Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics DOI Creative Commons

Tian‐Hua Wei,

Meng‐Yi Lu,

Sihui Yao

et al.

MedComm – Oncology, Journal Year: 2024, Volume and Issue: 3(1)

Published: March 1, 2024

Abstract Janus Kinases (JAKs) play a crucial role as therapeutic targets for various cancers. However, the current JAK inhibitors (JAKi) available have limited benefits due to their lack of selectivity. This review focuses on structural analysis elucidate molecular determinants JAKs specificity and discovery design selective JAKi. It includes descriptions comparison different structures binding sites, comparative JAKi modes, detailed interaction fingerprints (IFPs), an extensive structure‐selectivity relationship (SSRs). Moreover, also explores challenges possibilities using computational structure‐based methods discovering designing Other approaches, such targeting pseudokinase domain, well covalent allosteric designs, are covered. Based this analysis, key corresponding rational medicinal chemistry strategies proposed facilitate development highly Overall, we aim enhance understanding explore that can lead effective in cancer therapy, thus improving prognosis patients.

Language: Английский

JAK inhibitors in the treatment of atopic dermatitis DOI
Raj Chovatiya, Amy S. Paller

Journal of Allergy and Clinical Immunology, Journal Year: 2021, Volume and Issue: 148(4), P. 927 - 940

Published: Aug. 24, 2021

Language: Английский

Citations

241
Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer DOI Creative Commons
Xue Chen,

Qinfan Yao,

Xinyu Gu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 19, 2023

Abstract The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism transmembrane transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, other specific molecules activate JAK-STAT signaling drive a series physiological pathological processes, including proliferation, metabolism, immune response, inflammation, malignancy. Dysregulated related genetic mutations are strongly associated activation cancer progression. Insights into structures functions have led development approval diverse drugs for clinical treatment diseases. Currently, been developed mainly target commonly divided three subtypes: cytokine or receptor antibodies, JAK inhibitors, STAT inhibitors. And novel agents also continue be tested in preclinical studies. effectiveness safety each kind drug warrant further scientific trials before put being applications. Here, we review current understanding fundamental composition function pathway. We discuss advancements JAK-STAT–related pathogenic mechanisms; targeted therapies various diseases, especially disorders, cancers; newly inhibitors; challenges directions field.

Language: Английский

Citations

234
JAK–STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review DOI Creative Commons
I‐Hsin Huang, Yi‐Teng Hung, Po‐Chien Wu

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Dec. 8, 2022

Atopic dermatitis (AD) is a chronic, inflammatory, pruritic form of dermatosis with heterogeneous manifestations that can substantially affect patients' quality life. AD has complex pathogenesis, making treatment challenging for dermatologists. The Janus kinase (JAK)–signal transducer and activator transcription (STAT) pathway plays central role in modulating multiple immune axes involved the immunopathogenesis AD. In particular, Th2 cytokines, including interleukin (IL)-4, IL-5, IL-13, IL-31, thymic stromal lymphopoietin, which contribute to symptoms chronic inflammation pruritus AD, are mediated by JAK–STAT signal transduction. Furthermore, regulation epidermal barrier modulation peripheral nerves related transduction pruritus. Targeting may attenuate these signals show clinical efficacy through suppression various pathways associated Topical oral JAK inhibitors variable selectivity have emerged as promising therapeutic options Notably, topical ruxolitinib, upadacitinib, abrocitinib were approved U.S. Food Drug Administration treating patients Accordingly, present study reviewed pathogenesis explored updated applications

Language: Английский

Citations

143
Innovation in the treatment of atopic dermatitis: Emerging topical and oral Janus kinase inhibitors DOI Creative Commons
Chisa Nakashima, Shigeto Yanagihara, Atsushi Otsuka

et al.

Allergology International, Journal Year: 2021, Volume and Issue: 71(1), P. 40 - 46

Published: Nov. 21, 2021

Atopic dermatitis (AD) is characterized by chronic, eczematous, severe pruritic skin lesions. The knowledge on the pathogenesis of AD driving development new drugs. From research results, it has been revealed that Th2 cell-mediated immunity, barrier dysfunction, and pruritus cause a vicious cycle AD. On other hand, Janus kinase (JAK)/signal transducers activators transcription (STAT) pathway are one essential signaling pathways in various inflammatory diseases including In particular, TSLP, IL-4, IL-13 IL-22 occupy an important position for immune reaction. Moreover, experimentally pan-JAK inhibitor suppress STAT3 activation improved function. Furthermore IL-31 contribute lot to chronic AD, transmitted via JAK-STAT pathway. Therefore, JAK inhibitors promising candidates treatment Here we review clinical trials topical dergocitinib; inhibitor, ruxolitinib; JAK1 JAK2 tofacitinib; JAK1, JAK2, JAK3 oral baricitinib; abrocitinib upadacitinib; inhibitor. Significant improvements symptoms were obtained each drug with low frequency adverse events. have ability improve quickly. emergence these would be regarded as innovation atopic dermatitis.

Language: Английский

Citations

131
Novel insights into atopic dermatitis DOI Creative Commons
Charles F. Schuler, Allison C. Billi, Emanual Maverakis

et al.

