Medicinal Chemistry Perspective of JAK Inhibitors: Synthesis, Biological Profile, Selectivity, and Structure Activity Relationship

Overview

Journal Mol Divers

Date 2024 Jan 18

PMID 38236444

Authors

Lalmohan Maji

Sindhuja Sengupta

Gurubasavaraja Swamy Purawarga Matada

Ghanshyam Teli

Gourab Biswas

Pronoy Kanti Das

Manjunatha Panduranga Mudgal

Affiliations

Soon will be listed here.

Abstract

JAK-STAT signalling pathway was discovered more than quarter century ago. The JAK-STAT pathway protein is considered as one of the crucial hubs for cytokine secretion which mediates activation of different inflammatory, cellular responses and hence involved in different etiological factors. The various etiological factors involved are haematopoiesis, immune fitness, tissue repair, inflammation, apoptosis, and adipogenesis. The presence of the active mutation V617K plays a significant role in the progression of the JAK-STAT pathway-related disease. Consequently, targeting the JAK-STAT pathway could be a promising therapeutic approach for addressing a range of causative factors. In this current review, we provided a comprehensive discussion for the in-detail study of anatomy and physiology of the JAK-STAT pathway which contributes structural domain rearrangement, activation, and negative regulation associated with the downstream signaling pathway, relationship between different cytokines and diseases. This review also discussed the recent development of clinical trial entities. Additionally, this review also provides updates on FDA-approved drugs. In the current investigation, we have classified recently developed small molecule inhibitors of JAK-STAT pathway according to different chemical classes and we emphasized their synthetic routes, biological evaluation, selectivity, and structure-activity relationship.

References

Darnell Jr J . STATs and gene regulation. Science. 1997; 277(5332):1630-5. DOI: 10.1126/science.277.5332.1630. View

Fu X, Kessler D, Veals S, Levy D, Darnell Jr J . ISGF3, the transcriptional activator induced by interferon alpha, consists of multiple interacting polypeptide chains. Proc Natl Acad Sci U S A. 1990; 87(21):8555-9. PMC: 54995. DOI: 10.1073/pnas.87.21.8555. View

Wilks A, Harpur A, Kurban R, Ralph S, Zurcher G, Ziemiecki A . Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Mol Cell Biol. 1991; 11(4):2057-65. PMC: 359893. DOI: 10.1128/mcb.11.4.2057-2065.1991. View

Wilks A . Two putative protein-tyrosine kinases identified by application of the polymerase chain reaction. Proc Natl Acad Sci U S A. 1989; 86(5):1603-7. PMC: 286746. DOI: 10.1073/pnas.86.5.1603. View

Krolewski J, Lee R, Eddy R, Shows T, Dalla-Favera R . Identification and chromosomal mapping of new human tyrosine kinase genes. Oncogene. 1990; 5(3):277-82. View

Velazquez L, Fellous M, Stark G, Pellegrini S . A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell. 1992; 70(2):313-22. DOI: 10.1016/0092-8674(92)90105-l. View

Muller M, Briscoe J, Laxton C, Guschin D, Ziemiecki A, Silvennoinen O . The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature. 1993; 366(6451):129-35. DOI: 10.1038/366129a0. View

Fu X . A transcription factor with SH2 and SH3 domains is directly activated by an interferon alpha-induced cytoplasmic protein tyrosine kinase(s). Cell. 1992; 70(2):323-35. DOI: 10.1016/0092-8674(92)90106-m. View

Shuai K, Stark G, Kerr I, Darnell Jr J . A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. Science. 1993; 261(5129):1744-6. DOI: 10.1126/science.7690989. View

10.

Hou J, Schindler U, Henzel W, Ho T, Brasseur M, McKnight S . An interleukin-4-induced transcription factor: IL-4 Stat. Science. 1994; 265(5179):1701-6. DOI: 10.1126/science.8085155. View

11.

Zhong Z, Wen Z, Darnell Jr J . Stat3 and Stat4: members of the family of signal transducers and activators of transcription. Proc Natl Acad Sci U S A. 1994; 91(11):4806-10. PMC: 43877. DOI: 10.1073/pnas.91.11.4806. View

12.

Liu X, Robinson G, Gouilleux F, Groner B, Hennighausen L . Cloning and expression of Stat5 and an additional homologue (Stat5b) involved in prolactin signal transduction in mouse mammary tissue. Proc Natl Acad Sci U S A. 1995; 92(19):8831-5. PMC: 41061. DOI: 10.1073/pnas.92.19.8831. View

13.

Xin P, Xu X, Deng C, Liu S, Wang Y, Zhou X . The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol. 2020; 80:106210. DOI: 10.1016/j.intimp.2020.106210. View

14.

Cai B, Cai J, Luo Y, Chen C, Zhang S . The Specific Roles of JAK/STAT Signaling Pathway in Sepsis. Inflammation. 2015; 38(4):1599-608. DOI: 10.1007/s10753-015-0135-z. View

15.

OShea J, Pesu M, Borie D, Changelian P . A new modality for immunosuppression: targeting the JAK/STAT pathway. Nat Rev Drug Discov. 2004; 3(7):555-64. DOI: 10.1038/nrd1441. View

16.

Jaime-Figueroa S, De Vicente J, Hermann J, Jahangir A, Jin S, Kuglstatter A . Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors. Bioorg Med Chem Lett. 2013; 23(9):2522-6. DOI: 10.1016/j.bmcl.2013.03.015. View

17.

Speirs C, Williams J, Riches K, Salt I, Palmer T . Linking energy sensing to suppression of JAK-STAT signalling: A potential route for repurposing AMPK activators?. Pharmacol Res. 2017; 128:88-100. DOI: 10.1016/j.phrs.2017.10.001. View

18.

Shaposhnikov A, Komarkov I, Lebedeva L, Shidlovskii I . [Molecular components of JAK/STAT signaling pathway and its connection with transcription machinery]. Mol Biol (Mosk). 2013; 47(3):388-97. DOI: 10.7868/s0026898413030130. View

19.

Hu X, Li J, Fu M, Zhao X, Wang W . The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021; 6(1):402. PMC: 8617206. DOI: 10.1038/s41392-021-00791-1. View

20.

Rodig S, Meraz M, White J, Lampe P, Riley J, Arthur C . Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell. 1998; 93(3):373-83. DOI: 10.1016/s0092-8674(00)81166-6. View