JAK2 proteins. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 22

Chemical structures of the macrocycles synthesized by Diao et al. [81]. In the figure, the numbers in bold refer to the compounds described in the text, indicating their inhibitory values in JAK2 and distinct cancer cell lines. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 23

Compounds 33, 34, and 35 evaluated by Virtanen et al. [28]. In the figure, the numbers in bold refer to the compounds described in the text, indicating their inhibitory values in JAK2 and distinct cancer cell lines. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 24

Chemical structures of the selected compounds based on furopyridine. In the figure, the numbers in bold refer to the compounds described in the text, indicating their inhibitory values in JAK2. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 25

Chemical structures selected as potential JAK2 inhibitors through drug repositioning by Yasir et al. [83]. In the figure, the numbers in bold refer to the compounds described in the text. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 26

Chemical structure of 3-deoxy-2β, 16-dihydroxynagilactone E (43). In the figure, the number in bold refers to the compound described in the text. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 27

Chemical structure of 2-deoxy-4β-propylcarbamate-pulchelin (44). In the figure, the number in bold refers to the compound described in the text. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 28

Chemical structure of compounds 45 and 46 selected from a virtual screening by Li W et al. [75]. In the figure, the numbers in bold refer to the compounds described in the text. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 29

Chemical structure of Rosmanol (47). In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory values in distinct cancer cell lines. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 30

Chemical structure of triptolide (48). In the figure, the number in bold refers to the compound described in the text. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 31

Chemical structure of proanthocyanidins (49). In the figure, the number in bold refers to the compound described in the text. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 32

Chemical structure of licochalcone H (50). In the figure, the number in bold refers to the compound described in the text. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 33

Chemical structure of the natural products evaluated by Pölläniemi et al. [7]. In the figure, the numbers in bold refer to the compounds described in the text, indicating their inhibitory values in JAK2. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 34

Chemical structure of compound 55 identified through high-throughput virtual screening as a potential JAK2 inhibitor by Shaikh et al. [93]. In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory value in JAK2. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 35

Chemical structures of compounds obtained from natural products (Upreti et al.) [94]. In the figure, the numbers in bold refer to the compounds described in the text. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 36

Chemical structures of the natural compounds analyzed by Vaziri-Amjad et al. [95]. In the figure, the numbers in bold refer to the compounds described in the text. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 37

Chemical structure of the pyrimidine-4,6-diamine derivative as a selective JAK3 inhibitor described by Yu et al. [96]. In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory value in JAK3. The figures was drawn and labeled with ChemDraw v. 19.0.

Figure 38

Chemical structure of the phenylpyrimidine derivative analyzed by Shu et al. [20] as a potential JAK3 inhibitor. In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory value in JAK3. The figures was drawn and labeled with ChemDraw v. 19.0.

Figure 39

Chemical structure of the 1H-pyrrolo [2,3-b]pyridine derivative evaluated on JAK3 by Forster et al. [17]. In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory value in JAK3. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 40

Chemical structure of 3-(4-phenyl-1H-imidazol-2-yl)-1H-pyrazole derivatives synthesized and evaluated by Zheng et al. [97]. In the figure, the numbers in bold refer to the compounds described in the text, indicating their inhibitory values in JAK3 and distinct cancer cell lines. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 41

Chemical structure of the pyrido [2,3-d]pyrimidin-7-one derivative synthesized as a potential JAK3 inhibitor by Su et al. [21]. In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory value in JAK3 and a cancer cell line. The figure was drawn and labeled with ChemDraw v. 19.0.

Figure 42

Chemical structure of hybrid and chimeric derivatives of 4,5-dihydro-4,4-dimethyl-1H-[1,2]dithiolo [3,4-c]quinoline-1-thiones obtained as potential JAK3 inhibitors by Medvedeva et al. [98]. In the figure, the numbers in bold refer to the compounds described in the text, indicating their inhibitory values in JAK3 Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 43

Chemical structure of the potential JAK3 inhibitor identified by structure-based high-throughput virtual screening by Wei et al. [99]. In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory values in JAK3 and cancer cell lines. The figures was drawn and labeled with ChemDraw v. 19.0.

Figure 44

Chemical structures of compounds 82–85 identified as potential JAK3 inhibitors using predictive techniques by Faris et al. [100]. In the figure, the numbers in bold refer to the compounds described in the text. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 45

Chemical structure of the compounds selected as potential JAK3/STAT inhibitors based on the pyrimidine-4,6-diamine structure by Faris et al. [101]. In the figure, the numbers in bold refer to the compounds described in the text. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 46

Chemical structure of Chinses herbal compounds analyzed by Su et al. [102]. In the figure, the numbers in bold refer to the compounds described in the text. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 47

Chemical structure of natural products from B. japanensis analyzed by Yan et al. [103] as potential JAK3 inhibitors. In the figure, the number in bold refers to the compound described in the text, indicating its inhibitory values in JAK3 and distinct cancer cell lines. The figures was drawn and labeled with ChemDraw v. 19.0.

Figure 48

Chemical structure of tubulosin (93). In the figure, the number in bold refers to the compound described in the text. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 49

Chemical structure of the compounds selected by Sanachai et al. [49] from pharmacophore models built from the commercial drug tofacitinib. In the figure, the numbers in bold refer to the compounds described in the text, indicating their inhibitory values in JAK2 and JAK3. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 50

Chemical structure of the lead compound (97) identified as a potential quinoxalinone-based dual JAK2/3 inhibitor by Sanachai et al. [105]. In the figure, the number in bold refers to the compound described in the text, indicating their inhibitory values in JAK2 and JAK3, and distinct cancer cell lines. Figures were drawn and labeled with ChemDraw v. 19.0.

Figure 51

Chemical structures of naphthoquinones identified as potential JAK2/3 inhibitors by Sanachai et al. [106]. In the figure, the numbers in bold refer to the compounds described in the text, indicating their inhibitory values in JAK2 and JAK3, and distinct cancer cell lines. Figures were drawn and labeled with ChemDraw v. 19.0.