34 results about "Stat3 Signaling Pathway" patented technology

The invention discloses an STAT3 small molecular selective inhibitor and a preparation method and applications thereof, and the STAT3 small molecular selective inhibitor comprises four structure general formulae as shown in formula I, formula II, formula III and formula IV. The preparation comprises the following steps: allowing 2-phenyl substituted quinoline-4-carboxylic acid thionyl chloride or oxalyl chloride to react to generate substituted acyl chloride, reacting with substituted arylamine to generate substituted quinoline-4-amide derivatives. The applications comprise an application in the preparation of medicaments for treating cancers related to abnormally-activated STAT3 pathway, and an application in the preparation of antitumor medicaments where the STAT3 small molecular selective inhibitor is used as an inhibitor of the STAT3 signal pathway. The STAT3 inhibitor of the invention is a small molecular selective inhibitor; based on results obtained by detecting its effect on cancer cells and evaluating its activity, the small molecular STAT3 selective inhibitor of the invention is applicable to the development of related cancer-treatment medicaments, has quite wide applications, and has very good medicine curative effect. The small molecular STAT3 selective inhibitor of the invention has various types, easily available raw materials, a simple preparation method, high product purity, high yield, and strong practicality.

The present invention relates to a set of biomarkers, microarrays that provide for detection thereof, an expression signature comprising 16 genes or a subset thereof, and the use thereof in determining the regulation status of IL-6 / STAT3 signaling pathway in a cell sample or subject, as well as compositions for the detection thereof. The regulation status of IL-6 / STAT3 signaling pathway in a cell sample or subject may be assayed based on the level of expression of one or more of these genes. The methods and compositions provided herein may be used to evaluate IL-6 / STAT3 pathway regulation status in a sample; classify a cell sample as having a deregulated or regulated IL-6 / STAT3 signaling pathway; determine whether an agent modulates the IL-6 / STAT3 signaling pathway; predict the response of a subject to an agent that modulates the IL-6 / STAT3 signaling pathway; assign treatment to a subject; and / or evaluate the pharmacodynamic effects of therapies designed to regulate IL-6 / STAT3 pathway signaling. Expression of the biomarkers is preferably determined by RT-PCR using SYBR Green methods, and the expression data analyzed and compared to a control sample by use of the random forest method.

The invention discloses an STAT3 (Signal Transducer and Activator of Transcription 3)-targeting small molecular compound as well as a preparation method and application thereof. The STAT3 inhibitor is a compound shown as a general formula I in the specification, wherein R<1> is 5-chloro-2-hydroxyphenyl, (E)-3-(6-bromo-2-pyridine)-2-cyan or 4-(2-phenylquinoline); R<2> is hydrogen or C1-C6 linear alkyl or branched alkyl. The compound has the advantages that the proliferation and the survival of various tumor cells of breast cancer, lung cancer, liver cancer, cervical cancer, prostate cancer and the like can be remarkably inhibited; the STAT3 signal channel of the tumor cells is inhibited; therefore, the tumor cell apoptosis is induced and the effect of treating the tumor diseases is achieved.

The invention discloses an application of a compound as a JAK-STAT3 signal passage inhibitor, and particularly relates to an application of a compound with a formula I or pharmaceutically acceptable salt of the compound in the process of preparing an anti-tumor medicament. The application provides a novel treating candidate medicament for a tumor patient, thereby probably further improving the treatment effect on the patient and improving the prognosis of the patient. The compound with the formula I or the pharmaceutically acceptable salt of the compound has the effect on various tumor cells, which indicates that the compound can be used for treating various cancers including cerebral tumor, genitourinary system tumor, lymphatic system tumor, stomach cancer, laryngeal cancer, nasopharyngeal cancer, skin cancer, bone cancer, blood cancer, leukemia, breast cancer and histiocytic lymphoma, non-small cell lung cancer, small-cell lung cancer, lung adenocarcinoma, lung squamous cell cancer, pancreatic cancer, prostatic cancer, liver cancer, epithelial cell cancer and the like. The definition of genes in the formula refers to description for details.

