37 results about "Unfolded protein response" patented technology

Methods for identifying compounds that are inhibitors of the unfolded protein response are provided. In particular, the methods identify compounds that inhibit the activity of IRE1.

Described herein are methods for increasing the amount of protein secreted by a cell. In one case, a cell is provided which contains a heterologous nucleic acid encoding a protein having unfolded protein response modulating activity and a heterologous nucleic acid encoding a protein of interest to be secreted. In one case, the protein having unfolded protein response modulating activity is selected from the proteins selected from the group consisting of HAC1, PTC2 and IRE1. The protein of interest can be any secreted protein such as a therapeutic or an industrial enzyme. For example the protein can be selected from the group consisting of lipase, cellulase, endo-glucosidase H, protease, carbohydrase, reductase, oxidase, isomerase, transferase, kinase, phosphatase, alpha-amylase, glucoamylase, lignocellulose hemicellulase, pectinase and ligninase.

The invention is directed to substituted indoline derivatives. Specifically, the invention is directed to compounds according to Formula I:wherein R1, R2, and R3 are defined herein.The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer, ocular diseases, and diseases associated with activated unfolded protein response pathways, such as Alzheimer's disease, stroke, Type 1 diabetes Parkinson disease, Huntington's disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, and arrhythmias, and more specifically cancers of the breast, colon, pancreatic, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

The invention provides a method for inducing blood lymphocyte of litopenaeus vannamei to generate UPR (unfolded protein response) by means of an RNA interference technology. The method comprises the following steps: (1) synthesizing dsLvBip with sequence specificity according to a cDNA sequence of a Bip gene of litopenaeus vannamei; and (2) diluting dsLvBip, controlling the injection volume at 50 mu L and injecting dsLvBip into the litopenaeus vannamei according a dosage of 1 mu g / g. The method provided by the invention can be used for simply, conveniently, rapidly, efficiently and specifically inducing blood lymphocyte of litopenaeus vannamei to generate UPR.

Described herein are methods for increasing the amount of protein secreted by a cell. In one case, a cell is provided which contains a heterologous nucleic acid encoding a protein having unfolded protein response modulating activity and a heterologous nucleic acid encoding a protein of interest to be secreted. In one case, the protein having unfolded protein response modulating activity is selected from the proteins selected from the group consisting of HAC1, PTC2 and IRE1. The protein of interest can be any secreted protein such as a therapeutic or an industrial enzyme. For example the protein can be selected from the group consisting of lipase, cellulase, endo-glucosidase H, protease, carbohydrase, reductase, oxidase, isomerase, transferase, kinase, phosphatase, alpha-amylase, glucoamylase, lignocellulose hemicellulase, pectinase and ligninase.

The invention is directed to substituted isoquinoline derivatives and uses thereof. Specifically, the invention is directed to compounds according to Formula I and the use of compounds of Formula (I)in treating disease states: (I) wherein R1, R2, R3, R4, R5, R6, R7 and X are as defined herein. The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer, pre-cancerous syndromes and diseases associated with activated unfolded protein response pathways, such as Alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, Parkinson disease, diabetes, metabolic syndrome, metabolic disorders, Huntington's disease, Creutzfeldt-Jakob Disease, fatal familial insomnia, Gerstmann-Str ussler-Scheinker syndrome, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute diseases of the liver, fatty liver disease, liver steatosis, liver fibrosis, chronic and acute diseases of the lung, lung fibrosis, chronic and acute diseases of the kidney, kidney fibrosis, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, frontotemporal dementias, tauopathies, Pick's disease, Neimann-Pick's disease, amyloidosis, cognitive impairment, ather osclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The inventionis still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

The present invention provides compounds of Formula (I) or (II), which are thought to be able to inhibit mTOR (mammalian target of rapamycin) signaling pathway, induce UPR (unfolded protein response), and / or perturb mitochondrial function of a cyst cell (e.g., a cyst cell causing polycystic kidney disease (PKD, e.g., autosomal dominant PKD (ADPKD) or autosomal recessive PKD (ARPKD)) or polycystic liver disease (PLD, e.g., autosomal dominant PLD (ADPLD) or autosomal recessive PLD (ARPLD)). The invention also provides pharmaceutical compositions, kits, and methods involving the compounds described herein for use in treating PKD or PLD, inhibiting the growth of a cyst cell, and / or killing a cyst cell.

