JNK is named after c-Jun N-terminal kinase, as it is responsible for phosphorylating c-Jun. As a member of the mitogen-activated protein kinase (MAPK) family, JNK is also known as stress-activated kinase (SAPK) because it can be activated by extracellular stresses including growth factor, UV irradiation, and virus infection. Functionally, JNK regulates various cell behaviors such as cell differentiation, proliferation, survival, and metabolic reprogramming. Dysregulated JNK signaling contributes to several types of human diseases. Although the role of the JNK pathway in a single disease has been summarized in several previous publications, a comprehensive review of its role in multiple kinds of human diseases is missing. In this review, we begin by introducing the landmark discoveries, structures, tissue expression, and activation mechanisms of the JNK pathway. Next, we come to the focus of this work: a comprehensive summary of the role of the deregulated JNK pathway in multiple kinds of diseases. Beyond that, we also discuss the current strategies for targeting the JNK pathway for therapeutic intervention and summarize the application of JNK inhibitors as well as several challenges now faced. We expect that this review can provide a more comprehensive insight into the critical role of the JNK pathway in the pathogenesis of human diseases and hope that it also provides important clues for ameliorating disease conditions.

UNASSIGNED: The mitogen-activated protein kinase (MAPK) family consist of p38 MAP kinases, c-Jun N-terminal kinases (JNKs) and extracellular signal-regulated kinases (ERKs). They are involved in a multitude of diseases, including inflammatory, autoimmune, neurodegenerative, and metabolic diseases as well as cancer. In recent years, further developments in the field of MAPK-inhibitors have been reported, including an isoform or downstream target selective inhibition of MAPKs as well as target protein degradation approaches.
UNASSIGNED: This review summarizes newly patented MAPK-inhibitors that were claimed between 2018 and early 2023. Presented are the patents as well as their corresponding publications, the storyline of development, and clinical trials involving these compounds. This article elaborates a total of 27 patents, which were identified using established search engines.
UNASSIGNED: Although industrial research on MAPK-inhibitors has been ongoing for more than 20 years, novel clinical trials of MAPK-inhibitors as potential drug candidates are still being conducted in the period under review. Recently reported inhibitors show an excellent selectivity profile and are even achieving selectivity between closely related isoforms. This progression offers the possibility to eliminate unwanted side effects and may finally lead to the approval of the first MAPK-inhibitor.

Cancer is one of the prominent global causes of death and the foremost worldwide health concern. Despite unprecedented progress in cancer chemoprevention, a vast number of cancers, however, remain an undefeatable challenge for treatment modalities. Immense therapeutic activities of puerarin contribute to its use in various health disorders. In this review, we explored the potential molecular mechanisms and targets of puerarin, proving its potential as a novel anticancer agent, for future cancer therapy and chemoprevention. Several mechanisms account for anticancer activity of puerarin which includes downregulation of NF-kB signalling pathway, mTOR signalling pathway, PI3K and BCl-2 proteins and upregulation of miR-16, caspase proteins, c- Jun N terminal kinase and extracellular signal-regulated kinase 1/2. These alterations result in inhibition of cancer cell proliferation and/or induction of apoptosis. Understanding the molecular mechanisms involved in chemotherapy and chemoprevention could aid in the more pronounced exploration of puerarin in effective cancer treatment.

JNKs (c-Jun N-terminal kinases) belong to mitogen-activated protein kinases\' family and become activated by several growth factors, stress, radiation, and other extracellular signals. In turn, JNK activation results in phosphorylation of downstream molecules involved in many normal cellular processes. Nevertheless, recent data have linked JNK signaling with several pathological conditions, including neurodegenerative diseases, inflammation, and cancer. The role of JNK in cancer remains controversial. Initially, JNK was thought to play a rather oncosuppressive role by mediating apoptosis in response to stress stimuli, inflammatory, or oncogenic signals. However, a number of studies have implicated JNK in malignant transformation and tumor growth. The contradictory functions of JNK in cancer may be due to the diversity of JNK upstream and downstream signaling and are under intensive investigation. This review summarizes current literature focusing on the significance of JNK pathway in cancer development and progression, particularly addressing its role in oral cancer. Understanding the complexity of JNK signaling has the potential to elucidate important molecular aspects of oral cancer, possibly leading to development of novel and individualized therapeutic strategies.

