187 results about "De ubiquitination" patented technology

The description relates to imide-based compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and / or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation / inhibition of targeted polypeptides of nearly any type.

This invention describes compounds useful as ubiquitin ligase inhibitors. The compounds of the invention are useful as inhibitors of the biochemical pathways of organisms in which ubiquitination is involved. The invention also provides for pharmaceutical compositions comprising the compounds described in the invention for the treatment of conditions that require inhibition of ubiquitin ligases. Furthermore, the invention provides for methods of inhibiting ubiquitination in a cell comprising contacting a cell in which inhibition of ubiquitination is desired with a compound according to the invention.

The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and / or otherwise inhibited by bifunctional compounds according to the present disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation / inhibition of targeted polypeptides of nearly any type.

The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and / or otherwise inhibited by bifunctional compounds according to the present disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation / inhibition of targeted polypeptides of nearly any type.

The invention discloses a universal construction method for a protein-targeting chimeric molecule compound. The objective of the invention is to provide a method for adjusting the level of proteins by degrading the proteins through targeted ubiquitination. The construction method mainly comprises the following steps: 1) locating and analyzing a three-dimensional structure of a target protein and predicting active sites; 2) selecting a compound database; 3) virtually screening ligand compounds having high degrees of adaption to the target protein by using a computer; 4) acquiring the screened ligand compounds and screening an optimal ligand compound of the target protein through detection of interaction between micromolecules and the proteins; 5) constructing a protein-targeting chimeric molecule compound composed of the optimal ligand compound of the target protein, ubiquitin ligase E3 identification ligand and Linker connecting the optimal ligand compound of the target protein to the ubiquitin ligase E3 identification ligand by using a combination manner simulated by the computer; and 6) chemically synthesizing the protein-targeting chimeric molecule compound. With the method provided by the invention, the protein-targeting chimeric molecule compound can be rapidly and highly efficiently prepared, and specific degradation of intracellular target proteins is realized.

The present invention relates to methods and reagents for targeting proteolysis of a polypeptide by cis or trans association with a ubiquitin protein ligase, and further provides methods and reagents for inhibiting the ubiquitination and proteolysis of cellular proteins which are recognized by a ubiquitin protein ligase.

The present disclosure relates to bifunctional compounds, which find utility as modulators of receptor tyrosine kinase (RTK) proteins. In particular, the present disclosure is directed to bifunctionalcompounds, which contain on one end a ligand which binds to an E3 ubiquitin ligase and on the other end a moiety which binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effectuate ubiquitination, and therefore, degradation (and inhibition) of the target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation / inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions ofthe present disclosure.

This invention describes compounds and pharmaceutical compositions useful as ubiquitin agent inhibitors, particularly ubiquitin ligase inhibitors. The compounds and pharmaceutical compositions of the invention are useful as inhibitors of the biochemical pathways of organisms in which ubiquitination is involved, such as signal transduction pathways. The invention also comprises the use of the compounds and pharmaceutical compositions of the invention for the treatment of conditions that require inhibition of ubiquitination. Furthermore, the invention comprises methods of inhibiting ubiquitination in a cell comprising contacting a cell in which inhibition of ubiquitination is desired with a compound or pharmaceutical composition according to the invention. Particularly, the compounds and pharmaceutical compositions are useful to inhibit the ubiquitin ligase activity of MDM2.

The invention discloses a compound based on CRBN ligand inducing EGFR degradation as shown in the following formula I or a pharmacologically acceptable salt and hydrate. The invention further discloses a preparation method of the compound and a pharmaceutical composition of the compound, and application of the compound and the pharmaceutical composition to preparation of drugs for prevention or / and treatment of a cancer. The compound can carry out ubiquitination labeling on the EGFR, protein degradation can be induced with only less dosage, the process is similar to a catalytic reaction, drugswith same molar weight do not need, and the toxic and side effect on a human body can be reduced; and the excellent EGFR protein degradation effect and anticancer activity can be further shown, the anticancer effect of the compound is better than that of an EGFR inhibitor, the compound can be used for preventing or / and treating a variety of cancers, and has a great application prospect in the field of healing drugs.

This invention describes compounds and pharmaceutical compositions useful as inhibitors of ubiquitination. The compounds and compositions of the invention are useful as inhibitors of the biochemical pathways of organisms in which ubiquitination is involved. In particular, the compounds and compositions are useful for treating diseases caused by viruses such as poxviruses and retroviruses. The invention further provides for methods of treating smallpox, Herpes virus and HIV infection in patients using the compounds and compositions of the invention.

