32 results about "ERBB4" patented technology

The present invention provides sets of genes the expression of which is important in the prognosis of cancer. In particular, the invention provides gene expression information useful for predicting whether cancer patients are likely to have a beneficial treatment response to chemotherapy.FHIT; MTA1; ErbB4; FUS; BBC3; IGF1R; CD9; TP53BP1; MUC1; IGFBP5; rhoC; RALBP1; STAT3; ERK1; SGCB; DHPS; MGMT; CRIP2; ErbB3; RAP1GDS1; CCND1; PRKCD; Hepsin; AK055699; ZNF38; SEMA3F; COL1A1; BAG1; AKT1; COL1A2; Wnt.5a; PTPD1; RAB6C; GSTM1, BCL2, ESR1; or the corresponding expression product, is determined, said report includes a prediction that said subject has a decreased likelihood of response to chemotherapy.

The present invention provides polypeptide variants of neuregulin-1β (NRG-1β) that have enhanced or decreased binding affinity to ErbB3 and / or ErbB4. The invention also provides methods of screening and producing polypeptide variants of NRG-1β and methods of using polypeptide variants of NRG-1β for treating diseases.

The use of a compound for the manufacture of a medicament for the prophylaxis or treatment of: A. a disease state or condition mediated by a kinase which is BCR-abl, VEGFR, PDGFR, EGFR, Flt3, JAK (e.g. JAK2 or JAK3), C-abl, PDK1, Chk (e.g. Cbk1 or Chk2), FGFR (e.g. FGFR3), Ret, Eph (e.g. EphB2 or EphB4), or Src (e.g. cSrc); or B. a cancer in which the cancer cells thereof contain a drug resistant kinase mutation which is: (a) a threonine gatekeeper mutation; or (b) a drug-resistant gatekeeper mutation; or (c) an imatinib resistant mutation; or (d) a nilotinib resistant mutation; or (e) a dasatinib resistant mutation; or (f) a T670I mutation in KIT; or (g) a T674I mutation in PDGFR; or (h) T790M mutation in EGFR; or (i) a T315I mutation in abl; or C. a cancer which expresses a mutated molecular target which is a mutated form of BCRabl, c-kit, PDGF, EGF receptor or ErbB2; or D. a disease mediated by a kinase containing a mutation in a region of the protein that binds to or interacts with other cancer agents but does not bind to or interact with the compounds of formula (I) or (I′), for example a mutated kinase selected from c-abl, c-kit, PDGFR including PDGFR-beta and PDGFR-alpha, and ErbB family members such as EGFR (ErbB1), HER2 (ErbB2), ErbB3, and ErbB4, members of the Ephrin receptor family including EphA1, EphA2, EphA3, EphA4, EphA5, EphA8, EphA10, EphB1, EphB2, EphB3, EphB5, EphB6, c-Src and kinases of the JAK family such as TYK2; wherein the compound is a compound of the formula (I or I′): or a salt, solvate, tautomer or N-oxide thereof wherein R0′, R1, R1′, R2′, R3′, R4′, A′, X′, E, A and M are as defined in the claims.

The present invention provides a method of screening NRG mutant for activating ErbB acceptor specifically. The method includes the following steps: establishing 3D model of complex of NRG, ErbB3, ErbB4, NRG / ErbB3 and NRG / ErbB4 in a homogeneous model establishing process; molecular kinetically simulating conformation and stability of NRG / ErbB3 and NRG / ErbB4; MM / PBSA process of calculating the binding free energy between NRG and ErbB3 or ErbB4; scanning and calculating process based on alanine theory to determine the NRG and acceptor affinity change during the mutation from NRG residue to alanine and determining NRG mutant for activating ErbB acceptor specifically. The present invention also provides the NRG mutant and its application and preparation process.

The invention discloses a non-small cell lung cancer targeted therapy gene detection method, and belongs to the field of gene detection. The method for detecting 466 mutations of 12 oncogenes is developed by multiplex PCR and high throughput sequencing technologies, wherein the oncogenes are AKT1, ALK, BRAF, EGFR, ERBB4, FGFR1, FGFR2, FGFR3 , KRAS, MET, PIK3CA, and PTEN, and the mutations may be substitutions, insertions and / or deletions of one or more bases. The detection method provided by the invention has the advantages of high detection sensitivity of up to 0.01%, and clear and objective detection results, can be directly used for reflecting specific mutation sites of the relevant gene, directly used for guiding clinical non-small cell lung cancer targeted dosage, and used for early diagnosis or auxiliary diagnosis and screening of cancers as well as post-cancer surveillance.