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and c-Jun N-terminal kinase (JNK) pathway are responsible for regulating a variety of cellular processes including cell growth, migration, invasion and apoptosis. These two pathways are essential to the development and progression of tumors. The dual roles of JNK signaling in apoptosis and tumor development determine the different interactions between the PI3K/Akt and JNK pathways. Activation of PI3K/Akt signaling can inhibit stress- and cytokine-induced JNK activation through Akt antagonizing and the formation of the JIP1-JNK module, as well as the activities of upstream kinases ASK1, MKK4/7 and MLK. On the other hand, hyperactivation of Akt and JNK is also found in cancers that harbor EGFR overexpression or loss of PTEN. Understanding the activation mechanism of PI3K/Akt and JNK pathways, as well as the interplays between these two pathways in cancer may contribute to the identification of novel therapeutic targets. In the present report, we summarized the current understanding of the PI3K/Akt and JNK signaling networks, as well as their biological roles in cancers. In addition, the interactions and regulatory network between PI3K/Akt and JNK pathways in cancer were discussed.

BACKGROUND: c-Jun N-terminal kinases (JNKs) are involved in the emergence and progression of diverse pathologies such as neurodegenerative, cardiovascular and metabolic disorders as well as inflammation and cancer. In recent years, several highly selective pan-JNK inhibitors have been characterized and three chemical entities targeting JNKs have been investigated in clinical trials.
METHODS: This review summarizes patents claiming inhibitors of all JNK isoforms published between 2010 and 2014. Although primarily focusing on the patent literature, relevant peer-reviewed publications related to the covered patents have also been included. Moreover, key patents claiming novel applications of previously published chemical entities are reviewed. The article highlights a total of 28 patents from nine pharmaceutical companies and academic research groups.
CONCLUSIONS: Although some selective pan-JNK inhibitors with reasonable in vivo profiles are now available, little is known about the isoform selectivity required for each particular indication and the development of isoform-selective JNK inhibitors still represents a challenge in JNK drug discovery. Moreover, isoform-selective tool compounds are a prerequisite to a comprehensive understanding of the biology of each JNK isoform. Potential approaches towards such compounds include the design of type-II and type-I(1)/2 binders, which are absent in the current JNK inhibitor portfolios, as well as the design of novel allosteric inhibitors. Furthermore, covalent inhibition, which already led to the first high-quality probe for JNKs, might be further exploited for gaining selectivity and in vivo efficacy. With regard to a potential therapeutic application, the recently proposed concept of covalent reversible inhibitors is expected to be attractive.

This review provides a brief summary of thiadiazole ring containing compounds as antidiabetic agents. It covers the most active thiadiazole derivatives selected from reported literature of thiadiazole system as antidiabetic drug substance in the form of synthesis and structural activity relationship study reports. Some of the promising thiadiazole compounds interacting with targets such as sodium-glucose linked transporter, peroxisome proliferator-activated receptor, protein tyrosine phosphatase, c-Jun N-terminal kinase, dipeptidyl peptidase-4 and cannabinoid-1 receptor have been collected with their biological potency. The information provided in this review acts as important overview for medicinal chemist to develop a new chemical entity possessing antidiabetic activity.

The c-Jun N-terminal kinase (JNK) group of mitogen-activated protein kinases (MAPKs) is activated in mammalian cells by environmental stress, pro-inflammatory cytokines, and mitogenic stimuli. Biochemical and genetic studies demonstrate that JNK regulates the activities of many transcription factors, and that the JNK pathway is required for the regulation of inflammatory responses, cell proliferation, and apoptosis. The involvement of JNK in apoptotic cell death is particularly intriguing, and has been actively studied in recent years. An improved understanding of JNK-mediated apoptotic signaling may provide novel strategies in prevention and treatment of cancers.

Anthracycline-derivatives are frequently used chemotherapeutics in treatment of numerous human malignancies. Anthracyclines are known for their complex cytotoxic mechanism involving i) inhibition of enzymes such as topoisomerase II, RNA polymerase, cytochrome c oxidase and others; ii) intercalation into DNA; iii) chelation of iron and generation of reactive oxygen species (ROS); iv) induction of apoptosis. Here, mechanistic aspects for successful cytostasis and for side effects, e.g. cardiomyopathy, are discussed. We emphasize recent developments in anthracycline-mediated apoptosis and focus on a well known representative, doxorubicin (adriamycin, adriblastin). We reflect on the role of oxidative stress and interactions with intracellular signaling pathways.