4524 results about "Kinase" patented technology

The present invention relates to novel cytoplasmic tyrosine kinases isolated from megakaryocytes (megakaryocyte kinases or MKKs) which are involved in cellular signal transduction pathways and to the use of these novel proteins in the diagnosis and treatment of disease. The present invention further relates to specific megakaryocyte kinases, designated MKK1, MKK2 and MKK3, and their use as diagnostic and therapeutic agents.

The present invention includes the receptor protein 4-1BB and the cDNA gene encoding for receptor protein 4-1BB. The nucleotide sequence of the isolated cDNA is disclosed herein along with the deduced amino acid sequence. The 4-1BB protein and fragments and derivatives can be used: 1) as a probe to isolate ligands to receptor protein 4-1BB, 2) to stimulate proliferation of B-cell's expressing 4-1BB, or 3) to block 4-1BB ligand binding. A monoclonal antibody against 4-1BB was developed which specifically recognizes an epitope on the extracellular domain of receptor protein 4-1BB. The monoclonal antibody can be used enhance T-cell proliferation and activation by treating T-cells that have expressed receptor protein 4-1BB with the monoclonal antibody. The effectiveness of the treatment was enhanced when conducted in the presence of protein tyrosinase kinase. A fusion protein for detecting cell membrane ligands to receptor protein 4-1BB was developed. It comprises the extracellular portion of the receptor protein 4-1BB and a detection protein bound to the portion of the receptor protein 4-1BB.

The present invention provides substituted 2-aminopyridines useful in treating cell proliferative disorders. The novel compounds of the present invention are potent inhibitors of cyclin-dependent kinases 4 (cdk4)

It has been discovered that the stimulation of beta-adrenergic receptors, which activate cAMP formation, give rise to increased APP and GFAP synthesis in astrocytes. Hence, the in vitro or in vivo exposure of neuronal cells to certain compositions comprising beta-adrenergic receptor ligands or agonists, including, e.g., norepinephrine, isoproterenol and the like, increases APP mRNA transcription and consequent APP overproduction. These increases are blocked by beta-adrenergic receptor antagonists, such as propranolol. The in vitro or in vivo treatment of these cells with 8Br-cAMP, prostaglandin E2 (PG E2), forskolin, and nicotine ditartrate also increased APP synthesis, including an increase in mRNA and holoprotein levels, as well as an increase in the expression of glial fibrillary acidic protein (GFAP). Compositions and methods are disclosed of regulating APP overexpression and mediating reactive astrogliosis through cAMP signaling or the activation of beta-adrenergic receptors. It has further been found that the increase in APP synthesis caused by 8Br-cAMP, PG E2, forskolin, or nicotine ditartrate is inhibited by immunosuppressants or anti-inflammatory agents, such as cyclosporin A, and FK-506 (tacrolimus), as well as ion-channel modulators, including ion chelating agents such as EGTA, or calcium / calmodulin kinase inhibitors, such as KN93. The present invention has broad implications in the alleviation, treatment, or prevention of neurological disorders and neurodegenerative diseases, including Alzheimer's Disease.

