Current Medicinal Chemistry (v.24, #21)

Regulation of Ion Channels, Cellular Carriers and Na(+)/K(+)/ATPase by Janus Kinase 3 by Mentor Sopjani, Shpëtim Thaçi, Berat Krasniqi, Miranda Selmonaj, Mark Rinnerthaler, Miribane Dërmaku-Sopjani (2251-2260).
Janus kinase-3 (JAK3), a tyrosine kinase, is expressed in a variety of tissues, including the brain and is involved in the signaling of cytokine receptors. JAK3 participates in numerous functions, such as cell survival and proliferation, neuroprotection, apoptosis and the cellular response to hypoxia and ischemia-reperfusion. This kinase further contributes to the signaling of hematopoietic cell cytokine receptors, activation of dendritic cells, maturation, and immune suppression as well as to cell volume regulation. Recently, JAK3 has been demonstrated to be an important regulator of transport processes across the plasma membrane. Either directly or indirectly JAK3 affects the expression of transport proteins, including various ion channels, a number of cellular carriers and the Na+/K+ pump. More specifically, JAK3 is involved in the regulation of various potassium, sodium, and chloride ion channels, a wide variety of Na+-coupled cellular carriers including the high-affinity Na+ coupled glucose transporter SGLT1, the excitatory amino acid transporters EAAT1, EAAT2, EAAT3 and EAAT4, the peptide transporters PepT1 and PepT2, CreaT1 and theNa+/K+-ATPase. Via these transporters this kinase plays a role in various physiological and pathophysiological processes. Additional research is needed to investigate the effects of JAK3 on other cellular transporters and the underlying mechanisms.

P2X7 Receptor Orchestrates Multiple Signalling Pathways Triggering Inflammation, Autophagy and Metabolic/Trophic Responses by Elisa Orioli, Elena De Marchi, Anna Lisa Giuliani, Elena Adinolfi (2261-2275).
P2X7 receptor is an ion channel activated by extracellular adenosine trisphosphate (eATP) that attracted increasing attention for its role in immune reactions, neurobiology and oncology. As receptor for an extracellular ligand, P2X7 activates a series of intracellular signalling pathways mainly via alterations of the ion permeability, but also through formation of a large unselective pore and direct interaction with other proteins. Here we wish to give an overview on the main biochemical paths initiated by P2X7 activation by revising recent and established literature on P2X7-triggered signalling cascades leading to cell death, inflammatory and immune response activation, proliferation and metabolism modulation. We will focus on the well-known P2X7 inflammasome/NF-kB and pro-apoptotic networks but also cover P2X7-activated emerging autophagic, pyroptotic and proliferativeoncogenic pathways, like beclin-1/LC3-II, caspase-11, Akt and VEGF axes.

Structure, Roles and Inhibitors of a Mitotic Protein Kinase Haspin by Katrin Kestav, Asko Uri, Darja Lavogina (2276-2293).
Background: Haspin (haploid germ cell-specific nuclear protein kinase) is an atypical serine/threonine-protein kinase that was for a long time considered an inactive pseudokinase due to low degree of structural homology of Haspin with the ‘classical’ protein kinases. However, the discovery of Haspin-catalyzed phosphorylation of histone H3 at Thr3 residue unveiled importance of Haspin in mitosis and provided yet another link between mitotic phosphorylation pathways and chromatin modifications. <P></P> Results: In this review of 111 publications, we have (1) briefly summarized catalytic properties and physiological roles of Haspin, (2) focussed on the architecture of Haspin and mechanisms behind its substrate recognition, (3) provided detailed insight into the advances in the development and characterization of Haspin-selective inhibitors, and (4) given overview of inhibitor scaffolds that despite targeting other protein kinases feature Haspin as a common off-target. <P></P> Conclusion: The chemical space of Haspin-targeting low-molecular-weight-compounds has not yet been widely explored, but several scaffolds (<i>e.g</i>., derivatives of acridine, β-carboline or 5-iodotubercidin) have emerged as promising inhibitors. The inclusion of Haspin into protein kinase panels for profiling of low-molecular-weight-compounds in several recent studies has provided valuable information about the structure-affinity or structure-activity relationship of well-known or novel inhibitors towards Haspin.

Recent Advances of Hepsin-Targeted Inhibitors by Hongmok Kwon, JooYeon Han, Ki-Yong Lee, Sang-Hyun Son, Youngjoo Byun (2294-2311).
Hepsin is a type II transmembrane serine protease (TTSP) that plays a crucial role in cell growth and development. Hepsin is highly expressed in prostate cancer (PCa) and associated with its progression and metastasis. Therefore, it has been considered as an attractive biomarker of PCa. Recently, low molecular weight inhibitors targeting hepsin have been developed. Based on the key chemical scaffold, they can be classified into four classes: Indolecarboxamidines, benzamidines, peptide-based analogs, and 2,3-dihydro- 1H-perimidines. In this review, we discuss design strategy, structure-activity relationship (SAR), and binding mode of the four classes of hepsin inhibitors.

Malignant melanoma is the most aggressive and life-threatening skin cancer. Melanoma develops in melanocytes and is characterized by a very high tendency to spread to other parts of the body. Its pathogenesis depends on DNA mutations leading to the activation of oncogenes or to the inactivation of suppressor genes. The identification of misregulations in intracellular signal transduction pathways has provided an opportunity for the development of mutation-specific inhibitors, which specifically target the mutated signaling cascades. Over the last few years, clinical trials with MAPK pathway inhibitors have shown significant clinical activity in melanoma; however, their efficacy is limited due to the onset of acquired resistance. This has prompted a large set of preclinical studies looking at new approaches of pathway- or target-specific inhibitors. This review gives an overview of the latest developments of small molecule targeting multiple molecular pathways in both preclinical and clinical melanoma settings, with particular emphasis on additional strategies to tackle the reduced responsiveness to inhibitor treatment as possible future directions.

The Impact of IL-17 in Atherosclerosis by Xinjie Lu (2345-2358).
Atherosclerosis is a chronic vascular disease in which atherosclerotic plaques develop in the arterial wall. It is believed that inflammation plays a major role in atherosclerotic formation and progression. Thus, atherosclerosis can be considered as an inflammatory disease of the arterial vessel. Mouse model demonstrated that T and B cell deficiency reduces the atherosclerotic burden in the formation of an atherosclerotic lesion. CD4+ T helper cells (Th), such as Th1 cells known being the major CD4+ T cell subtype found in mouse models of atherogenesis, increase plaque formation caused by oxLDL. IL-17 (also known as IL-17A) was produced by T cells or by a unique subset of T helper cells. IL-17-producing T cells express interferon- gamma (IFN-γ), an important regulator of immune function, which is highly expressed in atherosclerotic lesions, defying their neat characteristics as Th17 cells. Regulation of Th17 signal pathway may play a significant role in the pathogenesis of multiple inflammatory and autoimmune disorders, such as atherosclerosis. In this review, the structural features of IL-17 family and their roles involved in atherosclerosis are described.