19 results about "PIN1" patented technology

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. In some embodiments, the compounds of the invention “re-program” the binding of the presenter proteins to protein targets that either do not normally bind to the presenter protein (e.g., do not show detectable binding in mammalian cells absent the compound). In some embodiments, provided compounds “re-program” presenter protein binding to greatly enhance interaction with a particular target with which it may have some interaction absent the compound. Interactions achieved through such reprogramming result in an ability to modulate the activity of these new targets.

The present application relates to a kind of biomarkers related to osteoarthritis, which is Pin1 protein, by detecting whether the expression level of Pin1 protein is abnormal, osteoarthritis can be diagnosed or osteoarthritis prognosis can be predicted, by testing the influence of drug on the expression level of Pin1 protein, osteoarthritis treating drug can be screened or prepared, the quality and efficacy of osteoarthritis treating or relieving drug can be evaluated.The present application uses TMT proteomics technology to complete the screening of biomarkers related to osteoarthritis, and finds the common intersection of 6 proteins in the results of osteoarthritis disease target, TMT proteomics and protein targeting verification through way analysis, wherein Pin1 is consistent with the trend of TMT proteomics and protein targeting verification, i.e.Pin1 is decreased in osteoarthritis.New biomarker related to osteoarthritis-Pin1 protein is found, which has important biological significance and pharmaceutical significance.

The purpose of the invention is to develop, as drug-candidate compounds, a group of novel compounds having the activity of inhibiting functions of Pin1. The invention provides: a compound represented by formula (I) or a salt thereof; and a Pin1 inhibitor, a pharmaceutical composition, a therapeutic or prophylactic agent for inflammatory diseases, a therapeutic or prophylactic agent for cancer, and a therapeutic or prophylactic agent for adiposity that use said compound / salt.

The invention relates to a Pin1 protein targeted antagonistic polypeptide, a targeted antagonistic polypeptide nano-micelle as well as a preparation method and application of the targeted antagonistic polypeptide nano-micelle. The Pin1 protein targeted antagonistic polypeptide comprises a targeted antagonistic polypeptide and a cell-penetrating peptide which are connected in sequence, the amino acid sequence of the targeted antagonistic polypeptide comprises any one of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4 or SEQ ID NO: 5; the amino acid sequence of the cell-penetrating peptide comprises SEQ ID NO: 6. The Pin1 protein targeted antagonistic polypeptide can efficiently cross cell membranes and nuclear membranes, is specifically combined with the Pin1 protein in human metastatic pancreatic adenocarcinoma cells, antagonizes the biological function of the Pin1 protein and kills tumor cells. Meanwhile, the Pin1 protein targeting antagonistic polypeptide is combined with gemcitabine, so that the sensitivity of a mixed in-situ tumor model of human metastatic pancreatic adenocarcinoma cells and cancer-related fibroblasts to gemcitabine can be enhanced, the anti-cancer effect of a single drug is amplified, and the anti-tumor effect of 1 + 1 > 2 is generated.

The invention discloses a nano material for specifically promoting PIN1 endocytosis. The nano material can specifically promote PIN1 protein to enter a cytoplasm region from a cytoplasmic membrane region. The invention specifically discloses a structure (formula (I)) of SPc and application of SPc or pharmaceutically acceptable salt thereof in promoting membrane protein internalization of PIN1 protein of a tested plant. The PIN1 protein at the root of arabidopsis thaliana can be promoted to enter a cytoplasm region from a cytoplasm membrane region by applying SPc to arabidopsis thaliana. The PIN1 protein can be used as a positive inducer for researching a PIN1 protein endocytosis related metabolic pathway, and can be used for industrial production.

The present invention belongs to the field of biotechnology, and specifically relates to a biological probe for detecting Pin1 isomerase activity and its application. The biological probe consists of a donor-acceptor pair, a linker, and a Pin1 recognition domain; wherein the donor is a green fluorescent protein called mClover3, and the acceptor is a red fluorescent protein called mRuby3; the recognition domain is a peptide segment containing the potential recognition site Ser / Thr-Pro of Pin1; and the linker is a short peptide rich in hydrophobic amino acid residues. Based on the principle of fluorescence resonance energy transfer, this patent proposes for the first time to use the Ser / Thr-Pro motif as a recognition domain to construct a FRET biological probe that can detect Pin1 isomerase activity in different living cells. This patent not only provides a new method for studying the pathogenesis and early diagnosis of cancer and AD, but can also evolve into a high-throughput screening device for anti-cancer drugs and anti-AD drugs.

The present invention provides: a compound represented by the following Formula (I) or a salt thereof, as well as a Pin1 inhibitor, a pharmaceutical composition, a therapeutic or prophylactic agent for inflammatory diseases, a therapeutic or prophylactic agent for fatty liver diseases, a therapeutic or prophylactic agent for obesity, and a therapeutic or prophylactic agent for COVID-19 that utilize the aforementioned compounds or the salts thereof to develop a group of novel compounds with an inhibitory activity against the function of Pin1 so as to use them as candidate compounds for medicaments.

Disclosed are compounds which inhibit Pin1 activity, methods of making the compounds, pharmaceutical compositions containing the compounds, and methods of using the compounds in combination with immunotherapy and chemotherapy to treat diseases or disorders characterized or mediated by dysregulated Pin1 activity, and wherein the disease comprising cancer. Further disclosed are different type of cancers that can be treated using the methods.