The invention discloses a plant in-vitro ubiquitin protein degradation system and an application thereof. The plant in-vitro ubiquitin protein degradation system provided by the invention is a composition consisting of one ubiquitin activating enzyme from arabidopsis thaliana, 14 ubiquitin-conjugating enzymes and wild-type K48R and K63R point mutation ubiquitin protein. Compared with the currently common used in-vitro ubiquitination reaction component, all components of the composition provided by the invention come from the model plant arabidopsis thaliana; when the composition is used for detecting whether the to-be-detected protein of plant origin has ubiquitination activity, the analysis result is more real and credible; the composition provided by the invention contains the component capable of representing most of the subfamily characteristics of the ubiquitin-conjugating enzyme of arabidopsis thaliana, and the coverage is wide; the activity of ubiquitin ligase can be detected and the specific binding condition of E2-E3 can be analyzed more comprehensively by use of the components, and more clues can be provided for studying the gene functions; and moreover, the type of polyubiquitin chain formed by the ubiquitination reaction can be analyzed by use of the point mutation ubiquitin protein.

The present invention relates to an isolated chimeric molecule comprising a degradation domain including a eukaryotic U-box motif and a targeting domain capable of immuno specifically directing the degradation domain to a substrate where the targeting domain is heterologous to the degradation domain. A linker couples the degradation domain to the targeting domain. Also disclosed are compositions as well as methods of treating a disease, substrate silencing, screening agents for therapeutic efficacy against a disease, and methods of screening for disease biomarkers.

The invention discloses an application of PA200 proteins in preparation of products. The products have at least one of the following functions from (1) to (4): (1) combining with acetylated proteins; (2) promoting the degradation of the acetylated proteins; (3) participating in repair of DNA (deoxyribonucleic acid) damages of somatic cells; and (4) participating in the formation of sperms. The invention has breakthroughs in four following aspects: (1) finding a mechanism of regulation and control of degradation of the histones, the sperm formation and the DNA repair by acetylation; (2) revealing the degradation of the histones medicated by acetylation rather than ubiquitination through PA200 / Blm10 proteasome; (3) finding novel testis-specific proteasome containing PA200 and alpha 4s, and revealing the core histones as a first type biological substrate for the proteasome; and (4) revealing that a histone deacetylase inhibitor can promote the degradation of the histones which are induced by DNA double-strand breaks and medicated by acetylation, enhance the sensitivity of cells to DNA damages and easily lead to the death of the cells.

The invention discloses a ubiquitin ligase gene participating in symbiotic nodulation of leguminous plants and application thereof. A membrane outer part of crowtoe symbiotic receptor kinase serves as bait; partial sequence of the gene is screened from a crowtoe AD-cDNA library; and full-length sequence is obtained through amplification by gene splicing and reverse transcription-polymerase chain reaction (RT-PCR) methods according to two expression sequence tags Lj-G0027263 and Lj-G0032470 overlapped with the partial sequence. Gene cloning and sequencing comparative analysis proves that the gene is cloned from crowtoe genome and cDNA. Sequence analysis and in vitro ubiquitin activity test prove that the gene is novel ubiquitin ligase. According to the application of the gene to the leguminous plants, the biological function of the gene in a symbiotic nodulation process is researched by RNAi and overexpression methods. The results show that, compared with the control plants, the plants with he gene has the advantages that the number of root nodules is increased obviously after overexpression, and the number of root nodules is reduced obviously after RNAi, so the gene has an application prospect in symbiotic nitrogen fixation of the leguminous plants.

The present invention related to a method of assaying ubiquitination in a sample by combining ubiquitin and two or more of E1, E2, E3 and a substrate protein in a sample under conditions suitable for ubiquitination to take place, exposing the sample with a labelled binding partner which is specific for the ubiquitin and measuring the amount of labelled ubiquitin bound to any one of the components in the sample, wherein one or more of the components in the sample comprises an immobilisation tag which facilitates its immobilisation onto a solid surface.

The invention discloses small molecule degradation agents targeting at androgen receptors, belongs to the field of biological medicines, and particularly relates to a series of compounds for degradingandrogen receptor proteins in a targeted ubiquitination manner, a synthesis method and medical applications of the compounds, in particular in prevention or treatment of androgen receptor related diseases. Meanwhile, a series of in-vitro anti-tumor activity evaluation tests are carried out on the synthesized compounds by invertors of the invention, and the compounds have certain inhibitory activity on cancer cells.

The invention relates to a lenalidomide-based small-molecular compound targeting to EGFR protein degradation, and preparation and application thereof, and provides a compound targeting to ubiquitination induced EGFR protein degradation and shown as a formula (I) which is described in the specification, and a preparation method and application thereof. Based on lenalidomide, chimeric small molecules capable of targeting to EGFR protein degradation are designed; in-vitro anti-tumor activity tests and in-vitro EGFR protein degradation activity show that the compound has good anti-tumor activity and EGFR protein degradation level, can be used for preventing or / and treating various cancers, and has good application prospects in the field of medicine.

The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs) and / or desumoylating enzymes. In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase 7 or ubiquitin specific peptidase 7 (USP7). The invention further relates to the use of DUB or desumoylating inhibitors in the treatment of cancer. Described herein are compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1a, R1b, R1c and R1d each independently represent hydrogen, optionally substituted C1-C6 alkyl or R1a and R1b together form an optionally substituted C3-C6 cycloalkyl ring, or R1c and R1d together form an optionally substituted C3-C6 cycloalkyl ring; A is a 5 membered nitrogen-containing aromatic ring and is substituted with at least one optionally substituted 5 to 10 membered monocyclic or bicyclic heteroaryl or aryl ring attached through an optional linker.