This invention relates to a method for prevention and treatment of aging, age-related disorders and / or age-related manifestations including atherosclerosis, peripheral vascular disease, coronary artery disease, osteoporosis, type 2 diabetes, dementia and some forms of arthritis and cancer in a subject comprising administering to said subject, separately, sequentially or simultaneously a therapeutically effective dosage of each component or combination of statins, bisphosphonates, cholesterol lowering agents or techniques, interleukin-6 inhibitor / antibody, interleukin-6 receptor inhibitor / antibody, interleukin-6 antisense oligonucleotide (ASON), gp130 protein inhibitor / antibody, tyrosine kinases inhibitors / antibodies, serine / threonine kinases inhibitors / antibodies, mitogen-activated protein (MAP) kinase inhibitors / antibodies, phosphatidylinositol 3-kinase (PI3K) inhibitors / antibodies, Nuclear factor κB (NF-κB) inhibitors / antibodies, IκB kinase (IKK) inhibitors / antibodies, activator protein-1 (AP-1) inhibitors / antibodies, STAT transcription factors inhibitors / antibodies, altered IL-6, partial peptides of IL-6 or IL-6 receptor, or SOCS (suppressors of cytokine signaling) protein, or a functional fragment thereof, administered separately, in sequence or simultaneously. Inhibition of the signal transduction pathway for Interleukin 6 mediated inflammation is key to the prevention and treatment of atherosclerosis, peripheral vascular disease, coronary artery disease, aging, age-related disorders and / or age-related manifestations including osteoporosis, type 2 diabetes, dementia and some forms of arthritis and tumors. Inhibition of Interleukin 6 mediated inflammation may be achieved indirectly through regulation of endogenous cholesterol synthesis and isoprenoid depletion or by direct inhibition of the signal transduction pathway utilizing interleukin-6 inhibitor / antibody, interleukin-6 receptor inhibitor / antibody, interleukin-6 antisense oligonucleotide (ASON), gp130 protein inhibitor / antibody, tyrosine kinases inhibitors / antibodies, serine / threonine kinases inhibitors / antibodies, mitogen-activated protein (MAP) kinase inhibitors / antibodies, phosphatidylinositol 3-kinase (PI3K) inhibitors / antibodies, Nuclear factor κB (NF-κB) inhibitors / antibodies, IκB kinase (IKK) inhibitors / antibodies, activator protein-1 (AP-1) inhibitors / antibodies, STAT transcription factors inhibitors / antibodies, altered IL-6, partial peptides of IL-6 or IL-6 receptor, or SOCS (suppressors of cytokine signaling) protein, or a functional fragment thereof. Said method for prevention and treatment of said disorders is based on inhibition of Interleukin-6 inflammation through regulation of cholesterol metabolism, isoprenoid depletion and / or inhibition of the signal transduction pathway

The invention relates generally to methods for inhibiting angiogenesis. More particularly, methods for inhibiting angiogenesis comprise selectively inhibiting phosphoinositide 3-kinase delta (PI3Kδ) activity in endothelial cells. The methods may comprise administration of one or more cytotoxic therapies including but not limited to radiation, chemotherapeutic agents, photodynamic therapies, radiofrequency ablation, anti-angiogenic agents, and combinations thereof.

The present invention relates to novel pyrimidine, pyrrolo-pyrimidine, pyrrolo-pyridine, pyridine, purine and triazine compounds which are able to modulate epidermal growth factor receptor (EGFR), including Her-kinases, and the use of such compounds in the treatment of various diseases, disorders or conditions.

Provided herein are substituted pyrrolopyridine heterocycles and substituted pyrazolopyridine heterocycles, pharmaceutical compositions comprising said heterocycles and methods of using said heterocycles in the treatment of disease. The heterocycles disclosed herein function as kinase modulators and have utility in the treatment of diseases such as cancer, allergy, asthma, inflammation, obstructive airway disease, autoimmune diseases, metabolic disease, infection, CNS disease, brain tumor, obesity, asthma, hematological disorder, degenerative neural disease, cardiovascular disease, or disease associated with angiogenesis, neovascularization, or vasculogenesis.

The present invention provides compounds that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.

The present invention relates to methods of treating cancer in a mammal comprising administering to the mammal a combination therapy comprising a vaccine and a multi-kinase inhibitor, wherein the vaccine comprises an isolated tumor associated peptide having the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I or class-II. Preferably the multi-kinase inhibitor is sunitinib malate and / or sorafenib tosylate or a pharmaceutically acceptable salt thereof.