The present invention concerns methods and means for controlling excessive proliferation and / or migration of smooth muscle cells, and in particular for treating stenosis, by using antagonists of a native ErbB4 receptor. The invention further concerns a method for the identification of ErbB4 agonists and antagonists capable of inhibiting or enhancing the proliferation or migration of smooth muscle cells.

The invention relates to methods for predicting an outcome of cancer in a patient suffering from cancer, said patient having been previously diagnosed as node positive and treated with cytotoxic chemotherapy, said method comprising determining in a biological sample from said patient an expression level of a plurality of genes selected from the group consisting of ACTG1, CAl2, CALM2, CCND1, CHPT1, CLEC2B, CTSB, CXCL13, DCN, DHRS2, EIF4B, ERBB2, ESR1, FBXO28, GABRP, GAPDH, H2AFZ, IGFBP3, IGHG1, IGKC, KCTD3, KIAA0101, KRT17, MLPH, MMP1, NAT1, NEK2, NR2F2, OAZ1, PCNA, PDLIM5, PGR, PPIA, PRC1, RACGAP1, RPL37A, SOX4, TOP2A, UBE2C and VEGF; ABCB1, ABCG2, ADAM15, AKR1C1, AKR1C3, AKT1, BANF1, BCL2, BIRC5, BRMS1, CASP10, CCNE2, CENPJ, CHPT1, EGFR, CTTN, ERBB3, ERBB4, FBLN1, FIP1L1, FLT1, FLT4, FNTA, GATA3, GSTP1, Herstatin, IGF1R, IGHM, KDR, KIT, CKRT5, SLC39A6, MAPK3, MAPT, MKI67, MMP7, MTA1, FRAP1, MUC1, MYC, NCOA3, NFIB, OLFM1, TP53, PCNA, PI3K, PPERLD1, RAB31, RAD54B, RAF1, SCUBE2, STAU, TINF2, TMSL8, VGLL1, TRA@, TUBA1, TUBB, TUBB2A.

The present invention concerns methods and means for controlling excessive proliferation and / or migration of smooth muscle cells, and in particular for treating stenosis, by using antagonists of a native ErbB4 receptor. The invention further concerns a method for the identification of ErbB4 agonists and antagonists capable of inhibiting or enhancing the proliferation or migration of smooth muscle cells.

The present invention provides polypeptide variants of neuregulin-1β (NRG-1β) that have enhanced or decreased binding affinity to ErbB3 and / or ErbB4. The invention also provides methods of screening and producing polypeptide variants of NRG-1β and methods of using polypeptide variants of NRG-1β for treating diseases.

This invention relates to methods and compositions for the treatment of schizophrenia. Specifically, provided herein are methods and compositions for the treatment of schizophrenia by modulating the effect of Neuregulin-1 on the stimulation of erbB and its subsequent effect on schizophrenic prefrontal cortex.

Disclosed herein are methods of treating diseases that exhibit over-activation of the ERBB4 pathway, such as breast cancer and lung cancer. The method comprises administering to a subject having a disease that exhibits over-activation of the ERBB4 pathway and a gene expression profile consistent with an ERBB4-sensitive profile a therapeutically effective amount of an ERBB4 inhibitor, wherein the disease is effectively treated. Gene expression profiles of ERBB4-sensitive cells and microarrays suitable for protein-tyrosine kinases are also provided.

The invention provides application of an ErbB receptor stimulant to preparation of a medicament for treating epilepsy. The ErbB receptor stimulant has the advantages: the inhibiting effect of the ErbB4 stimulant NRG1 on epilepsy is disclosed, the organism of epilepsy is studied intensively, a research direction for studying a novel effective 'target' and a molecule of an epilepsy inhibiting medicament is provided, and a basis is laid for the screening of a novel medicament for treating brain diseases based on neuronal excitability changes.

