公开(公告)号：US09326972B2

公开(公告)日：2016-05-03

申请号：US13370079

申请日：2012-02-09

申请人： Leonard D. Kohn ,  Norikazu Harii ,  Uruguaysito Benavides-Peralta ,  Mariana Gonzalez-Murguiondo ,  Christopher J. Lewis ,  Douglas J. Goetz ,  Giorgio Napolitano ,  Cesidio Giuliani ,  Ramiro Malgor ,  Frank Schwartz ,  Kelly D. McCall

发明人： Leonard D. Kohn ,  Norikazu Harii ,  Uruguaysito Benavides-Peralta ,  Mariana Gonzalez-Murguiondo ,  Christopher J. Lewis ,  Douglas J. Goetz ,  Giorgio Napolitano ,  Cesidio Giuliani ,  Ramiro Malgor ,  Frank Schwartz ,  Kelly D. McCall

IPC分类号： A61K31/4164 ,  A61P31/04 ,  A61P31/00 ,  A61P29/00 ,  A61K31/4166

CPC分类号： A61K31/4164 ,  A61K31/4166 ,  A61K31/56 ,  A61K45/06 ,  Y02A50/411

摘要： Treatment of autoimmune and/or inflammatory diseases associated with overexpression of Toll-like receptor 3 (TLR3) as well as Toll-like receptor 4 (TLR4) and/or TLR3/TLR4 signaling in nonimmune cells, monocytes, macrophages, and/or dendritic cells in association with related pathologies. The use of phenylmethimazoles, methimazole derivatives, and tautomeric cyclic thiones for the treatment of autoimmune and inflammatory diseases associated with TLR3 as well as TLR4 and/or TLR3/TLR4 cellular signaling in association with related pathologies is disclosed. Methods of treating a subject having a disease or condition associated with abnormal TLR-3 as well as TLR-4 and/or TLR3/TLR4 cellular signaling in association with related pathologies are also disclosed. The present disclosure also relates to the treatment of autoimmune-inflammatory pathologies and chemokine and cytokine-mediated diseases associated with TLR overexpression and signaling. The disclosure also relates to pharmaceutical formulations capable of inhibiting the IRF-3/Type 1 IFN/STAT/ISRE/IRF-1 pathway associated with Toll-like receptor overexpression or signaling.

摘要翻译： 治疗与非免疫细胞，单核细胞，巨噬细胞和/或树突状细胞中Toll样受体3（TLR3）以及Toll样受体4（TLR4）和/或TLR3 / TLR4信号传导过度表达相关的自身免疫和/或炎性疾病 细胞与相关病理相关。 公开了使用苯基甲基咪唑，甲巯咪唑衍生物和互变异构环状硫for素治疗与TLR3相关的自身免疫性和炎症性疾病以及与相关病理学有关的TLR4和/或TLR3 / TLR4细胞信号传导。 还公开了治疗具有与异常TLR-3以及与相关病理学相关的TLR-4和/或TLR3 / TLR4细胞信号传导相关疾病或病症的受试者的方法。 本公开还涉及治疗与TLR过表达和信号传导相关的自身免疫性炎症病症和趋化因子和细胞因子介导的疾病。 本公开还涉及能够抑制与Toll样受体过表达或信号传导相关的IRF-3/1型IFN / STAT / ISRE / IRF-1途径的药物制剂。

公开(公告)号：US20060211752A1

公开(公告)日：2006-09-21

申请号：US11130922

申请日：2005-05-17

申请人： Leonard Kohn ,  Norikazu Harii ,  Uruguaysito Benavides-Peralta ,  Mariana Gonzalez-Murguiondo ,  Christopher Lewis ,  Giorgio Napolitano ,  Cesidio Giuliani ,  Ramiro Malgor ,  Douglas Goetz

发明人： Leonard Kohn ,  Norikazu Harii ,  Uruguaysito Benavides-Peralta ,  Mariana Gonzalez-Murguiondo ,  Christopher Lewis ,  Giorgio Napolitano ,  Cesidio Giuliani ,  Ramiro Malgor ,  Douglas Goetz

IPC分类号： A61K31/4166

CPC分类号： A61K31/4164 ,  A61K31/4166 ,  A61K31/56 ,  A61K45/06 ,  Y02A50/411

摘要： The present invention relates to the treatment of autoimmune and/or inflammatory diseases associated with overexpression of Toll-like receptor 3 (TLR3) as well as Toll-like receptor 4 (TLR4) and/or TLR3/TLR4 signaling in nonimmune cells, monocytes, macrophages, and/or dendritic cells in association with related pathologies. This invention also relates to the use of phenylmethimazoles, methimazole derivatives, and tautomeric cyclic thiones for the treatment of autoimmune and inflammatory diseases associated with Toll-like receptor 3 (TLR3) as well as Toll-like receptor 4 (TLR4) and/or TLR3/TLR4 signaling in nonimmune cells, monocytes, macrophages, and/or dendritic cells in association with related pathologies. This invention also relates to treating a subject having a disease or condition associated with abnormal Toll-like receptor 3 as well as Toll-like receptor 4 and/or TLR3/TLR4 signaling in nonimmune cells, monocytes, macrophages, and/or dendritic cells in association with related pathologies. The present invention also relates to the treatment of autoimmune-inflammatory pathologies and chemokine and cytokine-mediated diseases associated with TLR overexpression and signaling. This invention also relates to pharmaceutical formulations capable of inhibiting the IRF-3/Type 1 IFN/STAT/ISRE/IRF-1 pathway associated with Toll-like receptor overexpression or signaling.