The invention relates to an enzymology measuring method and reagent with circular increment technology, applied to measure the content of homeotypic cysteine in the measured sample. The character is: with a circular increment technology, increases the measurement sensitivity, thus it can carries on automatic measurement to the homeotypic cysteine in the sample liquid like normal enzymology diagnosing agent. The homeotypic cysteine in the sample liquid reacts with the S-adenosine-L-methionine repeatedly and circularly under the effect of homeotypic cysteine methyl kinase and adenosine homeotypic cysteine, generates the adenosine, the speed of the adenosine generation is in direct proportion to the homeotypic cysteine in the sample, through the generation speed, the aim to measure the content of the homeotypic cysteine in sample can be achieved.

Disclosed herein are novel compounds of Formula (I),wherein the variables are defined as herein. The compounds of Formula (I) are useful as kinase inhibitors and as such would be useful in treating certain conditions and diseases, especially inflammatory conditions and diseases as well as proliferative disorders such as cancer.

The present invention provides compositions comprising interfering RNA (e.g., siRNA, aiRNA, miRNA) that target polo-like kinase 1 (PLK-1) expression and methods of using such compositions to silence PLK-1 expression. More particularly, the present invention provides unmodified and chemically modified interfering RNA molecules which silence PLK-1 expression and methods of use thereof. The present invention also provides serum-stable nucleic acid-lipid particles (e.g., SNALP) comprising an interfering RNA molecule described herein, a cationic lipid, and a non-cationic lipid, which can further comprise a conjugated lipid that inhibits aggregation of particles. The present invention further provides methods of silencing PLK-1 gene expression by administering an interfering RNA molecule described herein to a mammalian subject. The present invention additionally provides methods of identifying and / or modifying PLK-1 interfering RNA having immunostimulatory properties. Methods for sensitizing a cell such as a cancer cell to the effects of a chemotherapy drug comprising sequentially delivering PLK-1 interfering RNA followed by the chemotherapy drug are also provided.

This invention relates to a method for prevention and treatment of aging and age-related disorders including atherosclerosis, peripheral vascular disease, coronary artery disease, osteoporosis, type 2 diabetes, dementia and some forms of arthritis and cancer in a subject comprising administering to said subject, separately, sequentially or simultaneously a therapeutically effective dosage of each component or combination of statins, bisphosphonates, cholesterol lowering agents or techniques, interleukin-6 inhibitor / antibody, interleukin-6 receptor inhibitor / antibody, interleukin-6 antisense oligonucleotide (ASON), gp130 protein inhibitor / antibody, tyrosine kinases inhibitors / antibodies, serine / threonine kinases inhibitors / antibodies, mitogen-activated protein (MAP) kinase inhibitors / antibodies, phosphatidylinositol 3-kinase (PI3K) inhibitors / antibodies, Nuclear factor κB (NF-κB) inhibitors / antibodies, IκB kinase (IKK) inhibitors / antibodies, activator protein-1 (AP-1) inhibitors / antibodies, STAT transcription factors inhibitors / antibodies, altered IL-6, partial peptides of IL-6 or IL-6 receptor, or SOCS (suppressors of cytokine signaling) protein, or a functional fragment thereof, administered separately, in sequence or simultaneously. Inhibition of the signal transduction pathway for Interleukin 6 mediated inflammation is key to the prevention and treatment of atherosclerosis, peripheral vascular disease, coronary artery disease, aging and age-related disorders including osteoporosis, type 2 diabetes, dementia and some forms of arthritis and tumors. Inhibition of Interleukin 6 mediated inflammation may be achieved indirectly through regulation of endogenous cholesterol synthesis and isoprenoid depletion or by direct inhibition of the signal transduction pathway utilizing interleukin-6 inhibitor / antibody, interleukin-6 receptor inhibitor / antibody, interleukin-6 antisense oligonucleotide (ASON), gp130 protein inhibitor / antibody, tyrosine kinases inhibitors / antibodies, serine / threonine kinases inhibitors / antibodies, mitogen-activated protein (MAP) kinase inhibitors / antibodies, phosphatidylinositol 3-kinase (PI3K) inhibitors / antibodies, Nuclear factor κB (NF-κB) inhibitors / antibodies, IκB kinase (IKK) inhibitors / antibodies, activator protein-1 (AP-1) inhibitors / antibodies, STAT transcription factors inhibitors / antibodies, altered IL-6, partial peptides of IL-6 or IL-6 receptor, or SOCS (suppressors of cytokine signaling) protein, or a functional fragment thereof. Said method for prevention and treatment of said disorders is based on inhibition of Interleukin-6 inflammation through regulation of cholesterol metabolism, isoprenoid depletion and / or inhibition of the signal transduction pathway.

