44 results about "XIAP" patented technology

The present invention provides polypeptides and specific binding agents that modify the activity of an initiator caspase involved in apoptosis, caspase-9. The polypeptides include the third baculoviral IAP repeat (BIR3) of an IAP and form a heterodimer complex with caspase-9. Nucleic acid molecules including expression vectors encoding the polypeptides and variants thereof as well as variants of caspase-9 are provided. Such polypeptide and nucleic acid molecules may be used for modifying apoptosis.

T cell immune responses are enhanced by presentation of antigen to CD8+ T cells using a chimeric nucleic acid immunogen or vaccine that links DNA encoding an antigen with DNA encoding a polypeptide that targets or translocates the antigenic polypeptide to which it is fused (immunogenicity-potentiating polypeptides or “IPP”). By inhibiting apoptosis in the vicinity of a T cell responses to such a nucleic acid immunogen, even more potent immune responses are attained. The present strategy prolongs the survival of DNA-transduced cells, including dendritic cells (DCs), thereby enhancing the priming of antigen-specific T cells and increase potency. Co-delivery of DNA encoding an inhibitor of apoptosis, including (a) BCL-xL, (b) BCL-2, (c) XIAP, (d) dominant negative caspase-9, or (e) dominant negative caspase-8, or (f) serine protease inhibitor 6 (SPI-6) which inhibits granzyme B, with DNA encoding an antigen, prolongs the survival of transduced DCs and results in significant enhancement of antigenspecific T cell immune responses that provide potent antitumor effects. Thus, co-administration of a DNA vaccine encoding antigen linked to an IPP along with one or more DNA constructs encoding an anti-apoptotic protein provides a novel way to enhance vaccine potency.

The present invention provides an inhibitor of NF-κB, guggulsterone and its analogs. Guggulsterone suppresses NF-κB activation induced by TNF, phorbol ester, okadaic acid, cigarette smoke, H2O2 and IL-1β, as well as constitutive NF-κB activation expressed in most tumor cells. One mechanism by which guggulsterone inhibits activation of NF-κB is through suppression of IκBα phosphorylation and IκBα degradation. NF-κB-dependent gene transcription is modulated by guggulsterone and its analogs. In particular, induction by TNF, TNFR1, TRADD, TRAF2, NIK and IKK, is modulated by guggulsterone and its analogs. In addition, guggulsterone decreased the expression of genes involved in anti-apoptosis (IAP1, XIAP, Bfl-1 / A1, bcl-2, cFLIP, survivin), proliferation (cyclin D1, c-myc) and metastasis (MMP-9, COX2 and VEGF).

The present disclosure relates to XIAP inhibitor compounds of the formula I.

The present disclosure relates to XIAP inhibitor compounds of the formula I.

A Smac mimetic therapy wherein the Smac mimetic is selected and developed based at least in part on its poor inhibition of XIAP-dependent processes.

A treatment for cancer using a combination therapy including an inhibitor of the PI3K / Akt pathway in combination with roscovitine. It is shown that the combination of roscovitine and API-2 (Triciribine) or roscovitine and LY294002 induce the apoptosis of androgen-dependent (LNCaP) and androgen-independent (PC3) prostate cancer cells. Two important results have been observed. First, cells that respond to roscovitine alone (LNCaP) initiate apoptosis sooner when co-treated. Second, cells that do not respond to roscovitine alone (PC3) apoptose when co-treated, although with delayed kinetics. In the absence of roscovitine, AKT inhibitors had no effect on LNCaP or PC3 survival, and in both cell lines, the combined treatment activated the mitochondrial pathway of apoptosis. Importantly, normal epithelial cells (RPWE) remained viable in the presence of roscovitine and AKT inhibitors. Events elicited by roscovitine (down-regulation of XIAP) and AKT inhibitors (accumulation of Bim) in LNCaP and PC3 cells are identified. Additional data show that PC3 cells apoptose when treated with AKT inhibitors and depleted of either XIAP or Cdk9. Taken together, these important results lead to improved treatments for cancers, such as prostate cancer, through the combination therapies taught herein.

