47 results about "PIN1" patented technology

The invention features methods of treating a proliferative disorder characterized by elevated Pin1 marker levels and/or reduced Pin1 Ser71 phosphorylation in a subject by administering a retinoic acid compound. Additionally, the invention features methods of treating proliferative disorders (e.g., proliferative disorders characterized by elevated Pin1 marker levels) by administering a retinoic acid compound in combination with another anti-proliferative compound. Finally, the invention also features methods including high-throughput screens for discovering and validating Pin1 inhibitors.

The instant invention pertains to the discovery of two novel regulatory mechanisms of NF-kB. The instant invention demonstrates that NF-kB is regulated by Pin1-catalyzed prolyl isomerization and ubiquitin-mediated proteolysis of p65. Accordingly, the instant invention provides methods for regulating NF-kB, and diseases and disorders associated with NF-kB. Further, the invention provides compositions capable of modulating the activity or expression of NF-kB, Pin1, and/or the proteolysis of p65.

The invention is directed to modulators, e.g., inhibitors, of Pin1 and Pin1-related proteins and the use of such modulators for treatment of Pin1 associated states, e.g., for the treatment of cancer.

A novel class of NIMA interacting proteins (PIN), exemplified by Pin1, is provided. Pin1 induces a G2 arrest and delays NIMA-induced mitosis when overexpressed, and triggers mitotic arrest and DNA fragmentation when depleted. Methods of identifying other Pin proteins and Pin-interacting proteins and identifying compositions which affect Pin activity or expression are also provided.

Phosphate/sulfate ester compounds that modulate and/or inhibit the activity of protein interacting NIMA (PIN1), and to pharmaceutical compositions containing such compounds are described. The invention is also directed to the therapeutic or prophylactic use of such compounds and compositions, and to methods of treating disorders characterized by hypertension, inappropriate cell proliferation, infectious diseases, and neurodegenerative brain disorders, by administering effective amounts of such compounds.

Novel α-ketoamide-containing peptidomimetics are provided, such as peptidomimetics containing an α-ketoamide Ser-Pro dipeptide analogue. The α-ketoamide is preferably incorporated into another molecule as a Pin1 inhibitor (such as a pentapeptide analogue Ac-Phe-Tyr-pSer-Pro-Arg-NH₂).

The invention features all-trans retinoic acid (ATRA)-related compounds capable of associating with Pin1 and methods of treating a proliferative disorder characterized by elevated Pin1 marker levels, Pin1 degradation, and/or reduced Pin1 Ser71 phosphorylation in a subject by administering an ATRA-related compound. The invention also features methods of treating proliferative disorders, autoimmune diseases, and addiction conditions (e.g., diseases, disorders, and conditions characterized by elevated Pin1 marker levels) by administering an ATRA-related compound in combination with another therapeutic compound.

The invention features all-trans retinoic acid (ATRA)-related compounds capable of associating with Pin1 and methods of identifying the same. The invention also provides methods of treating a condition selected from the group consisting of a proliferative disorder, an autoimmune disease, and an addiction condition characterized by elevated Pin1 marker levels, Pin1 degradation, and/or reduced Pin1 Ser71 phosphorylation in a subject by administering a retinoic acid compound. Additionally, the invention features methods of treating proliferative disorders, autoimmune diseases, and addiction conditions (e.g., diseases, disorders, and conditions characterized by elevated Pin1 marker levels) by administering a retinoic acid compound in combination with another therapeutic compound. The invention also features a co-crystal including Pin1 and a retinoic acid compound. Finally, the invention also provides methods of developing and identifying enhanced Pin1-targeted ATRA-related compounds based on the newly defined unique binding pockets in the Pin1 active site revealed from the co-crystal structure, structure-activity relationship, and structural modeling.

The invention features compositions and methods for inhibiting the Pin1 protein, and the treatment of disorders characterized by elevated Pin1 levels.

A WW domain crystal structure of Pin1 is provided. In addition, methods of using the crystal structure and atomic coordinates for the development of WW domain binding agents is also provided. Also provided are computer programs on computer readable medium for use in developing WW domain binding agents.

