Development and Therapeutic Implications of Tyrosine Kinase 2 Inhibitors

Zhang, Kuojun; Yao, Ke; He, Ting; Qi, Zhihao; Wang, Tianyu; Mao, Jie; Zhang, Xiangyu; Jiang, Sheng

doi:10.1021/acs.jmedchem.2c01800

Cited by 5 publications

(8 citation statements)

References 150 publications

(452 reference statements)

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“…BMS-986165 is a highly selective, orally administered TYK2 inhibitor that blocks STAT1 and IL-23 phosphorylation by inhibiting the activity of both IFN-α and IL-23 ( 270 , 274 ). PF-06826647 is another TYK2 inhibitor currently in Phase II trials for moderate to severe psoriasis ( 275 ).…”

Section: Emerging Therapies Targeting Immune Cells In Psoriasismentioning

confidence: 99%

Immune cells in the epithelial immune microenvironment of psoriasis: emerging therapeutic targets

Li,

Lu,

Liu

et al. 2024

Front. Immunol.

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Psoriasis is a chronic autoimmune inflammatory disease characterized by erroneous metabolism of keratinocytes. The development of psoriasis is closely related to abnormal activation and disorders of the immune system. Dysregulated skin protective mechanisms can activate inflammatory pathways within the epithelial immune microenvironment (EIME), leading to the development of autoimmune-related and inflammatory skin diseases. In this review, we initially emphasized the pathogenesis of psoriasis, paying particular attention to the interactions between the abnormal activation of immune cells and the production of cytokines in psoriasis. Subsequently, we delved into the significance of the interactions between EIME and immune cells in the emergence of psoriasis. A thorough understanding of these immune processes is crucial to the development of targeted therapies for psoriasis. Finally, we discussed the potential novel targeted therapies aimed at modulating the EIME in psoriasis. This comprehensive examination sheds light on the intricate underlying immune mechanisms and provides insights into potential therapeutic avenues of immune-mediated inflammatory diseases.

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Section: Emerging Therapies Targeting Immune Cells In Psoriasismentioning

confidence: 99%

Immune cells in the epithelial immune microenvironment of psoriasis: emerging therapeutic targets

Li,

Lu,

Liu

et al. 2024

Front. Immunol.

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“…This stability is likely attributed to the strong acidic nature of pyrazole, which renders its derivatives less susceptible to oxidative metabolism. Drugs incorporating N-substituted pyrazoles as part of their structure frequently experience the removal of the substituent attached to the pyrazole ring [ 30 ].…”

Section: The Chemical Profile Of the Pyrazole Ringmentioning

confidence: 99%

“…Ropsacitinib (PF-06826647) contains two pyrazole rings directly attached to a pyrazolopyrazine scaffold and can be considered a baricitinib derivative. It is a selective inhibitor of Tyk2, and, currently, there are clinical trials for it as treatment for various autoimmune disorders [ 30 ].…”

Section: Jak Inhibitorsmentioning

confidence: 99%

The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies

Nitulescu,

Stancov,

Seremet

et al. 2023

Molecules

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The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of medicinal chemistry and drug development strategies, playing a vital role as a fundamental framework in the structure of various PKIs. This scaffold holds major importance and is considered a privileged structure based on its synthetic accessibility, drug-like properties, and its versatile bioisosteric replacement function. It has proven to play a key role in many PKI, such as the inhibitors of Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, and RET. Of the 74 small molecule PKI approved by the US FDA, 8 contain a pyrazole ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib. The focus of this review is on the importance of the unfused pyrazole ring within the clinically tested PKI and on the additional required elements of their chemical structures. Related important pyrazole fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[3,4-d]pyrimidine are beyond the subject of this work.

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“…There is also a host of patents that have been filed recently for TYK2 JH2 ligands whose results go beyond the scope of this review. To this end, there are some recent reviews of this patent literature that have been published for curious readers. , …”

Section: Small-molecule Targeting Of the Jak Pseudokinasesmentioning

confidence: 99%

“…To this end, there are some recent reviews of this patent literature that have been published for curious readers. 142,143 ■…”

Section: ■ the Jak Trans-activation State: A Tentative Keystonementioning

confidence: 99%

Progress on the Pharmacological Targeting of Janus Pseudokinases

Henry

Jorgensen

2023

J. Med. Chem.

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The Janus kinases (JAKs) are key components of the JAK-STAT signaling pathway and are involved in myriad physiological processes. Though they are the molecular targets of many FDA-approved drugs, these drugs manifest adverse effects due in part to their inhibition of the requisite JAK kinase activity. However, the JAKs uniquely possess an integrated pseudokinase domain (JH2) that regulates the adjacent kinase domain (JH1). The therapeutic targeting of JH2 domains has been less thoroughly explored and may present an avenue to modulate the JAKs without the adverse effects associated with targeting the adjacent JH1 domain. The potential of this strategy was recently demonstrated with the FDA approval of the TYK2 JH2 ligand deucravacitinib for treating plaque psoriasis. In this light, the structure and targetability of the JAK pseudokinases are discussed, in conjunction with the state of development of ligands that bind to these domains. ■ SIGNIFICANCEThe JAK pseudokinase (JH2) domains present attractive targets for modulation of JAK-STAT pathways to circumvent adverse side effects of traditional Jakinibs. This has been demonstrated by the recent FDA approval of the TYK2 JH2 ligand deucravacitinib. Understanding the structure of these domains and the state of development of their ligands is important for future development of the JAK pseudokinases as therapeutic targets.

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Development and Therapeutic Implications of Tyrosine Kinase 2 Inhibitors

Cited by 5 publications

References 150 publications

Immune cells in the epithelial immune microenvironment of psoriasis: emerging therapeutic targets

Immune cells in the epithelial immune microenvironment of psoriasis: emerging therapeutic targets

The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies

Progress on the Pharmacological Targeting of Janus Pseudokinases

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