The invention belongs to the technical field of genetic engineering drugs, and discloses a double-target-spot fusion protein capable of enhancing the TRAIL antitumor activity. The cDNA sequence of the overall-length fusion gene sequence 1 is shown in SEQ ID NO1; the coding amino acid sequence of the overall-length fusion gene sequence 1 is shown in SEQ ID NO2; the coding cDNA sequence of the overall-length fusion gene sequence 2 is shown in SEQ ID NO4; and the coding amino acid sequence of the overall-length fusion gene sequence 2 is shown in SEQ ID NO5. In comparison with the prokaryotic expression carrier of separate TRAIL protein soluble fragment coding cDNA sequence, the fusion protein of the prokaryotic expression carrier has higher soluble expression, and the recycling and purifying efficiency of the fusion protein is higher; and the in-vitro biological activity analysis indicates that the fusion protein can activate death receptors on the cell membrane and inhibit expression of an XIAP gene in the cell plasma, enhance the activity of inducing tumor cell apoptosis through the double-target-spot function in apoptotic pathway and ensure stronger antitumor effect.

Assays are disclosed for identifying peptides and peptidomimetics for promoting apotosis in cells, through a pathway involving the Inhibitor of Apoptosis Proteins (IAPs), exemplified by XIAP, and the mitochondrial protein Smac / DIABOLO (hereinafter Smac) and homologs thereof. Also disclosed are IAP-binding peptides and peptidomimetics identified through the use of the assay.

The present invention relates to naturally occurring and chemically synthesized small molecule antagonists of XIAP family proteins. In particular, the present invention provides embelin and other XIAP inhibitors and methods of using these compounds as antagonists of the anti-apoptotic effects of XIAP family member proteins. The present invention also provides methods for treating diseases and pathologies (e.g., neoplastic diseases).

Disclosed herein are compounds that inhibit Hsp90 interactions with IAP proteins, such as Survivin, XIAP, cIAP1, or cIAP2, and methods for identifying and using such compounds.

A method and compound for enhancing the lethality of an anti-cancer therapy, such as radiation, chemotherapy, or TRAIL protein, are disclosed. The compound is composed of morpholino subunits joined by phosphorodiamidate linkages, and has a targeting sequence that is complementary to an AUG start, IRES, or splice-donor region of the transcript for human X-linked inhibitor of apoptosis protein (XIAP). The method includes exposing cancer cells to the compound.

The invention discloses a small peptide TAT-AVPY for treating ischemic brain damage, and an application thereof. The complete sequence of the small peptide TAT-AVPY is H-YGRKKRRQRRR-AVPY-OH, represented by SEQ ID NO:1. With the small peptide TAT-AVPY provided by the invention, the binding of XIAP and proaspase-9 (Casp 9) can be reduced; nitrosylation of XIAP and proaspase-9 (Casp 9) can be alleviated; and proaspase-9 activation can be alleviated. Therefore, cell apoptosis induced by cerebral ischemia can be alleviated. Also, TAT can directly bring fused small peptide into cells, such that a problem of the approach for the drug to enter cells is solved, and medication is convenient. The small peptide TAT-AVPY has no immunogenicity, and does not cause an immune response of a body. Therefore, side effects are reduced, and the effectiveness of secondary medication or more is ensured.

A treatment for prostate cancer using cyclin-dependent kinase inhibitors is provided. The effects of cyclin-dependent kinase inhibitors on the survival of prostate cancer cells was examined. Roscovitine, R-roscovitine, and CGP74514A were shown to induce the apoptosis of LNCaP and LNCaP-Rf cells, both of which express wild-type p53. The cyclin-dependent kinase inhibitors of the present invention induce the mitochondria-mediated apoptosis of prostate cancer cells by a dual mechanism: p53 accumulation and XIAP depletion.

The present invention relates to naturally occurring and chemically synthesized small molecule antagonists of XIAP family proteins. In particular, the present invention provides embelin and other XIAP inhibitors and methods of using these compounds as antagonists of the anti-apoptotic effects of XIAP family member proteins. The present invention also provides methods for treating diseases and pathologies (e.g., neoplastic diseases).