The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and / or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation / inhibition of targeted polypeptides.

There is provided antibodies, epitopes and methods for detecting ubiquitinated polypeptides and ubiquitination sites in proteins. The antibodies recognize a fragment of ubiquitin that is created after samples are treated with the proteoloytical enzyme LysC (or LysN).

The invention provides a deubiquitinating enzyme gene UPB5 for regulating and controlling a grain shape and leaf color of rice. The deubiquitinating enzyme gene UPB5 has a nucleotide sequence as shown in SEQ ID No.1 in the description. The invention further provides a protein with a UBP5 gene code of the rice, and the protein has an amino acid sequence as shown in SEQ ID No.3 in the description. The experiment proves that the deubiquitinating enzyme gene UPB5 of the rice can cause the leaf blade color and seed shape of the rice to change; the invention further finds that after the ubiquitination enzyme gene UPB5 of the rice mutates, the leaf blades of the rice show the shape of a stripe; the seeds are elongated; the ripening rate becomes lower; the total content of chlorophyll is obviously reduced. The invention provides the application of the UBP5 gene and the mutant of the UBP5 gene to genetic improvement breeding of rice germplasm resources, thereby having a relatively good application prospect.

The invention relates to an ubiquitin E1 inhibitor and a preparation method thereof. Series compound Y-1-benzene pyrazole silane-3,5-diketone and relevant derivative (such as 4-(4-ethyoxyl-3-methoxybenzylidene)-1-benzene pyrazole silane-3,5-diketone, and the like) with different alternative groups are prepared by a liquid-phase organic synthesis method according to the structure of PRY-41(4(4-(5-nitro-furan group-methylene]-3,5-dioxo-pyrazolidine-1-radical)-ethyl benzoate). The ubiquitin E1 inhibitor can be used for inhibiting protein degradation mediated by ubiquitination and nondegradation of ubiquitination, and can kill transformed cells containing p53 in the process of blocking up the NFkB activity by the inhibitor, that is to say, the inhibitor possibly has the potential property of treating tumor and can be used as an important tool for researching ubiquitin proteinase system mechanism.

The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and / or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation / inhibition of targeted polypeptides.

The invention relates to a proteolytic targeting chimera, and a preparation method and application thereof. The structure of the proteolytic targeting chimera is as in the description, wherein L is aconnecting group containing at least one heteroatom of N and O, and can be used to connect a pseudolaric acid part capable of being specifically combined with a target CD147 protein and a thalidomidepart capable of being connected with E3 ubiquitin ligase. Through simultaneous action on the target protein and the E3 ubiquitin ligase, activated ubiquitin is transferred to the target protein, so that selective ubiquitination on the target protein is realized, and finally the ubiquitinated target protein is recognized and degraded by a proteasome. The preparation method of the compound is simpleand is easy to realize, and the proteolytic targeting chimera can obviously reduce the level of the CD147 protein, and has high application value in preparation of medicaments for treating or preventing cancers, in particular in preparation of antitumor medicaments taking CD147 as a target point.

The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and / or otherwise inhibited by bifunctional compounds according to the present disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation / inhibition of targeted polypeptides of nearly any type.

The invention discloses anti-tumor ubiquitinated protein which is mainly extracted from the following steps: (1) culture of tumor cells: resuscitating cryopreserved tumor cells and culturing the tumor cells according to a conventional culture method; (2) treatment of the tumor cells; and (3) extraction of the ubiquitinated protein. The invention further discloses an extraction method of the anti-tumor ubiquitinated protein as well as application of the anti-tumor ubiquitinated protein in preparing tumor therapeutic vaccines. Compared to the prior art, the protein disclosed by the invention can be used for greatly improving the effect of cross-immuno reaction and improving the inhibitory effect on different types of tumors to a great extent; in addition, the problem that ubiquitinated short-lived protein is fast to degrade is further overcome, and a lot of ubiquitinated protein can be quickly obtained. Finally, the asymmetry between the short-lived protein and the long-lived protein is overcome, the target spots for inducing specific effector cells are increased, and the defect that the anti-tumor vaccines are poor in anti-tumor effect based on the long-lived protein is remedied.

LAT (Linker for Activation of T-cells) is a protein involved in signaling through the T-cell receptor (TCR). The invention provides a LAT protein including mutations at ubiquitylation sites that result in an increase in stability of LAT in stimulated and unstimulated cells, and enhanced signaling through the TCR. The invention further provides use for a LAT protein including mutations at ubiquitylation sites for therapeutic and laboratory methods.

The invention features methods and kits for determining the presence of, or a predisposition to develop, Sjögren's syndrome in humans. The invention features methods to detect changes in the levels of one or more LMP-2 protein isoforms, in particular phosphorylated isoforms of LMP-2, and to detect changes in cellular protein phosphorylation and ubiquitination in samples from Sjögren's patients.