The invention relates to an application of neuregulin 1 (NRG1) and acceptor thereof as a target for preparing and screening anti-epileptic drugs. The application of NRG1 for inhibiting the development and progression of epilepsy by activating leukemia virus oncogene homolog 4 (ErbB4) of bird red blood cells in inhibitory neurons in the brain is proposed for the first time; and novel target is provided for effective prevention, control or treatment of the epilepsy.

The invention discloses use of neuregulin 1, belongs to the technical field of a biomedicine, and particularly relates to application of the neuregulin 1 inpreparation of a drug for treating lead encephalopathy. The characteristics of the lead encephalopathy are high expression of inflammatory cells and inflammatory factors and wide neuronal cell death. Neuron loss and nerve inflammatory reaction play a crucial role in the lead encephalopathy process. The neuregulin 1 has a significant nerve inflammatory reaction and a role of protecting cell apoptosis in the lead encephalopathy, can inhibit inflammatory activation, reduces the quantities of microglial cells and astrocytes, reduces the expression level of inflammatory cytokines COX-2, and improves the learning and memory defects caused by lead poisoning. In addition, the quantity of ErbB4 positive cells can be increased by the neuregulin 1; the inhibition apoptosis activity of anti-apoptosis protein Bc1-2 is improved; expression of pro-apoptotic protein Bax is reduced, so that apoptosis is inhibited, and neuregulin 1 has significant neuroprotective effects on the lead encephalopathy.

The invention discloses application of an NRG (neuregulin) 1beta1 / ErbB4 / Akt signal pathway in preparing or screening a drug target for resisting Alzheimer disease neuronal loss. Experiments discover the protection effect of the NRG1beta1 / ErbB4 / Akt in resisting neuronal loss in Alzheimer disease, the application firstly provides that NRG1beta1 plays the occurrence development process of resisting apoptosis in brain of Alzheimer disease by activating an ErbB4 receptor in brain, and a more specific novel target is provided to effective prevention, control or treatment of Alzheimer disease.

The invention discloses a marker for assisting epilepsy diagnosis and a detection kit of the marker, and relates to the field of the epilepsy diagnosis. Research for detecting an ERBB4 gene of membersof an epilepsy family discovers that the ERBB4 gene of the members suffering from epilepsy in the family has mutant c.A1972T; the gene mutation results in variation of 658th amino acid of the corresponding ERBB4 gene protein from isoleucine (I) to phenylalanine (F), and the variation is missense mutation; nucleic acid molecules containing the mutant c.A1972T or protein containing mutant p.I658F can be used as a biomarker for the epilepsy diagnosis, and a quick and reliable detection auxiliary marker is provided for the epilepsy diagnosis in molecular level.

A method for detecting gene fusion that is a mutation responsible for cancer (driver mutation), wherein the method includes a step for detecting, in an isolated sample derived from a subject having cancer, any fusion polynucleotide among an EZR-ERBB4 fusion polynucleotide, KIAA1468-RET fusion polynucleotide, TRIM24-BRAF fusion polynucleotide, CD74-NRG1 fusion polynucleotide, or SLC3A2-NRG1 fusion polynucleotide, or a polypeptide encoded thereby.

Polypeptides of the neuregulin (NRG) heparin binding domain (N-HBD) and nucleic acids coding therefor are disclosed. In particular, fusion polypeptides are produced that comprise, as a targeting structure, a N-HBD polypeptide, fragment, homologue or functional derivative and a protein to be targeted. This is fused to a polypeptide or peptide being targeted (Ptrg) to cell surfaces rich in heparan sulfate proteoglycans to either activate or inhibit interactions at tyrosine kinase receptors. A preferred fusion polypeptide comprises an N-HBD, a spacer and the extracellular domain of erbB4, one of several receptors signaled by NRG, which is potent NRG antagonist. Such products are used to treat diseases or conditions where either agonism or antagonism at tyrosine kinase receptors has beneficial effects, including cancer and a multitude of diseases of the nervous system.

Polypeptides of the neuregulin (NRG) heparin binding domain (N-HBD) and nucleic acids coding therefor are disclosed. In particular, fusion polypeptides are produced that comprise, as a targeting structure, a N-HBD polypeptide, fragment, homologue or functional derivative and a protein to be targeted. This is fused to a polypeptide or peptide being targeted (P<SUB>trg< / SUB>) to cell surfaces rich in heparan sulfate proteoglycans to either activate or inhibit interactions at tyrosine kinase receptors. A preferred fusion polypeptide comprises an N-HBD, a spacer and the extracellular domain of erbB4, one of several receptors signaled by NRG, which is potent NRG antagonist. Such products are used to treat diseases or conditions where either agonism or antagonism at tyrosine kinase receptors has beneficial effects, including cancer and a multitude of diseases of the nervous system.