The invention discloses an STAT (Signal Transducer And Activator Of Transcription)3 signal channel small-molecule inhibitor and application thereof. The inhibitor is expressed in a chemical structural formula which is shown in the specification, wherein R1 is halogenated aryl, R2 is halogenated aryl, R3 is oxygen or sulphur. The inhibitor has functions of effectively inhibiting the multiplication of various tumor cells and inducing the apoptosis of the various tumor cells. The newly developed STAT3 signal channel small-molecule inhibitor not only has a remarkable inhibition effect on the phosphorylation of the STAT3, but also has the remarkable inhibition effect on the IL-6-induced STAT3 activation and the activation of the STAT3 upstream signal CrC and Jak2, and therefore, the multiplication of the various tumor cells can be inhibited and the apoptosis of tumor cells can be induced. Besides, the STAT3 signal channel small-molecule inhibitor has an in-vitro and vivo treatment effect on various tumors of acute and chronic leukemia, multiple myeloma, lymphoma, lung cancer, prostate cancer, cervical cancer and the like.

The invention discloses a micromolecule selective depressant for STAT3 (Signal transducer and activator of transcription 3), as well as a preparation method and an applications thereof. The micromolecule selective depressant for the STAT3 comprises a structural formula I and a structural formula II; the preparation method comprises the steps of: taking alkaline as a catalyst in DMSO (Dimethyl sulfoxide) or DMF (Dimethylformamide) solvent, and carrying out cyclization on N-bis(methylthio) methylene-arylsulfonamide and 3.3'-dihydroxyl benzidine in the DMSO; and the applications are shown in aspects of preparing medicaments for treating cancers related to an abnormally activated STAT3 pathway and anti-tumor medicaments as an STAT3 signal pathway depressant. The STAT3 depressant is a micromolecule selective depressant, can be used for developing related cancer treating medicaments by determining action on cancer cells to evaluate the active result, thus having a wide range of application,as well as good curative effect of the medicaments. The varieties of the micromolecule selective depressants for the STAT3 are multiple, the preparation method is simple, the product purity is high, the yield is high and the practicability is strong.

The invention discloses a function and application of SH2B adapter protein 1 (SH2B1) in myocardial hypertrophy treatment. According to the function and application, the mutual relation between SH2B1 genetic expression and myocardial hypertrophy is determined; the SH2B1 expression rises obviously when the myocardial hypertrophy happens; SH2B1 interference and overexpression adenovirus are used for restraining and promoting cardiomyocyte hypertrophy respectively; the SH2B1 gene defect and overexpression are used for restraining and obviously raising Jak2 / Stat3 signal pathway activation respectively, so that cardiac hypertrophy and fibrosis are restrained and promoted, and the cardiac function can be protected and deteriorated. Hence, the SH2B1 gene can be used as a drug target to be used for screening drugs for protecting the cardiac function and / or preventing, relieving and treating cardiac hypertrophy; the SH2B1 gene can be used as a target gene in gene therapy to be used for designing and preparing the drugs for protecting the cardiac function and / or preventing, relieving and treating cardiac hypertrophy; a new path is provided for cardiac hypertrophy treatment.

The invention relates to an application of atopaxar hydrobromide as a novel JAK-STAT3 signal channel inhibitor. The atopaxar hydrobromide can be used for inhibiting STAT3 activity and STAT3 downstreamgene expression to control cell proliferation; the atopaxar hydrobromide has an inhibition effect on STAT3 activation induced by cytokines and JAKs self-phosphorylation; in computer molecular simulation, the atopaxar hydrobromide can be combined with an SH2 structural domain of STAT3 and has very high affinity with a JAK kinase JH1 structural domain; and the atopaxar hydrobromide can horizontallyinhibit the tumor cell growth. A research method of the atopaxar hydrobromide as a novel JAK-STAT3 signal pathway inhibitor comprises the following steps: cell culturing; protein extraction; western-Blot; RNA extraction; RT-PCR (Reverse Transcription-Polymerase Chain Reaction) and fluorescent quantitative PCR; luciferase activity analysis; cell viability analysis; cell cycle detection by flow cytometry; cell apoptosis detection by flow cytometry; nude mouse transplantation tumor experiments; computer molecular dynamics simulation docking analysis; and data calculation and processing. The invention lays a foundation for further cell cycle detection and subsequent research and development of novel small molecule drugs.

