Biological Evaluations and Computer-Aided Approaches of Janus Kinases 2 and 3 Inhibitors for Cancer Treatment: A Review
Abstract
:1. Introduction
2. The JAK2 Target
3. The JAK3 Target
4. JAK2 Inhibitors
5. Natural Derived JAK2 Inhibitors
6. JAK3 Inhibitors
7. Natural Derived JAK3 Inhibitors
8. Dual JAK2/3 Inhibitors
9. Summary
Author Contributions
Funding
Conflicts of Interest
References
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Compound | Activity | Disease | Toxic Effects |
---|---|---|---|
Ruxolitinib | IC50 = 2.8 nM | Polycythemia, Myelofibrosis, Various cancers | Diarrhea, abdominal pain, anemia, thrombocytopenia |
Pacritinib | IC50 = 23 nM | Myeloid leukemias, Myelofibrosis | Cardiovascular and hemorrhagic events |
AZD1480 | Ki = 0.26 nM | Myeloproliferative diseases, Solid tumors | Dizziness, anxiety, memory loss, ataxia, hallucinations, behavior changes |
Compound | Activity | Disease | Toxic Effects |
---|---|---|---|
Ritlecitinib | IC50 = 33.1 nM | Alopecia areata, Vitiligo, Ulcerative colitis, Rheumatoid arthritis, Crohn’s disease | Hepatotoxicity, Pruritus, Influenza |
Tofacitinib | IC50 = 1 nM | Transplant patients, Autoimmune disease, Rheumatoid arthritis | Infection, Cytopenias |
Compound | Anticancer Activity | Enzyme Activity | In Silico Analysis | References |
---|---|---|---|---|
JAK2 | ||||
3 | GI50 HEL = 4.3 μM GI50 MV4-11 = 11.0 μM GI50 HL60 = 16.5 μM | IC50 = 0.027 μM | Binds to the ATP-binding site, two hydrogen bonds with Leu932, a network-like alkyl-π interaction with the adjacent Ala880, Leu855, a hydrogen bond with Lys943 and another with Leu855. | [53] |
5 | IC50 HEL = 6.46 μM | IC50 = 0.0065 μM | Two hydrogen bonds with Leu932 and two π-π interactions with Tyr931, a hydrogen bond with Lys857, two hydrogen bonds with residue Tyr931, and hydrogen bonding with Ser936 and Asp939 via a water molecule, near the ATP-binding site. | [39] |
15 | IC50 MCF-7 = 6.39 µM IC50 A549 = 6.9 µM | - | Hydrogen bond with the residue Leu932, lipophilic interactions with the nonpolar amino acid residues Leu83, Leu855, Val863, Pro933, Met929, Ala880 and Leu932 within the receptor pocket. | [70] |
20 | IC50 = 0.01 μM | Hydrogen bonds with Glu930 and Leu932, hydrogen bonds with Lys882. | [74] | |
30 | - | IC50 = 0.022 μM | Hydrogen bonds with Pro375, Lys378, Asp381, Tyr390, and Asn433 | [80] |
34 | IC50 HEL = 5.6 µM IC50 SET-2 = 5.8 µM | IC50 = 0.04 µM | Two hydrogen bonds with Val629 and Glu627, hydrogen bond with the Lys640 side chain of the αD helix. | [28] |
46 | - | - | Hydrogen bonding interactions with Lys882, Arg980, Ser936, Asp939, and Lys943, carbon hydrogen bonding interactions with Leu932 and Leu855, and a sulfur bonding interaction with Lue855 | [71] |
55 | - | IC50 = 131.8 nM | Interacts with the amino acid residues Ala880, Val863, Tyr931, Leu855 Asp994, Leu983, Asn981 and Arg980 | [93] |