摘要翻译： 本发明涉及治疗与非免疫细胞，单核细胞中Toll样受体3（TLR3）和Toll样受体4（TLR4）和/或TLR3 / TLR4信号传导过度相关的自身免疫性和/或炎性疾病， 巨噬细胞和/或与相关病理学相关的树突状细胞。 本发明还涉及苯甲基咪唑，甲巯咪唑衍生物和互变异构环状硫堇用于治疗与Toll样受体3（TLR3）以及Toll样受体4（TLR4）和/或TLR3相关的自身免疫性和炎性疾病的用途 / TLR4信号传导在非免疫细胞，单核细胞，巨噬细胞和/或树突状细胞中，与相关病理学相关。 本发明还涉及在非免疫细胞，单核细胞，巨噬细胞和/或树突细胞中治疗具有与异常Toll样受体3以及Toll样受体4和/或TLR3 / TLR4信号传导相关的疾病或病症的受试者 与相关病理学关联。 本发明还涉及治疗与TLR过表达和信号传导相关的自身免疫性炎症病理和趋化因子和细胞因子介导的疾病。 本发明还涉及能够抑制与Toll样受体过表达或信号传导相关的IRF-3/1型IFN / STAT / ISRE / IRF-1途径的药物制剂。

公开(公告)号：US20100004304A1

公开(公告)日：2010-01-07

申请号：US12286880

申请日：2008-10-01

申请人： Leonard D. Kohn ,  Douglas J. Goetz ,  Kelly D. McCall ,  Anthony Schwartz ,  Frank Schwartz ,  Ramiro Malgor ,  Glorglo Napolitano ,  Cesidio Giullant

发明人： Leonard D. Kohn ,  Douglas J. Goetz ,  Kelly D. McCall ,  Anthony Schwartz ,  Frank Schwartz ,  Ramiro Malgor ,  Glorglo Napolitano ,  Cesidio Giullant

IPC分类号： A61K31/4164 ,  C12N5/06

CPC分类号： A61K31/4166 ,  A61K31/4164

摘要： It is now recognized that chronic inflammation is an important risk factor for the development of cancer. The proinflammatory cytokine IL-6 is implicated in cancer because it is important for the activation of STAT, a key regulator of cancer growth, survival, metastasis, immune evasion and angiogenesis. Increased IL-6 and Stat-3 exists in vitro in pancreatic cancer, malignant melanoma, papillary thyroid cancer, breast cancer, colon cancer, and prostate cancer cells with high basal expression of Toll-like receptor 3 (TLR3) and Wnt5a. IL6/STAT3 activation, mediated by overexpressed TLR3 signaling, appears important in the tumor growth process, it may increase Wnt5a signaling, and be associated with increased cellular growth and migration. Using a novel inhibitor of pathologic TLR3 signaling (5-phenylmethimazole [C10]) we have demonstrated decreases in these markers plus suppression of cell growth and migration in human pancreatic cancer, malignant melanoma, papillary thyroid cancer, breast cancer, colon cancer, and prostate cancer cells.

摘要翻译： 现在认识到慢性炎症是癌症发展的重要危险因素。 促炎细胞因子IL-6涉及癌症，因为它对于STAT的活化是重要的，STAT是癌症生长，存活，转移，免疫逃避和血管生成的关键调节剂。 在胰腺癌，恶性黑素瘤，乳头状甲状腺癌，乳腺癌，结肠癌和前列腺癌细胞中，增加的IL-6和Stat-3在Toll样受体3（TLR3）和Wnt5a具有高基础表达。 由过表达的TLR3信号传导介导的IL6 / STAT3激活在肿瘤生长过程中似乎很重要，它可能增加Wnt5a信号传导，并且与增加的细胞生长和迁移相关。 使用新型的病理性TLR3信号抑制剂（5-苯基咪唑[C10]），我们已经证明这些标志物的减少加上抑制人胰腺癌，恶性黑素瘤，乳头状甲状腺癌，乳腺癌，结肠癌和前列腺癌细胞生长和迁移 癌细胞。

公开(公告)号：US20140186824A1

公开(公告)日：2014-07-03

申请号：US14130083

申请日：2012-06-29

申请人： Monica Maki Burdick ,  Doug Goetz ,  Ventesh Sridmar Shirure ,  Ramiro Malgor ,  Vicente Resto

发明人： Monica Maki Burdick ,  Doug Goetz ,  Ventesh Sridmar Shirure ,  Ramiro Malgor ,  Vicente Resto

IPC分类号： G01N33/569

CPC分类号： G01N33/56966 ,  G01N33/5085 ,  G01N33/54313 ,  G01N33/54366

摘要： Described herein is a method, and compositions useful with the method, of analyzing a tissue from a subject. The method includes contacting a probe conjugate (10) including a probe molecule (12), to a biological tissue 146 from a subject. The probe conjugate (10) is contacted with the biological tissue (14) under a well defined and easily controlled force field(s) and that tends to result in an interaction between the molecular probe (12) and the tissue (14) and/or tends to disrupt such interactions. The resulting interaction of the molecular probe (12) with the tissue (14) is then quantified. The analytical methods may be useful for diagnostic and prognostic applications as well as in the discovery of novel drug delivery systems and novel therapeutic substances and targets.

摘要翻译： 本文描述了一种用于分析来自受试者的组织的方法和用于该方法的组合物。 该方法包括使包含探针分子（12）的探针缀合物（10）与受试者的生物组织146接触。 探针结合物（10）在良好限定和容易控制的力场下与生物组织（14）接触，并且倾向于导致分子探针（12）和组织（14）之间的相互作用和/ 或者倾向于破坏这种相互作用。 然后量化分子探针（12）与组织（14）的相互作用。 分析方法可能对于诊断和预后应用以及发现新的药物递送系统和新的治疗物质和靶标是有用的。