The invention belongs to the field of medicinal chemistry, and discloses a pyrimidine Pin1 covalent inhibitor with a novel structure, and a preparation method, a pharmaceutical composition and application thereof. Specifically, the invention relates to a pyrimidine compound with a new structure as shown in a formula I, a pharmaceutically acceptable salt thereof, a preparation method of the pyrimidine compound, a composition containing one or more of the compounds, and application of the compounds in inhibition of Pin1-related diseases and in preparation of drugs for prevention and / or treatment of neuropsychiatric system diseases and cancers.

The invention provides a PD-L1 targeting bionic exosome, the PD-L1 targeting bionic exosome comprises a bionic exosome and a PD-L1 single-chain antibody, the bionic exosome is formed by fusing an exosome derived from fibroblast and a liposome loaded with a Pin1 inhibitor, and the PD-L1 single-chain antibody is coupled to the bionic exosome. The invention also provides a pharmaceutical composition containing the PD-L1 targeting bionic exosome, and an application of the PD-L1 targeting bionic exosome. According to the present invention, the PD-L1 targeting bionic exosome and the ceritinib-loaded PD-L1 targeting bionic exosome are subjected to drug combination so as to achieve the purposes of simultaneous removal of tumor fibroblasts and tumor cells and improvement of the pancreatic cancer tumor microenvironment.

The application relates to a construction method of a biomimetic nano-drug delivery system based on a PD1 engineered cancer cell membrane, which comprises the following steps: preparing a nanoparticle inner core of a Pin1 inhibitor by using PLGA, and assisting with fluorescent labeling; engineering PD1 expression on a cancer cell, extracting a PD1-rich cell membrane, and wrapping and modifying API-1-NPs with the PD1 engineered cancer cell membrane to obtain composite nanoparticles API-1@PD1-CCNPs, which can not only guarantee stability and long-term circulation in the delivery process, but also can track the process of the carrier being quickly and effectively targeted to tumor cells and organs in the body in real time, and once internalized by the cancer cell, the wrapped drug API-1 can be effectively released and play a role to inhibit the Pin1 function; the composite nanoparticles API-1@PD1-CCNPs can effectively down-regulate the protein levels of MYC and PD-L1 in hepatocarcinoma cells, thereby effectively synergistically reprogramming the tumor immune microenvironment and affecting tumor immune escape.

Certain embodiments of the invention provide new compounds, conjugates, and salts as described herein that may inhibit and / or degrade PIN1. Also described methods of inhibiting and / or degrading PIN1 and methods of treating a PIN1 associated disease, and methods of developing degrader compounds for a target protein.

The invention discloses an application of a Pin1-YAP signal channel in treatment of atherosclerosis. Hydrogel and an animal model are adopted to research a specific molecular pathway that matrix hardness affects plaque stability, and research results show that increase of the matrix hardness promotes mesenchymal transformation of endothelial cells and vulnerability of atherosclerotic plaques; meanwhile, the increased matrix hardness stimulates the expression of Pin1, and the nuclear translocation of YAP is regulated by regulating cytoskeleton protein and using a time sequence; this indicates that the matrix hardness induces EndMT by triggering a Pin1 dependent downstream signaling pathway, and is associated with enhancing the vulnerability of atherosclerotic plaques. The invention explains the specific mechanism of matrix hardness adjustment plaque vulnerability, and provides a new mechanical target for treatment of atherosclerosis.

The present application provides a PD-L1 targeting biomimetic exosome, which comprises a biomimetic exosome formed by fusion of a fibroblast-derived exosome and a liposome loaded with a Pin1 inhibitor and a PD-L1 single-chain antibody, wherein the PD-L1 single-chain antibody is coupled to the biomimetic exosome. The present application also provides a pharmaceutical composition comprising the PD-L1 targeting biomimetic exosome and use of the PD-L1 targeting biomimetic exosome. The present application realizes the purposes of simultaneously eliminating tumor fibroblasts and tumor cells and improving the pancreatic cancer tumor microenvironment by combination of the PD-L1 targeting biomimetic exosome and a PD-L1 targeting biomimetic exosome loaded with ceritinib.

The invention discloses a method for converting portulaca oleracea into hard-grain corn, which comprises the following steps of: A, down-regulating expression of auxin transporter gene PIN1 in portulaca oleracea genome, inactivating, weakening function or knocking out, so that the portulaca oleracea is converted into the hard-grain corn; or B. enabling the 467th tryptophan codon TGG of the overexpressed auxin transporter gene PIN1 of the portulaca mays to be mutated into a PIN1W467X mutant of a termination codon, the mutant does not express the complete auxin transporter gene PIN1 any more, and the expressed protein loses the original PIN1 function or changes the original PIN1 function, so that the portulaca mays is converted into the dura grain phenotype.

This disclosure provides a pharmaceutical combination for treating non-small cell lung cancer, comprising a therapeutically effective amount of a PIN1 inhibitor and a therapeutically effective amount of neratinib.

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. In some embodiments, the compounds of the invention "re-program" the binding of the presenter proteins to protein targets that either do not normally bind to the presenter protein (e.g., do not show detectable binding in mammalian cells absent the compound). In some embodiments, provided compounds "re-program" presenter protein binding to greatly enhance interaction with a particular target with which it may have some interaction absent the compound. Interactions achieved through such reprogramming result in an ability to modulate the activity of these new targets.