It has been discovered that the stimulation of beta -adrenergic receptors, which activate cAMP formation, give rise to increased APP and GFAP synthesis in astrocytes. Hence, the in vitro or in vivo exposure of neuronal cells to certain compositions comprising beta -adrenergic receptor ligands or agonists, including, e.g., norepinephrine, isoproterenol and the like, increases APP mRNA transcription and consequent APP overproduction. These increases are blocked by beta -adrenergic receptor antagonists, such as propranolol. The in vitro or in vivo treatment of these cells with 8Br-cAMP, prostaglandin E2 (PG E2), forskolin, and nicotine ditartrate also increased APP synthesis, including an increase in mRNA and holoprotein levels, as well as an increase in the expression of glial fibrillary acidic protein (GFAP). Compositions and methods are disclosed of regulating APP overexpression and mediating reactive astrogliosis through cAMP signaling or the activation of beta -adrenergic receptors. It has further been found that the increase in APP synthesis caused by 8Br-cAMP, PG E2, forskolin, or nicotine ditartrate is inhibited by immunosuppressants or anti-inflammatory agents, such as cyclosporin A, and FK-506 (tacrolimus), as well as ion-channel modulators, including ion chelating agents such as EGTA, or calcium / calmodulin kinase inhibitors, such as KN93. The present invention has broad implications in the alleviation, treatment, or prevention of neurological disorders and neurodegenerative diseases, including Alzheimer's Disease.

The invention is related to phosphorus substituted kinase inhibitory conjugates, compositions containing such conjugates, and therapeutic methods that include the administration of such conjugates, as well as to processes and intermediates useful for preparing such conjugates.

Compounds of the present invention, alone and in combination with other active agents, find utility in the treatment of hyperproliferative diseases, mammalian cancers and especially human cancers including but not limited to for example malignant melanomas, myeloproliferative diseases, chronic myelogenous leukemia, acute lymphocytic leukemia, a disease caused by c-ABL kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof.

The invention provides a compound of the formula (I) for use in the prophylaxis or treatment of a disease state or condition mediated by a cyclin dependent kinase: wherein A is a group R2 or CH2—R2 where R2 is a carbocyclic or heterocyclic group having from 3 to 12 ring members; B is a bond or an acyclic linker group having a linking chain length of up to 3 atoms selected from C, N, S and O; R1 is hydrogen or a group selected from SO2Rb, SO2NR7R8, CONR7R8, NR7R9 and carbocyclic and heterocyclic groups having from 3 to 7 ring members; R3, R4, R5 and R6 are the same or different and are each selected from hydrogen, halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group Ra—Rb wherein Ra is a bond, O, CO, X1C(X2), C(X2)X1, X1C(X2)X1, S, SO, SO2, NRc, SO2NRc or NRcSO2; and Rb is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRc, X1C(X2), C(X2)X1 or X1C(X2)X1; Rc is hydrogen or C1-4 hydrocarbyl; X1 is O, S or NRc and X2 is ═O, ═S or ═NRc; R7 is selected from hydrogen and a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRc, X1C(X2), C(X2)X1 or X1C(X2)X1; R8 is selected from R7 and carbocyclic and heterocyclic groups having from 3 to 12 ring members; R9 is selected from R8, COR8 and SO2R8; or NR7R8 or NR7R9 may each form a heterocyclic group having from 5 to 12 ring members; but excluding the compounds N-[(morpholin-4-yl)phenyl-1H-indazole-3-carboxamide and N-[4-(acetylaminosulphonyl)phenyl-1H-indazole-3-carboxamide.