The invention discloses a molecular method for association detection of the risk of nasopharyngeal carcinoma, belonging to the field of detection technology for nasopharyngeal carcinoma. The molecular method for association detection of the risks of nasopharyngeal carcinoma comprises the following steps: extraction of genomic DNAs in blood; treatment with PCR technology; and analysis of restriction fragment length polymorphisms. Discovery results in the invention show that two polymorphic sites, i.e., -842G>C(rs2233678) and -667C>T(rs2233679), of a Pin1 gene are associated with the risk of nasopharyngeal carcinoma in Guangdong Province, China; the Pin1 gene may be an important biomarker for the risk of nasopharyngeal carcinoma; and a Pin1 promoter can regulate the activity of a transcription factor AP2alpha.

The invention discloses a novel biodegradable controlled-release preparation of a Pin1 inhibitor ATRA, and a preparing method and an application thereof; the preparing method includes the following steps: a, dissolving ATRA and PLLA in an organic solvent, and preparing ATRA-loaded PLLA microspheres under a condition of supercritical carbon dioxide; and b, with liver cancer as a model, researchingthe anti-cancer efficacy and action mechanism of the ATRA-PLLA microspheres in vivo and in vitro. Under mild conditions, the ATRA-PLLA microspheres are obtained by the one-step method; the microspheres have uniform particle size, high encapsulation efficiency and high yield, can effectively slowly release ATRA, and have a main pharmacokinetic index better than that of commercialized ATRA slow-release tablets (the slow-release tablets can be used only for animals). The ATRA-PLLA microspheres have good biocompatibility and can selectively enhance the ATRA inhibition on tumor growth, and have theanti-cancer efficacy better than that of the ATRA slow-release tablets. ATRA plays an anti-cancer role by degrading Pin1 and inhibiting multiple Pin1-regulated oncogenic signaling pathways and cell cycle progression. The ATRA-PLLA microspheres are expected to be used in clinic treatment of Pin1-related diseases such as tumor, inflammation, arthritis, lupus erythematosus and asthma.

The invention provides pharmaceutical compositions and methods of treating immunological disorders. The invention also provides pharmaceutical compositions and methods of inducing eosinophil apoptosis, and methods for treating eosinophil-associated disorders comprising inducing eosinophil apoptosis in an individual in need thereof.

The invention discloses application of Pin1 siRNA in preparation of a targeted medicine for treating the alcoholic cardiomyopathy, and belongs to the field of prevention and treatment of the alcoholic cardiomyopathy. It is proved through experiments that Pin1 takes participate in the cardiac muscle cell apoptosis process caused by alcohol and high-dosage alcohol stimulates the expression and activity of Pin1. By means of Pin1 gene knock-out mediated by Pin1 siRNA, cardiac muscle cell apoptosis mediated by alcohol can be remarkably restrained; due to the over-expression of Pin1, the number of apoptosis muscle cells is further increased. It is further proved that Pin1 promotes mitochondria oxidative stress mediated by alcohol and restrains the expression of endothelial nitric oxide synthase. Through Pin1 gene knock-out mediated by Pin1 siRNA, mitochondria oxidative stress mediated by alcohol, the production decrease of NO and the level decrease of eNOS can be remarkably restrained, and therefore the occurrence and development process of the alcoholic cardiomyopathy is further delayed. An effective technological means is put forward to prevent and treat the alcoholic cardiomyopathy.

Disclosed herein are compounds comprising an electrophilic moiety and rigid moiety for use in modulating an activity of Pin1. The rigid moiety comprises at least one functional group that is capable of forming hydrogen bonds with hydrogen atoms, wherein the electrophilic moiety and the rigid moiety are arranged such that the electrophilic moiety is capable of covalently binding to the Cys113 residue of Pin1, and the rigid moiety is capable of forming hydrogen bonds with the Gln131 and His 157 residues of Pin1. Further disclosed are novel compounds having Formula Id:

wherein the dashed line, W, X, Y, Z, Ra-Rc, R₁, R₂, L₁, L₂ and n are as defined herein, and libraries comprising such compounds. Further disclosed are methods of identifying a compound capable of modulating an activity of Pin1, by screening a library of compounds.

The invention features compounds (e.g., macrocyclic compounds) capable of modulating biological processes, for example through binding to a presenter protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1) and a target protein (e.g., a eukaryotic target protein such as a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein). These compounds bind endogenous intracellular presenter proteins, such as the FKBPs or cyclophilins, and the resulting binary complexes selectively bind and modulate the activity of intracellular target proteins. Formation of a tripartite complex among the presenter protein, the compound, and the target protein is driven by both protein-compound and protein-protein interactions, and both are required for modulation of the targeted protein's activity.