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      Pharmacological Control of Receptor of Advanced Glycation End-Products and its Biological Effects in Psoriasis

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          Abstract

          Receptor for advanced glycation end-products is implicated in a development of chronic inflammatory response. Aim of this paper is to provide a review on commercial and experimental medicines that can interfere with RAGE and signaling through RAGE. We searched three bibliographical databases (PubMed, Web of Science and MEDLINE) for the publications from 2005 to March 2012 and identified 5 major groups of agents that can interfere with RAGE biological effects. In the first part of this paper, we discuss AGE crosslink breakers. These chemicals destroy advanced glycation end products (AGEs) that are crosslinked to the extracellular matrix proteins and can interact with RAGE as ligands. Then, we describe two non-conventional agents SAGEs and KIOM-79 that abolish certain biological effects of RAGE and have a strong anti-inflammatory potential. In the third part, we evaluate the inhibitors of the signaling cascades that underlie RAGE. Particularly, we discuss two groups of kinase inhibitors tyrphostins and the inhibitors of JAK kinases. Considering RAGE as a potential master regulator of processes that are crucial for the pathogenesis of psoriasis, we propose that these medicins may help in controlling the disease by abolishing the chronic inflammation in skin lesions.

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          Most cited references 126

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          Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms.

          Constitutive JAK2 activation in hematopoietic cells by the JAK2V617F mutation recapitulates myeloproliferative neoplasm (MPN) phenotypes in mice, establishing JAK2 inhibition as a potential therapeutic strategy. Although most polycythemia vera patients carry the JAK2V617F mutation, half of those with essential thrombocythemia or primary myelofibrosis do not, suggesting alternative mechanisms for constitutive JAK-STAT signaling in MPNs. Most patients with primary myelofibrosis have elevated levels of JAK-dependent proinflammatory cytokines (eg, interleukin-6) consistent with our observation of JAK1 hyperactivation. Accordingly, we evaluated the effectiveness of selective JAK1/2 inhibition in experimental models relevant to MPNs and report on the effects of INCB018424, the first potent, selective, oral JAK1/JAK2 inhibitor to enter the clinic. INCB018424 inhibited interleukin-6 signaling (50% inhibitory concentration [IC(50)] = 281nM), and proliferation of JAK2V617F(+) Ba/F3 cells (IC(50) = 127nM). In primary cultures, INCB018424 preferentially suppressed erythroid progenitor colony formation from JAK2V617F(+) polycythemia vera patients (IC(50) = 67nM) versus healthy donors (IC(50) > 400nM). In a mouse model of JAK2V617F(+) MPN, oral INCB018424 markedly reduced splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects. Preliminary clinical results support these preclinical data and establish INCB018424 as a promising oral agent for the treatment of MPNs.
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            The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses.

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              SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo.

              FLT3 (fms-related tyrosine kinase/Flk2/Stk-2) is a receptor tyrosine kinase (RTK) primarily expressed on hematopoietic cells. In blasts from acute myelogenous leukemia (AML) patients, 2 classes of FLT3 activating mutations have been identified: internal tandem duplication (ITD) mutations in the juxtamembrane domain (25%-30% of patients) and point mutations in the kinase domain activation loop (7%-8% of patients). FLT3-ITD mutations are the most common molecular defect identified in AML and have been shown to be an independent prognostic factor for decreased survival. FLT3-ITD is therefore an attractive molecular target for therapy. SU11248 is a recently described selective inhibitor with selectivity for split kinase domain RTKs, including platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and KIT. We show that SU11248 also has potent activity against wild-type FLT3 (FLT3-WT), FLT3-ITD, and FLT3 activation loop (FLT3-Asp835) mutants in phosphorylation assays. SU11248 inhibits FLT3-driven phosphorylation and induces apoptosis in vitro. In addition, SU11248 inhibits FLT3-induced VEGF production. The in vivo efficacy of SU11248 was investigated in 2 FLT3-ITD models: a subcutaneous tumor xenograft model and a bone marrow engraftment model. We show that SU11248 (20 mg/kg/d) dramatically regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model and prolongs survival in the bone marrow engraftment model. Pharmacokinetic and pharmacodynamic analysis in subcutaneous tumors showed that a single administration of an efficacious drug dose potently inhibits FLT3-ITD phosphorylation for up to 16 hours following a single dose. These results suggest that further exploration of SU11248 activity in AML patients is warranted.
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                Author and article information

                Journal
                Int J Biomed Sci
                Int J Biomed Sci
                IJBS
                International Journal of Biomedical Science : IJBS
                Master Publishing Group
                1550-9702
                1555-2810
                September 2013
                : 9
                : 3
                : 112-122
                Affiliations
                Federal Non-profit Research Institute of Russian Academy of Sciences, N.I. Vavilov Institute of General Genetics, Moscow 119991, Russia
                Author notes
                Corresponding author: Prof. E. S. Piruzian, D.Sci, PhD; IOGen, 3 Gubkina Street, suite 303, Moscow 119991, Russia, Tel: +7(499) 132-0874; Fax: (499) 132-89-62; E-mail: eleopiru@ 123456vigg.ru .

                Note: This work was supported by Russian Ministry of Education and Science (grant # 16.512.11.2049), Russian Academy of Sciences via federal program “Fundamental science to medicine”, and Russian Fund of Fundamental Research (grant # 12-04-32009 Mol_A) as one the best projects supervised by a junior scientist in the field of molecular biology, section #04, “Biology and medical sciences”.

                Article
                IJBS-9-112
                3809352
                24170986
                © A. V. Mezentsev et al. Licensee Master Publishing Group

                This is an open-access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.5/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Categories
                Review Article

                sage, tyrphostins, kiom-79, psoriasis, rage, age, jak kinases

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