The invention provides application of Neuregulin-1 (NRG1) in preparation of a product to enhance Transient Receptor Potential Cation Channel Subfamily C Member 6 (TRPC6) channel activity. The invention discovers that TRPC6 channel protein is co-labeled with ErbB4 receptor of NRG1 in hippocampus through immunofluorescence experiment; and moreover, it is further proven by Western blot that the NRG1can promote nitrosylation of the TRPC6 channel protein. Then, it is proven by whole cell patch clamp experiment that both nitrosylation inhibitors and TRPC6 channel blockers can block the NRG1-ErbB4 pathway as well as promote release of gamma aminobutyric acid (GABA); and moreover, TRPC6 channel is knocked-out on intermediate neurons expressing the ErbB4 receptor so as to block effect of the NRG1on GABA release, thereby leading to neuronal rhythmic oscillations and schizophrenia-like behavioral abnormalities. Research results of the invention show that the NRG1 can activate the TRPC6 channelby promoting nitrosylation of the TRPC6 channel protein, thereby increasing the release of the GABA.

The present invention relates to a 6-(isooxazolidin-2-yl)-N-phenylpyrimidin-4-amine derivative, and a pharmaceutical composition for preventing or treating cancer comprising the compound as an effective component. The compound exhibits high inhibitory activity against an epidermal growth factor receptor (EGFR) variant, or wild-type or variants of one or more of ERBB2 and ERBB4, and thus may be usefully used in the treatment of cancers in which same are expressed. In particular, the compound exhibits excellent inhibitory activity on proliferation of lung cancer cell lines, and thus can be usefully used in the treatment of lung cancer.

An object of the present invention is to provide a molecular targeted drug effective for diffuse gastric cancer. According to the present invention, there is provided a pharmaceutical composition for treating diffuse gastric cancer in a patient, which comprises an EGF receptor inhibitor having an ErbB1 inhibitory activity and an ErbB4 inhibitory activity. According to the present invention, there is provided the aforementioned pharmaceutical composition for use in a combination therapy with an anti-VEGF receptor 2 antibody and / or a cMET inhibitor. According to the present invention, there is provided a method for treating diffuse gastric cancer in a patient, which comprises the step of administering an EGF receptor inhibitor having an ErbB1 inhibitory activity and an ErbB4 inhibitory activity to the patient.

The invention discloses an antigen peptide related to esophagus cancer driver gene mutation. Esophagus cancer driver genes are at least two of EPCAM, MUC1, GPC3, LRP1B, ERBB4 and PREX2; the sequence of the antigen peptide includes at least two of SEQ No.1-12; according to the application of the antigen peptide, the antigen peptide is used for inducing generation of specific cytotoxic T cell clone; the antigen peptide has high affinity with MHC I molecules on DC cells, can effectively stimulate and induce generation of specific cytotoxic T lymphocytes, can be used for immune clearance of esophagus cancer related driver gene mutation tumor cells, and has good treatment potential.

The invention provides application of a membrane protein molecule ErbB4 in preparation of medicines for treating of cerebral ischemic injury. The application comprises the following steps: establishing an injury model, AND performing treatment on the injury model by using a medicine prepared from a membrane protein molecule ErbB4, that is, promoting total expression and activity of ErbB4 in the injury model, and inhibiting injury of ischemia to neurons. The invention further provides a medicine for treating cerebral ischemic injury. The medicine comprises a regulatory protein NRG1 for promoting total expression and activity of the membrane protein molecule ErbB4. The invention further provides a method for promoting total expression and activity of the membrane protein molecule ErbB4. Themethod comprises the following processes: (1) establishing a cerebral ischemia model; (2) observing total expression and active fragment expression of ERBB4 in the cerebral ischemia model; (3) confirming whether the activity and expression regulation of the membrane molecule ErbB4 can affect cholesterol synthesis or not; and (4) adding NRG1 in the cerebral ischemia model to promote total expression and activity of ERBB4. The application provided by the invention inhibits injury of ischemia to neurons and has a protection function on cerebral ischemic injury.