The invention belongs to the technical field of gene engineering, and particularly relates to a fusion protein formed by fusing a protein transduction domain (PTD) coded by TAT (trans-activator of transcription) genes of HIV (human immunodeficiency viruses) and an X-linked inhibitor of apoptosis protein (XIAP) nucleotide sequence. The amino acid sequence of the fusion protein is expressed as SEQ ID No: 1. Compared with the prior art, the original XIAP genes with nucleotide sequence expressed as SEQ ID No: 3 are optimized by using escherichia coli preferred codons so that the original XIAP genes are efficiently expressed in escherichia coli, the defect that the XIAP cannot stride the blood brain barrier or enter the brain to play a role in apoptosis resistance is made up by using the transduction capability of the PTD coded by the TAT genes of the HIV so that the final expression product of the genes can enter the brain tissue cells to play a role in cell apoptosis resistance, and the fusion protein is used for therapy and research of central nervous system diseases.

The invention relates to a biomarker of granulosa cells used for polycystic ovary syndrome (PCOS) diagnosis as well as a screening method and a diagnostic kit thereof. The novel diagnostic biomarker is discovered by screening PCOS-related biomarkers in the whole genome by adopting combined analysis of RNA-seq, miRNA-seq and MBD-seq. The biomarker comprises miR-429, miR-141-3p and miR-126-3p, and / or XIAP gene, BRD3 gene, MAPK14 gene and SLC7A5 gene. Compared with the prior art, the biomarker of granulosa cells used for PCOS diagnosis has the advantages of being high in detection sensitivity, high in accuracy and so on.

The invention belongs to the field of genetically engineered drugs and provides a mutant protein MuR5S4TR of TRAIL, and a preparation method and use thereof. The 2-10th bits of an N-terminal amino acid sequence of the mutant protein are composed of a transmembrane peptide sequence RRRRR (R5) and a binding sequence AVPI of an apoptosis inhibitor XIAP, and the 11-169th bits are TRAIL protein peptide segments (123-281aa). The specific sequence is shown in SEQ ID NO:2.

This invention relates to compounds, compositions, and methods useful for modulating XIAP gene expression using short interfering nucleic acid (siNA) molecules. This invention also relates to compounds, compositions, and methods useful for modulating the expression and activity of other genes involved in pathways of XIAP gene expression and / or activity by RNA interference (RNAi) using small nucleic acid molecules. In particular, the instant invention features small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules and methods used to modulate the expression of XIAP genes.

The invention relates to the field of targeted treatment medicines for tumors and in particular relates to an anti-tumor polypeptide Sur-X targeting to a survivin-XIAP complex and application of the anti-tumor polypeptide Sur-X in treatment on multiple tumors including colorectal cancer and gastric cancer. The anti-tumor polypeptide Sur-X provided by the invention is capable of rapidly and efficiently inducing death of colorectal and gastric cancer cells by inhibiting formation of the survivin-XIAP complex, does not affect normal cells of human beings, and thus takes a treatment effect of specifically targeting to tumor cells. In addition, the polypeptide is easy to synthesize in vitro, and is convenient in clinical application. Therefore, the polypeptide Sur-X has potential commercial andindustrial value and can be widely used in the technical field of targeted treatment on tumors.

The present disclosure relates to XIAP inhibitor compound of the formula I:

The invention provides a novel apoptosis protein inhibitor or pharmaceutically acceptable salts and isomers as well as preparation methods thereof and a pharmaceutical composition. The definition of each group is shown in the description. The invention further provides application of the compound and pharmaceutically acceptable salts and isomers thereof to preparation of medicines for treating IAP(Immimmunosuppressive Acidic Protein) related diseases. The compound disclosed by the invention has high binding affinity to XIAP, cIAP1 and cIAP2 proteins, has an excellent inhibiting effect on cellgrowth in MDA-MB-231 breast cancer and PC-3 pancreatic cancer cell lines, and also has high medicinal value and wide market prospects.

Disclosed is a method of treating or preventing hearing loss in a subject. The method comprises administering to the subject in need thereof, an adeno-associated viral expression vector encoding X-linked inhibitor of apoptosis protein (XIAP). The XIAP is positioned in the vector for expression in an inner ear organ, or associated neural structures, of the subject so as to treat or prevent the hearing loss. Also disclosed is a method of treating or preventing impaired balance.

