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Medicinal chemistry perspective of JAK inhibitors: synthesis, biological profile, selectivity, and structure activity relationship

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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.

Graphical abstract

The JAK-STAT pathway is mainly involved in pathological conditions such as Rheumatoid arthritis, Parkinson’s disease, Atopic dermatitis, Myeloproliferative neoplasm, T-cell leukaemia, Systemic lupus erythematosus, Haematological malignancies, and Idiopathic pulmonary fibrosis. The development of JAK-STAT pathway inhibitors mainly focusses on the inhibition of those diseased conditions. The in-depth review mainly describes the synthetic scheme, structure activity relationship, selectivity and biological activity of globally approved drugs along with recent development of small molecule inhibitors containing different heterocyclic scaffolds (pyridine, pyrimidine, imidazole, indole, pyrazole, pyrrole and triazine).

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Abbreviations

JAK1:

Janus kinase 1

JAK2:

Janus kinase 2

JAK3:

Janus kinase 3

TYK2:

Tyrosine-kinase 2

STAT:

Signal transducer and activator of transcription

IFNs:

Interferons

ILs:

Interleukins

ISGF3:

Interferon-stimulated gene factor 3

FDA:

Food and Drug Administration

RTK-:

Receptor tyrosine kinase

kDa:

Kilodalton

JH:

JAK homology

CNTF:

Ciliary neurotrophic factor

GM-CSF:

Granulocyte macrophage colony-stimulating factor

LIF:

Leukemia inhibitory factor

OSM:

Oncostatin M

CT-1:

Cardiotrophin-1

DNA:

Deoxyribonucleic acid

PDGF:

Platelet-derived growth factor

GH:

Growth hormone

EGF:

Epidermal growth factor

SOCS:

Suppressors of cytokine signaling

PTP:

Protein tyrosine phosphatase

TNF:

Tumor necrosis factor

RA:

Rheumatoid arthritis

VEGF:

Vascular endothelial growth factor

AD:

Atopic dermatitis

PD:

Parkinson’s disease

MHC:

Main histocompatibility complex

AMP:

Antimicrobial peptides

MPN:

Myeloproliferative neoplasm

EPO:

Erythropoietin

TPO:

Thyroid peroxidase

MF:

Myelofibrosis

SLE:

Systemic lupus Erythematosus

ISG:

Immune serum globulin

HM:

Hematological malignancies

IPF:

Idiopathic pulmonary fibrosis

nM:

Nano molar

L-DTTA:

Di-p-toluyl-l-tartaric acid

EMA:

European medicines agency

SEM:

2-(Trimethylsilyl)ethoxy methyl

CDI:

Carbonyldiimidazole

TIPSCl:

Triisopropylsilyl chloride

UK:

United Kingdom

SAR:

Structure activity relationship

DMF-DMA:

N,N-Dimethylformamide dimethyl acetal

DCM:

Dichloromethane

µM:

Micro molar

BTK:

Bruton tyrosine kinase

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Acknowledgements

This study was supported by the Acharya & B M Reddy College of Pharmacy in Bengaluru and the Indian Council of Medical Research (ICMR) under grants (No. 5/13/79/2020/NCD-III and No. 5/13/12/2020/NCD-III).

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Authors and Affiliations

  1. Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, Karnataka, India

    Lalmohan Maji, Sindhuja Sengupta, Gurubasavaraja Swamy Purawarga Matada & Pronoy Kanti Das

  2. School of Pharmacy, Sangam University, Atoon, Bhilwara, 311001, Rajasthan, India

    Ghanshyam Teli

  3. Department of Pharmaceutical Technology, Brainware University, Kolkata, West Bengal, India

    Gourab Biswas

  4. Department of Pharmacology Acharya, BM Reddy College of Pharmacy, Bengaluru, Karnataka, India

    Manjunatha Panduranga Mudgal

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  1. Lalmohan Maji
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Contributions

LM: conceptualization, original draft preparation, data collection, figure preparation and sorting of data. SS: original draft preparation, data collection and design. GSPM: supervising the work and scientific advisor. GT: primary editing and design. GB, PKD and MPM: secondary editing, proof reading, scientific evaluation.

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Correspondence to Gurubasavaraja Swamy Purawarga Matada.

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Maji, L., Sengupta, S., Purawarga Matada, G.S. et al. Medicinal chemistry perspective of JAK inhibitors: synthesis, biological profile, selectivity, and structure activity relationship. Mol Divers (2024). https://doi.org/10.1007/s11030-023-10794-5

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