The invention relates to an application of neuregulin 1. Research finds that mechanical induced pain and hyperalgesia induced by carrageenan or a complete Freund's adjuvant can be obviously relieved by intrathecal injection of NRG1 into spinal cord, and the effect can be blocked by NRG1 neutralizing peptide (ecto-ErbB4) capable of specifically inhibiting activation of an ErbB4 tyrosine kinase receptor. Therefore, NRG1 can be applied to preparation of a medicine for treating or relieving inflammatory pain or can be applied to preparation of a medicine for activating the activity of ErbB4 tyrosine kinase expressed by spinal dorsal horn. The medicines have the advantages of clear targeting, safety, no addiction or other side effects, and obvious curative effect. The research of the inventionprovides a new treatment target and treatment scheme for the treatment of inflammatory pain.

The present invention discloses applications of iron oxide nanoparticles in preparation of a drug for improving erlotinib resistance, wherein a mass ratio of the iron oxide nanoparticles to the erlotinib is generally 1-40:1 and the consumption of the iron oxide nanoparticles in each day is not more than 10 mg / kg when the iron oxide nanoparticles are used for preparing the drug for improving erlotinib resistance. According to the present invention, lung cancer cells H 358 cultured in vitro and a drug resistance cell line A549 cultured in vitro are concurrently treated with the iron oxide nanoparticles and the erlotinib, and the results show that the anti-tumor-cell-proliferation effect can be significantly enhanced; further experiment results show that the tumor growth can be significantly inhibited through the combination of the iron oxide nanoparticles and the erlotinib, such that it is suggested that the iron oxide nanoparticles can enhance the sensitivity of the lung cancer cells on the erlotinib through the ERBB2, ERBB3, ERBB4 downstream signaling pathway; and the solving scheme is provided for the clinical treatment of the erlotinib resistant lung cancer patient.

Methods for promoting maturation of cardiomyocytes, involving introducing a microRNA combination containing miR-125b, miR-199a, miR-221, and / or miR222, or suppression of ErbB4 in immature cardiomyocytes, which may be co-cultured with endothelial cells.

The present invention provides a method of screening NRG mutant for activating ErbB acceptor specifically. The method includes the following steps: establishing 3D model of complex of NRG, ErbB3, ErbB4, NRG / ErbB3 and NRG / ErbB4 in a homogeneous model establishing process; molecular kinetically simulating conformation and stability of NRG / ErbB3 and NRG / ErbB4; MM / PBSA process of calculating the binding free energy between NRG and ErbB3 or ErbB4; scanning and calculating process based on alanine theory to determine the NRG and acceptor affinity change during the mutation from NRG residue to alanine and determining NRG mutant for activating ErbB acceptor specifically. The present invention also provides the NRG mutant and its application and preparation process.

The invention discloses an antigen peptide (neoantigen) related to liver cancer driver gene mutation. A liver cancer driver gene is at least two of CDKN2A, ERBB4, HNF1A, NFE2L2, NTRK3, LRP1B, PREX2, ZFHX3 and ZNF521; the sequences of the antigen peptide are at least two of SEQ No.1-17; according to the application of the antigen peptide, the antigen peptide is used for inducing generation of specific cytotoxic T cell clone; and the antigen peptide has high affinity with MHC I molecules on DC cells, can effectively stimulate and induce generation of specific cytotoxic T lymphocytes, can be used for immune clearance of tumor cells with driver gene mutation related to liver cancer, and has good treatment potential.

The invention discloses an application of NRG1 and a receptor thereof to preparation of a skin wound repair medicine or reagent. The NRG1 promotes the skin wound repair by promoting phosphorylation of ErbB4. The invention also discloses a pharmaceutical composition for promoting skin wound repair. The pharmaceutical composition is a carrier containing an NRG1 gene. In addition, the invention also provides a method for screening potential substances for promoting skin wound repair. The NRG1 and the pharmaceutical composition thereof disclosed by the invention have a relatively good promotion effect on skin wound repair, and have important reference and practical significance in skin wound repair. In addition, the method for screening the potential substances for promoting skin wound repair, provided by the invention, has a good effect on screening medicines and substances for skin wound repair, and has better measuring and guiding effects on screening proper substances for skin wound repair.