56–67 | IC50 TNBC = 90.09 to 172.16 μg/mL IC50 HEK293T = 732.52 to 1367.25 μg/mL | - | Interaction with residues of catalytic sites such as Leu983, Leu855, Val863, Arg980, Val863, Ala880, Leu855 and Leu932, in the binding pocket | [94] |
JAK3 | ||||
71 | - | IC50 = 2.1 nM | Bidentate hydrogen bonds with Leu905, and the Cys909, van der Waals contact with Leu956 and Leu828 in the ATP-binding pocket, a hydrogen bond with Arg953 | [96] |
72 | - | IC50 = 1.7 nM | Bidentate hinge hydrogen bonds with Leu905, covalent bonds with Cys909, two σ-π interactions and one σ-π interaction with amino acid residues Leu828 and Gly908, a hydrogen bond with Asp912 | [20] |
73 | - | IC50 < 0.1 nM | Hinge interaction pattern and the covalent binding of Cys909, two hydrogen bonds with Lys905, a hydrogen bond with Glu903. | [17] |
74 | IC50 K562 = 6.72 µM | IC50 = 0.057 µM | Interaction at the binding site with Glu930, Tyr931, Leu932, Ser936 and Gly993. | [97] |
81 | IC50 MOLM-16 = 1.83 nM | IC50 = 4.11 nM | Hydrogen bond interaction with Lys855, hydrogen bond interaction with Leu905, hydrophobic interactions with Leu905, Gly906, and Arg953 | [99] |
92 | IC50 A549 = 1.68 µM IC50 Huh-7 = 4.88 µM IC50 K562 = 2.13 µM | IC50 = 1.72 µM | - | [103] |
93 | - | EC50 = 1.4 μmol/L | Interaction with Val812, Ala829, Glu847, Met878, Leu881, Leu932 y Asp943. | [104] |
JAK2/3 | ||||
95 | - | IC50 JAK2 = 12.61 nM IC50 JAK3 = 15.80 nM | Hydrogen bonds in the hinge region with residues Glu930 and Lys932 of JAK2 and Glu903 and Lys905. | [49] |
97 | IC50 TF1 = 15.53 μM IC50 HEL = 17.90 μM | IC50 JAK2 = 13.00 nM IC50 JAK3 = 14.86 nM | Hydrogen bonds in the hinge region with residues Ser936 and Arg938. | [105] |
99 | IC50 TF1 = 18.10 μM IC50 HEL = 6.65 μM | IC50 JAK2 = 11.11 nM IC50 JAK3 = 10.24 nM | Hydrogen bonds with residues Y931 and L932 and hydrophobic contact with the hinge region, the G loop and the catalytic loop. | [106] |
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Vázquez-Jiménez, L.K.; Rivera, G.; Juárez-Saldivar, A.; Ortega-Balleza, J.L.; Ortiz-Pérez, E.; Jaime-Sánchez, E.; Paz-González, A.; Lara-Ramírez, E.E. Biological Evaluations and Computer-Aided Approaches of Janus Kinases 2 and 3 Inhibitors for Cancer Treatment: A Review. Pharmaceutics 2024, 16, 1165. https://doi.org/10.3390/pharmaceutics16091165
Vázquez-Jiménez LK, Rivera G, Juárez-Saldivar A, Ortega-Balleza JL, Ortiz-Pérez E, Jaime-Sánchez E, Paz-González A, Lara-Ramírez EE. Biological Evaluations and Computer-Aided Approaches of Janus Kinases 2 and 3 Inhibitors for Cancer Treatment: A Review. Pharmaceutics. 2024; 16(9):1165. https://doi.org/10.3390/pharmaceutics16091165
Chicago/Turabian StyleVázquez-Jiménez, Lenci K., Gildardo Rivera, Alfredo Juárez-Saldivar, Jessica L. Ortega-Balleza, Eyra Ortiz-Pérez, Elena Jaime-Sánchez, Alma Paz-González, and Edgar E. Lara-Ramírez. 2024. "Biological Evaluations and Computer-Aided Approaches of Janus Kinases 2 and 3 Inhibitors for Cancer Treatment: A Review" Pharmaceutics 16, no. 9: 1165. https://doi.org/10.3390/pharmaceutics16091165