The invention discloses application of isorhapontigenin (ISO) to preparation of drugs with antitumor activity. The activity of the X-linked inhibitor of apoptosis protein (XIAP) is inhibited by lowering gene expression of the XIAP. Western-blotting, reverse transcription-polymerase chain reaction (RT-PCR), an adenosine triphosphate (ATP) bioluminescence detection method, chromatin immunoprecipitation (CHIP) and other methods are utilized to prove that the XIAP gene expression level can be obviously inhibited, then tumor cell apoptosis is induced and tumor cell proliferation is inhibited by pretreating various tumor cells with ISO, ISO can not obviously induce tumor cell proliferation and apoptosis, the endogenous XIAP gene is the effective target treated with ISO and ISO is used for specifically inhibiting gene expression of the XIAP. Experiments prove that ISO can effectively improve the sensitivity of chemotherapy drugs and promote tumor cell apoptosis and has extensive application prospects in foundation medicine, clinical treatment, new drug research and development and the like.

The present invention relates to an action between an inhibitor of apoptosis (IAP) protein and members of the caspase family of cell death proteases, for example, an interaction of the X chromosome linked IAP (XIAP) and caspase-3, caspase-7 or caspase-9, wherein the IAP regulates the activity of the caspases. The invention provides screening assays for identifying agents that alter the specific association of an IAP such as XIAP, c-IAP-1 or c-IAP-2 and a caspase such as caspase-3 or caspase-7. The invention also provides screening assays for identifying agents that alter the specific association of an IAP such as XIAP, c-IAP-1 or c-IAP-2 and a pro-caspase such as pro-caspase-9. In addition, the invention also provides methods for identifying agents that modulate the activity of a caspase in the presence of an IAP and that regulate the activation of a pro-caspase by an IAP. The invention further provides methods of reducing the severity of a pathologic condition in an individual by administering to the individual an agent that alters the caspase inhibitory activity of an IAP. In addition, the invention provides methods of modulating the ability of a population of cells to survive ex vivo by contacting the cells with an agent that alters the caspase inhibitory activity of an IAP in the cells.

Disclosed herein, inter alia, are methods of use and composition of novel inhibitors that target the Smac binding site of a variety of inhibitor of apoptosis proteins that contain a Bir domain, including XIAP, cIAP1, cIAP2, or other IAP proteins.

The invention belongs to the field of biomedical technology and particularly relates to isoquinoline compounds capable of inhibiting inhibitor-of-apoptosis proteins and a preparation method and an application of the isoquinoline compounds. According to the invention, a series of isoquinoline compounds capable of being interacted with a BIR2 structural domain of an IAP family are designed and synthesized, so that the activities of various IAPs are decreased; on one hand, an inhibition effect of XIAP on Caspase-3 is antagonized, and on the other hand, the ubiquitination of cIAP and degradation of proteasome are promoted and thus the isoquinoline compounds have biological activity against the growth of ovarian cancer. The isoquinoline compounds disclosed by the invention play roles in resisting ovarian cancer and reversing the drug resistance to ovarian cancer by inhibiting IAPs, and the roles can be confirmed by CCK-8 and a large number of experiments, such as in vivo nude mice subcutaneously transplanted tumors experiment. The compounds disclosed by the invention have the advantages of small molecular mass, high oral bioavailability, flexibility in clinical medication and relatively high anti-tumor activity; combined with the BIR2 structural domains of various IAPs, the compounds have broader action objects and action routes, and have more advantages in clinical application.

The invention provides an experimental method for rabbit KOA model chondrocytes by adopting a medicine scraping method, which is characterized by comprising the following steps: 1, establishing a rabbit KOA model; 2, regularly smearing the knee joint of the rabbit with the berchemia lineate massage cream by adopting a medicine scraping method; 3, preparing an animal specimen; 4, performing morphological observation on cartilage tissue in the specimen; and 5, carrying out immunohistochemical detection on caspase-3, caspase-9 and XIAP proteins in the cartilage tissue. The research of the invention proves that the medicine scraping method can reduce the expression quantity of caspase-3 and caspase-9 in the rabbit articular cartilage of the K0A model and up-regulate the content of XIAP in cytobiology, so that the articular cartilage is protected from being damaged, and the joint senescence is delayed.