The present invention provides a bifunctional fusion protein targeting VEGF and EGFR and an application of the bifunctional fusion protein. The provided fusion protein can specifically bind epidermalgrowth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). The provided fusion protein provides targeting with exact curative effect and high stability, and synergistically inhibitsEGFR / VEGF(R) pathway. The fusion protein blocks phosphorylation of Akt / Stat3 signaling pathway, thus inhibits angiogenesis or cell growth and has a significant targeting imaging effect and a significant anti-PDAC tumor effect. The provided fusion protein has very strong targeting specificity to induce tumor cell apoptosis and can be used for treatment of malignant tumors.

The invention discloses the use of Worenine as JNK2 kinase inhibitor. The Worenine can specifically combine JNK2 kinase and the two have strong binding ability, and simultaneously inhibit JNK2 activity in a dose-dependent manner. Worenine has good therapeutic activity against psoriasis, which is closely related to the inhibition of JNK, STAT3 signal pathway activation and the expression of psoriasis marker S1007 by Worenine, so it can be used as an active ingredient to prepare drugs for treating psoriasis.

The invention discloses an application of physalin A in preparation of a JAK2-STAT3 signal channel inhibitor and an antitumor drug. The physalin A is a compound with a structure shown in a formula I. The JAK2-STAT3 signal channel inhibitor can inhibit various tumor cells. As the JAK2-STAT3 is abnormally activated to lead to uncontrollable growth of tumor and apoptosis resistance of tumor cells, tumor cell proliferation is further inhibited and tumor cell apoptosis is further induced. The physalin A can be applied to preparation of the antitumor drug. The physalin A is combined with the chemotherapeutic drug (cis-platinum) can remarkably inhibit tumor cell proliferation so as to realize the purpose of enhancing effect and reducing toxicity. Particularly, the physalin A and cis-platinum combined in use to prepare the antitumor drug troches can generate a very strong synergistic effect, and the antitumor drug troches prepared have very good antitumor activity.

The invention mainly belongs to the field of tumor immunology and in particular relates to a gp 130 extracellular domain protein as well as a production method and an application thereof, particularly an application of the gp 130 extracellular domain protein for preparing medicines for inhibiting tumor cell proliferation and preventing and treating liver cancer diseases. The amino acid sequence of the gp 130 extracellular domain protein is shown as SEQ ID NO.1, the extracellular domain protein is an IL-6 / IL-6R molecule complex which can be subjected to competitive binding with a tumor cell surface model gp130 protein, and an IL-6-STAT3 signal pathway is blocked, so that the tumor cell growth is inhibited, and the liver cancer is prevented and treated. A proliferation test is performed by using tumor cells, a liver cancer prevention and treatment test is performed by using a male KM mouse, an effect similar to that of an IL-6 or IL-6R monoclonal antibody can be achieved by virtue of the protein, and side effects of antibody molecules are avoided.

The present invention relates to an application of a KMT1A inhibitor in preparation of an anticancer drug for bladder cancers and discloses that the KMT1A inhibitor can effectively inhibit bladder cancer growth. Compared with normal bladder epithelial cells, KMT1A is specifically highly expressed in bladder cancer cells, so that the KMT1A inhibitor acts on a KMT1A-GATA3-STAT3 signaling pathway bytarget inhibiting KMT1A genes, and enables a transcriptional level of GATA3 gene to be increased; and an up-regulation of the GATA3 further represses STAT3 transcription, leads to a decreased level ofSTAT3 protein phosphorylation, and thus inhibits dry maintenance and tumor formation of bladder cancer stem cells.