The present invention relates to diaryl pyrimidine-2,4-diamines, pharmaceutical compositions thereof, and the use of the compounds and compositions for the inhibition of kinases. The compounds, analogs, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions can be used in the treatment and prevention of cancer.

The present invention relates to trans-capsularly administering into a diseased joint a high specificity antagonist selected from the group consisting of: i) an inhibitor of a pro-inflammatory interleukin; ii) an inhibitor of TNF-α synthesis; iii) an inhibitor of membrane-bound TNF-α; iv) an inhibitor of a natural receptor of TNF-α; v) an inhibitor of NO synthase, vi) an inhibitor of PLA2 enzyme; vii) an anti-proliferative agent; viii) an anti-oxidant; ix) an apoptosis inhibitor selected from the group consisting of EPO mimetic peptides, EPO mimetibodies, IGF-I, IGF-II, and caspase inhibitors, and x) an inhibitor of MMPs; and xi) an inhibitor of p38 kinase.

The present invention provides diagnostic and prognostic methods for predicting the effectiveness of treatment of a cancer patient with an EGFR kinase inhibitor. Methods are provided for predicting the sensitivity of tumor cell growth to inhibition by an EGFR kinase inhibitor, comprising assessing whether the tumor cell has undergone an epithelial to mesenchymal transition (EMT), by determining the expression level of epithelial and / or mesenchymal biomarkers, wherein tumor cells that have undergone an EMT are substantially less sensitive to inhibition by EGFR kinase inhibitors. Improved methods for treating cancer patients with EGFR kinase inhibitors that incorporate the above methodology are also provided. Additionally, methods are provided for the identification of new biomarkers that are predictive of responsiveness of tumors to EGFR kinase inhibitors. Furthermore, methods for the identification of agents that restore the sensitivity of tumor cells that have undergone EMT to inhibition by EGFR kinase inhibitors are also provided.

The present invention provides compounds that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.

Disclosed are novel substituted 2H-isoquinolin-1-one and 3H-quinazolin-4-one derivatives useful as inhibitors of Rho kinase and for treating a variety of diseases and disorders that are mediated or sustained through the activity of Rho kinase, including cardiovascular diseases, pharmaceutical compositions comprising such compounds, methods for using such compounds and processes for making such compounds.

This invention is directed to methods for identifying apoptosis signal-regulated kinase 1 (“ASK1”) inhibitors useful for preventing and / or treating cardiovascular disease. This invention also relates to methods for preventing and / or treating cardiovascular disease in an animal by administering to the animal an ASK1 inhibitor.

The invention is related to polynucleotide-based cytomegalovirus vaccines. In particular, the invention is plasmids operably encoding HCMV antigens, in which the naturally-occurring coding regions for the HCMV antigens have been modified for improved translation in human or other mammalian cells through codon optimization. HCMV antigens which are useful in the invention include, but are not limited to pp65, glycoprotein B (gB), IE1, and fragments, variants or derivatives of either of these antigens. In certain embodiments, sequences have been deleted, e.g., the Arg435-Lys438 putative kinase in pp65 and the membrane anchor and endocellular domains in gB. The invention is further directed to methods to induce an immune response to HCMV in a mammal, for example, a human, comprising delivering a plasmid encoding a codon-optimized HCMV antigen as described above. The invention is also directed to pharmaceutical compositions comprising plasmids encoding a codon-optimized HCMV antigen as described above, and further comprising adjuvants, excipients, or immune modulators.

The present invention relates to diaryl pyrimidine-2,4-diamines, pharmaceutical compositions thereof, and the use of the compounds and compositions for the inhibition of kinases. The compounds, analogs, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions can be used in the treatment and prevention of cancer.