Journal of Allergy and Clinical Immunology, Journal Year: 2022, Volume and Issue: 151(5), P. 1145 - 1154

Published: Nov. 22, 2022

Language: Английский

Citations

126
Neuroimmune communication regulating pruritus in atopic dermatitis DOI Creative Commons
Martin Steinhoff, Fareed Ahmad, Atul Kumar Pandey

et al.

Journal of Allergy and Clinical Immunology, Journal Year: 2022, Volume and Issue: 149(6), P. 1875 - 1898

Published: March 23, 2022

Atopic dermatitis (AD) is a common, chronic-relapsing inflammatory skin disease with significant burden. Genetic and environmental trigger factors contribute to AD, activating 2 of our largest organs, the nervous system immune system. Dysregulation neuroimmune circuits plays key role in pathophysiology causing inflammation, pruritus, pain, barrier dysfunction. Sensory nerves can be activated by or endogenous factors, transmitting itch stimuli brain. On stimulation, sensory nerve endings also release neuromediators into skin, contributing again dysfunction, itch. In addition, dysfunctional peripheral central neuronal structures neuroinflammation, sensitization, elongation, neuropathic itch, thus chronification therapy resistance. Consequently, may targets treat pruritus AD. Cytokines, chemokines, proteases, lipids, opioids, ions excite/sensitize endings, which not only induces but further aggravates/perpetuates disruption, as well. Thus, targeted therapies for well pathway inhibitors (eg, kinase inhibitors) beneficial control AD either systemic and/or topical form. Understanding signaling will optimize approach all pathological mechanisms pruritus.

Language: Английский

Citations

90
Enhanced early skin treatment for atopic dermatitis in infants reduces food allergy DOI
Kiwako Yamamoto‐Hanada, T. Kobayashi, Masashi Mikami

et al.

Journal of Allergy and Clinical Immunology, Journal Year: 2023, Volume and Issue: 152(1), P. 126 - 135

Published: March 22, 2023

Language: Английский

Citations

51
JAK-STAT pathway inhibitors in dermatology DOI Creative Commons
Hélio Amante Miot, Paulo Ricardo Criado, Caio César Silva de Castro

et al.

Anais Brasileiros de Dermatologia, Journal Year: 2023, Volume and Issue: 98(5), P. 656 - 677

Published: May 23, 2023

The JAK-STAT signaling pathway mediates important cellular processes such as immune response, carcinogenesis, cell differentiation, division and death. Therefore, drugs that interfere with different patterns have potential indications for various medical conditions. main dermatological targets of inhibitors are inflammatory or autoimmune diseases psoriasis, vitiligo, atopic dermatitis alopecia areata; however, several dermatoses under investigation to expand this list indications. As should gradually occupy a relevant space in prescriptions, review presents the available drugs, their immunological effects, pharmacological characteristics, related clinical efficacy safety, aiming validate best practice.

Language: Английский

Citations

48
Optimal Use of Jak Inhibitors and Biologics for Atopic Dermatitis on the Basis of the Current Evidence DOI Creative Commons
Masahiro Kamata, Yayoi Tada

JID Innovations, Journal Year: 2023, Volume and Issue: 3(3), P. 100195 - 100195

Published: Feb. 24, 2023

Recently, Jak inhibitors such as baricitinib, upadacitinib, and abrocitinib were approved for the treatment of atopic dermatitis (AD) in addition to biologics, including dupilumab, tralokinumab, nemolizumab. The increase options can be a benefit patients with AD. Meanwhile, it could make difficult physicians choose best among those options. Biologics differ efficacy, safety, route administration, whether or not there is concern about immunogenicity evidence on comorbidities. Among three inhibitors, degree inhibition signal transducer activator transcription differs each inhibitor. Therefore, efficacy safety profiles are different. Physicians who treat AD biologics need understand current individual patients. In this review, we discuss how integrating knowledge mechanisms action potential significant adverse events these drugs, age comorbidities patient help achieve optimal clinical moderate-to-severe refractory topical agents.

Language: Английский

Citations

46
The JAK/STAT Pathway and Its Selective Inhibition in the Treatment of Atopic Dermatitis: A Systematic Review DOI Open Access
Aikaterini Tsiogka, Maria Kyriazopoulou,

George Kontochristopoulos

et al.

Journal of Clinical Medicine, Journal Year: 2022, Volume and Issue: 11(15), P. 4431 - 4431

Published: July 29, 2022

In recent years, the broadening understanding of pathogenesis atopic dermatitis (AD) has led to development novel therapeutic molecules, that target core inflammatory components disease. The Janus kinase (JAK)/signal transducer and activation transcription (STAT) pathway constitutes principal signaling cascade for a large number cytokines growth factors is involved in intracellular signal transduction subsequent regulation gene transcription. Current knowledge suggests robust T-helper (Th)-2 [interleukin (IL)-4, IL-5, IL-13, IL-31] Th22 (IL-22) immune responses both skin serum plays pivotal role immunopathogenesis AD especially at acute stage, followed by variable degree Th1 (interferon-γ, tumor necrosis factor alpha) Th17 (IL-17) chronic Of note, most aforementioned utilize JAK/STAT downstream transduction, explaining emerging JAK inhibitors armamentarium AD. present systematic review aims discuss involvement summarize clinical data available on efficacy safety which have been used treatment thus far.

Language: Английский

Citations

55