The present invention relates to methods and compositions for modulating the unfolded protein response. The method further relates to methods and compositions for the treatment and diagnosis of protein conformational diseases or disorders, including, but not limited to, α1-antitrypsin deficiency, cystic fibrosis, and autoimmune diseases and disorders. The invention further provides methods for modulating the unfolded protein response by modulating XBP1 mRNA splicing.

Compounds that are inhibitors of the unfolded protein response and endonuclease IRE1 are provided, together with compositions comprising such compounds, and methods for their use in the treatment of various disorders, such as cancer, autoimmune disorders, and diabetes. Also provided are packaged pharmaceuticals comprising these compositions. The compositions may be administered in combination with another therapeutic agent.

A set of small molecules ERα biomodulators that kill therapy-resistant ERα positive breast, ovarian, and endometrial cancer cells. These small molecules have increased therapeutic potential because of an increased ability to kill therapy-resistant breast cancer cells compared to BHPI and other conventional therapies (endocrine therapies, tamoxifen and fulvestrant / ICI). The new compounds do not only inhibit proliferation of the cancer cells but actually kills them, which prevents reactivation of tumors years later.

The present invention provides compounds of Formula (I) or (II), which are thought to be able to inhibit mTOR (mammalian target of rapamycin) signaling pathway, induce UPR (unfolded protein response), and / or perturb mitochondrial function of a cyst cell (e.g., a cyst cell causing polycystic kidney disease (PKD, e.g., autosomal dominant PKD (ADPKD) or autosomal recessive PKD (ARPKD)) or polycystic liver disease (PLD, e.g., autosomal dominant PLD (ADPLD) or autosomal recessive PLD (ARPLD)). The invention also provides pharmaceutical compositions, kits, and methods involving the compounds described herein for use in treating PKD or PLD, inhibiting the growth of a cyst cell, and / or killing a cyst cell.

The invention discloses a method for enhancing secretion of glucose oxidase by coexpression of UPR (unfolded protein response) key genes and downstream target genes, and belongs to the technical field of genetic engineering. The method comprises the steps of respectively cloning and connecting pichia pastoris UPR key gene Haclp and the downstream target genes Pdi1, Erol, Lhs1, Kar2 and Sil1 to pichia pastoris expression carriers pPICZ alpha and pPIC3.5K, transforming into a Pichia pastoris GS115-pPIC9K-GOD strain of which the preservation number is CCTCC NO: M 2012266, and obtaining a strain with enhanced secretion expression of the glucose oxidase compared with the original strain by screening and identifying. The enzyme activity of the glucose oxidase expressed by the strain on a 3L of fermentation tank is 585U / mL. Therefore, good foundation is established for large-scale production of the glucose oxidase.

The invention discloses a screening method and application of an ERO1alpha molecular marker related to liver injury endoplasmic reticulum stress unfolded protein response. CBS<+ / ->gene knockout mice and liver cells are taken as research objects, RNA and protein of tissues or cells are extracted, genes related to HHcy induced liver injury are screened out, the expression change of ERO1alpha and UPRrelated proteins is verified at the cellular level, and the Hcy-induced liver injury specific disease combined diagnosis method composed of ERO1alpha and UPR protein gene networks is established. Themethod is simple and reliable, materials are convenient to obtain, the sensitivity and specificity are highly matched with those of biochemical diagnosis results, and the method has great applicationvalue in early diagnosis and prognosis evaluation of HHcy induced liver injury diseases.

The invention is directed to substituted pyrrolidinone and imidazolidinone derivatives. Specifically, the invention is directed to compounds according to Formula I:wherein R1, R2, R3, R4, R5, R6, R7, X and Y are as defined herein.The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer, pre-cancerous syndromes and diseases / injuries associated with activated unfolded protein response pathways, such as Alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, Parkinson's disease, diabetes, metabolic syndrome, metabolic disorders, Huntington's disease, Creutzfeldt-Jakob Disease, fatal familial insomnia, Gerstmann-Sträussler-Scheinker syndrome, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute diseases of the liver, fatty liver disease, liver steatosis, liver fibrosis, chronic and acute diseases of the lung, lung fibrosis, chronic and acute diseases of the kidney, kidney fibrosis, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, frontotemporal dementias, tauopathies, Pick's disease, Neimann-Pick's disease, amyloidosis, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

N-substituted sulfonylphenyl-5-mitrofuranyl-2-carboxamide derived compounds, which selectively activate the apoptotic, but not the adaptive arm, of the Unfolded Protein Response are provided as is their use in the treatment of diseases such as diabetes, Alzheimer's, Parkinson's, hemophilia, lysosomal storage diseases and cancer.