The invention discloses a peptide and application thereof in regulating megakaryocyte differentiation and treating platelet-related diseases. The invention discloses application of AGK as a marker for preventing / relieving / treating platelet-related diseases, and the deficiency of AGK significantly damages platelet generation and further leads to thrombocytopenia; the AGK plays an important role in megakaryocyte differentiation and platelet formation by regulating and controlling JAK2 / STAT3 signal pathway; the peptides 617V and 617F enhance JAK2 / STAT3 signal transduction by promoting combination of the AGK and the JAK2, so that megakaryocyte differentiation is accelerated; the megakaryocyte differentiation can be inhibited by blocking the combination of the AGK and the JAK2; regulating the combination of the AGK and the JAK2 can be used to treat thrombocytopenia and thrombocythemia. The invention discloses an application of a medicament for regulating combination of AGK and JAK2 in preparation of a medicine for treating platelet-related diseases, the AGK plays an important role in megakaryocyte differentiation and thrombopoiesis, and prompts that a new strategy may be provided for treatment of thrombocytopenia or thrombocythemia through interaction of targeted AGK and JAK2.

STAT3 hyperphosphorylation, dimerization and DNA binding are required for its ability to contribute to malignant transformation. As such, STAT3 has been recognized as a promising target for cancer therapy. Although a number of inhibitors of STAT3-STAT3 dimerization have been reported, molecular ligands that prevent interactions between STAT3 and DNA are very rare. The γ-AApeptide-based one-bead-one-compound (OBOC) combinatorial library was used, and identified γ-AApeptides that can selectively inhibit STAT3 / DNA interaction and suppress the expression levels of STAT3 target genes in intact cells. The results not only validate γ-AApeptides as novel inhibitors of STAT3 signaling pathway, but also demonstrate that in addition to the SH2 domain, the DNA binding domain of STAT3 is targetable for the development of new generation of anti-cancer therapeutics. This also validates the approach of OBOC combinatorial library for the identification of ligands targeting traditionally recognized “undruggable targets”.

The invention discloses the use of methyl berberine as a JNK2 kinase inhibitor. The methyl berberine can specifically bind to the JNK2 kinase and the two have strong binding ability, and at the same time inhibit the activity of JNK2 in a dose-dependent manner. Methyl berberine has good therapeutic activity on psoriasis, which is closely related to methyl berberine inhibiting the activation of JNK and STAT3 signaling pathways and the expression of psoriasis marker molecule S1007, so it can be used as an active ingredient in the preparation of Medicines to treat psoriasis.

The invention discloses an STAT3 (Signal Transducer and Activator of Transcription 3)-targeting small molecular compound as well as a preparation method and application thereof. The STAT3 inhibitor is a compound shown as a general formula I in the specification, wherein R<1> is 5-chloro-2-hydroxyphenyl, (E)-3-(6-bromo-2-pyridine)-2-cyan or 4-(2-phenylquinoline); R<2> is hydrogen or C1-C6 linear alkyl or branched alkyl. The compound has the advantages that the proliferation and the survival of various tumor cells of breast cancer, lung cancer, liver cancer, cervical cancer, prostate cancer and the like can be remarkably inhibited; the STAT3 signal channel of the tumor cells is inhibited; therefore, the tumor cell apoptosis is induced and the effect of treating the tumor diseases is achieved.

The invention discloses application of recombinant porcine-source IL-6 to medicine preparing. The application of the recombinant porcine-source IL-6 comprises application to preparation of medicine for activating signal channels in human cells, application to preparation of medicine for up regulating expressions of adherence factors or inflammatory cell factors or tissue factors in human cells andapplication to preparation of medicine for regulating expressions of chemotactic factors in human cells; medicine for regulating signal channels or downstream gene expressions in human umbilical veinendothelial cells is provided based on the application, and an active ingredient in the medicine comprises the recombinant porcine-source IL-6. Through research findings, the recombinant porcine-source IL-6 can up regulate expressions of adherence factors ICAM-1, inflammatory cell factors IL-6, chemotactic factors MCP-1 and tissue factors, expressions of chemotactic factors IL-8 are reduced, andSTAT3 signal channels can be activated, and therefore the recombinant porcine-source IL-6 can serve as the active ingredient of the medicine capable of achieving the functions.

The present disclosure discloses the use of Tegaserod or a pharmaceutically acceptable salt thereof as a JAK-STAT3 signaling pathway inhibitor and an immunomodulator in the preparation of an anti-tumor drug. Tegaserod and the pharmaceutically acceptable salt thereof show a very excellent inhibitory effect on the growth of various tumor cells in vivo and in vitro, and are expected to be used in the treatment of various cancers.

The invention discloses an STAT3 small molecular selective inhibitor and a preparation method and applications thereof, and the STAT3 small molecular selective inhibitor comprises four structure general formulae as shown in formula I, formula II, formula III and formula IV. The preparation comprises the following steps: allowing 2-phenyl substituted quinoline-4-carboxylic acid thionyl chloride or oxalyl chloride to react to generate substituted acyl chloride, reacting with substituted arylamine to generate substituted quinoline-4-amide derivatives. The applications comprise an application in the preparation of medicaments for treating cancers related to abnormally-activated STAT3 pathway, and an application in the preparation of antitumor medicaments where the STAT3 small molecular selective inhibitor is used as an inhibitor of the STAT3 signal pathway. The STAT3 inhibitor of the invention is a small molecular selective inhibitor; based on results obtained by detecting its effect on cancer cells and evaluating its activity, the small molecular STAT3 selective inhibitor of the invention is applicable to the development of related cancer-treatment medicaments, has quite wide applications, and has very good medicine curative effect. The small molecular STAT3 selective inhibitor of the invention has various types, easily available raw materials, a simple preparation method, high product purity, high yield, and strong practicality.

The invention discloses a function and application of SH2B adapter protein 1 (SH2B1) in myocardial hypertrophy treatment. According to the function and application, the mutual relation between SH2B1 genetic expression and myocardial hypertrophy is determined; the SH2B1 expression rises obviously when the myocardial hypertrophy happens; SH2B1 interference and overexpression adenovirus are used for restraining and promoting cardiomyocyte hypertrophy respectively; the SH2B1 gene defect and overexpression are used for restraining and obviously raising Jak2 / Stat3 signal pathway activation respectively, so that cardiac hypertrophy and fibrosis are restrained and promoted, and the cardiac function can be protected and deteriorated. Hence, the SH2B1 gene can be used as a drug target to be used for screening drugs for protecting the cardiac function and / or preventing, relieving and treating cardiac hypertrophy; the SH2B1 gene can be used as a target gene in gene therapy to be used for designing and preparing the drugs for protecting the cardiac function and / or preventing, relieving and treating cardiac hypertrophy; a new path is provided for cardiac hypertrophy treatment.

The present invention relates to a set of biomarkers, microarrays that provide for detection thereof, an expression signature comprising 16 genes or a subset thereof, and the use thereof in determining the regulation status of IL-6 / STAT3 signaling pathway in a cell sample or subject, as well as compositions for the detection thereof. The regulation status of IL-6 / STAT3 signaling pathway in a cell sample or subject may be assayed based on the level of expression of one or more of these genes. The methods and compositions provided herein may be used to evaluate IL-6 / STAT3 pathway regulation status in a sample; classify a cell sample as having a deregulated or regulated IL-6 / STAT3 signaling pathway; determine whether an agent modulates the IL-6 / STAT3 signaling pathway; predict the response of a subject to an agent that modulates the IL-6 / STAT3 signaling pathway; assign treatment to a subject; and / or evaluate the pharmacodynamic effects of therapies designed to regulate IL-6 / STAT3 pathway signaling. Expression of the biomarkers is preferably determined by RT-PCR using SYBR Green methods, and the expression data analyzed and compared to a control sample by use of the random forest method.

The invention belongs to the field of medicines, and particularly relates to an application of an icaritin hydrate for preparing a medicine capable of inhibiting a STAT3 (Signal Transducer and Activator 3 of Transcription) signal pathway and preventing and curing an oral carcinoma, in particular to the application of the icaritin hydrate of a formula I for preparing the medicine capable of inhibiting the STAT3 signal pathway. The icaritin hydrate of the embodiment of the invention can inhibit the STAT3 and the protein phosphorylation of an upstream pathway JAK2 (Janus Kinase 2) of the STAT3 inoral carcinoma cells, accelerates autophagic vacuole to be increased, accelerates an autophagy-related labelled protein to be transformed to LC3 (light chain)-II from LC3-I, increases the expressionof BECN1 and ATG9 proteins, and reduces the expression of an autophagy-related labelled protein p62 / SQSTM1. The invention takes an amphipathic block high-molecular polymer as a carrier to prepare an icaritin hydrate nanometer medicine preparation, the water solubility of the medicine is enhanced, encapsulation efficiency is 80% and above, an effect on inhibiting the oral carcinoma is better, and in addition, biotoxicity is small.

The invention discloses an STAT (Signal Transducer And Activator Of Transcription)3 signal channel small-molecule inhibitor and application thereof. The inhibitor is expressed in a chemical structural formula which is shown in the specification, wherein R1 is halogenated aryl, R2 is halogenated aryl, R3 is oxygen or sulphur. The inhibitor has functions of effectively inhibiting the multiplication of various tumor cells and inducing the apoptosis of the various tumor cells. The newly developed STAT3 signal channel small-molecule inhibitor not only has a remarkable inhibition effect on the phosphorylation of the STAT3, but also has the remarkable inhibition effect on the IL-6-induced STAT3 activation and the activation of the STAT3 upstream signal CrC and Jak2, and therefore, the multiplication of the various tumor cells can be inhibited and the apoptosis of tumor cells can be induced. Besides, the STAT3 signal channel small-molecule inhibitor has an in-vitro and vivo treatment effect on various tumors of acute and chronic leukemia, multiple myeloma, lymphoma, lung cancer, prostate cancer, cervical cancer and the like.

The invention provides a bifunctional fusion protein targeting VEGF and EGFR and application thereof. The fusion protein provided by the invention can specifically bind epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). The invention provides a fusion protein targeting and synergistically inhibiting the EGFR / VEGF(R) pathway with definite curative effect and high stability. The fusion protein inhibits angiogenesis or cell growth by blocking the phosphorylation of the Akt / Stat3 signaling pathway. It has a remarkable targeted imaging effect and a remarkable curative effect against PDAC tumors. The fusion protein provided by the invention has a strong effect of targeting and specifically inducing tumor cell apoptosis, and can be used for the treatment of malignant tumors.

The invention discloses an application of physagulin P in preparation of antitumor drug. The physagulin P is a compound, the structure of which is shown as formula I in the specification; the invention firstly finds that the physagulin P can lower the expression level of tumor apoptosis resistance genes XIAP and Mcl-1 so as to further inhibit tumor cell proliferation and induce tumor cell apoptosis through inhibiting phosphorylation of STAT3 kinase 705 tyrosine (Tyr705); the physagulin P can obviously inhibit the growths of a variety of malignant tumor cells, such as stomach cancer, lung cancer, liver cancer, myeloma, breast cancer, and the like. The physagulin P shows excellent anti-tumor activity when being used as an anti-tumor activity containing inhibitor of a new specific STAT3 signaling pathway, especially in conjunction with resveratrol and arsenic trioxide. The formula I is as shown in the specification.