51 results about "BRD4" patented technology

The invention discloses a self-assembled PROTAC nano material based on natural product mitochondria targeting, which is a nano particle prepared from mitochondria targeting molecules, a photosensitizer and PROTAC as raw materials through a nano precipitation method. The mitochondrial targeting molecule is berberine, the photosensitizer is hypericin, and the PROTAC is dBET57; the ratio of the amount of substance of the dBET57 to the amount of substance of the berberine is (1-10): (1-10), and the ratio of the amount of substance of the dBET57 to the amount of substance of the hypericin is (1-10): (1-10). The nano material can be used for blocking multiple energy metabolism pathways of tumor cells, including glycolysis and oxidative phosphorylation, meanwhile, mitochondria is damaged, ferroptosis is induced, and the anti-tumor capacity of pharmacodynamic molecules is improved; bRD4 in tumor cells and downstream carcinogenic protein c-Myc of the BRD4 can be efficiently degraded. The invention also discloses an application of the nano material in preparation of antitumor drugs.

The invention discloses a degradation agent based on benzimidazole fused covalent warheads as well as a preparation method and application of the degradation agent, and relates to the technical field of drug development. The structural formula of the degradation agent based on the benzimidazole fused covalent warhead is shown in the specification, wherein, is phenyl or substituted phenyl; r is methyl or tertiary butyl; the structure is selected from one of the following structures:,,,,,,,,, and; and a connection site is represented. According to the invention, a series of degradation agents based on benzimidazole fused covalent warheads are obtained by utilizing the modular design of a benzimidazole guiding group and an acrylate covalent warhead and then connecting with a BRD4 protein inhibitor JQ1 through a connexon. The degradation agent based on the benzimidazole fused covalent warhead can target the BRD4 protein and efficiently degrade the BRD4 protein. Therefore, targeted degradation of the BRD4 protein is realized while a protein degradation targeted chimera molecular library is enriched.

The invention relates to a marker for predicting the prognosis of ovarian cancer and application thereof, and the marker is used for predicting the prognosis condition of ovarian cancer by detecting any one or more of BRD4, H4K12la and Ube2v1. Compared with the prior art, it is found for the first time that BRD4 can be used as a histone milk acylation transferase to enzymatically modify a histone lysine site H4K12, so that the histone lysine site H4K12 is subjected to milk acylation modification, then gene transcription of Ube2v1 is increased, and proliferation and growth of ovarian cancer cells are promoted. The invention not only discovers that BRD4 can be used as histone milk acylation transferase to play a new function of milk acylation modification, but also clarifies the effect of the BRD4-H4K12la-Ube2v1 pathway in the growth process of the ovarian cancer, and provides a new method for targeted therapy of the ovarian cancer.

The application discloses an EZH2 and BRD4 double-target inhibitor and application thereof, wherein the double-target inhibitor is obtained by coupling a structural fragment for inhibiting a BRD4 protein and a structural fragment for inhibiting an EZH2 protein through a linker. The inventors find that the structural fragment for inhibiting the EZH2 protein and the structural fragment for inhibiting the BRD4 protein are restructured, coupled together through the linker, and the length of the linker is adjusted, so that the obtained EZH2 and BRD4 double-target inhibitor has an unexpected anti-tumor effect, the anti-tumor effect is better than that of an individual EZH2 inhibitor or BRD4 inhibitor, and is also better than that of a combination of the two under the same conditions.

The invention discloses diE3-PROTAC selected from a compound with a structure as shown in a formula I or pharmaceutically acceptable salt and racemate thereof, n is an integer from 2 to 8, R1 and R2 are respectively and independently selected from X selected from CH2 and C = O, and m is an integer from 2 to 3. The double E3-PROTACs disclosed by the invention have good degradation activity on the BRD4 protein, and the degradation efficiency of the double E3-PROTACs on the BRD4 protein is superior to that of the corresponding traditional PROTACs. The invention also discloses an application of the compound or the pharmaceutically acceptable salt and racemate thereof in preparation of a targeted BRD4 degradation agent. The invention also discloses application of the compound or the pharmaceutically acceptable salt and racemate thereof in preparation of drugs for treating BRD4 protein related diseases.

The present invention relates to compounds that bind to and otherwise modulate the activity of bromodomain-containing proteins, including BRD4, to processes for preparing these compounds, to pharmaceutical compositions containing these compounds, and to methods of using these compounds for treating a wide variety of conditions and disorders. In particular, this disclosure provides certain BRD4 inhibitors for the treatment of fibrotic diseases or conditions.

The invention discloses a method for detecting aortic dissection through peripheral blood BRD4 based on flow cytometry and application. The invention belongs to the technical field of biology, and particularly relates to a method for detecting aortic dissection through peripheral blood BRD4 based on flow cytometry and application. The method for detecting the content or expression level of the bromodomain-containing protein 4 in the sample to be detected comprises the following steps: 1) treating the sample to be detected to obtain mononuclear cells; the method comprises the following steps of (1) determining a mononuclear cell, (2) determining a fluorescein coupling antibody composition of a detection index according to a flow cytometry color matching scheme, (3) uniformly mixing the mononuclear cell in the step (1) and the fluorescein coupling antibody in the step (2), incubating in a dark place and dyeing, (4) loading and testing a sample by a spectrum flow cytometry, and (5) analyzing a data result, and the detection indexes in the step (2) are CD45, CD11B, CD66B, CD14, CC16 and BRD4.

The application discloses a new use of a BET inhibitor YD-851 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating pulmonary fibrosis. The application finds that YD-851 can inhibit the expression of BRD4 and fibrosis-related markers in pulmonary fibrosis tissues, reduce the structural damage of bleomycin-induced mouse lung tissues, inflammatory cell infiltration and fibrosis pathological changes, and improve lung function damage. Experimental results show that YD-851 can reduce the pulmonary fibrosis score, inflammation score and area ratio of consolidation, improve the lung imaging abnormalities, and down-regulate the expression of fibrosis-related genes such as Col1a1, Fn1 and Acta2. It is shown that YD-851 has the effect of treating pulmonary fibrosis, and can be used for preparing a drug for treating pulmonary fibrosis, and a new use of YD-851 is developed.

Provided herein are compositions and methods for treating an autoimmune disease or disorder in a subject. In some cases, the compositions and methods use chemical inducers of proximity (CIPs). In some cases, the CIPs include a first moiety having specific binding for a BTB domain-containing protein or a transcriptional repressor expressed in B cell subpopulations and a second moiety having specific binding for a modulator of gene regulation. In some cases, the BTB domain-containing protein comprises BCL6. In some cases, the transcriptional repressor expressed in B cell subpopulations is PRDM1 or IRF4. In some cases the modulator of gene regulation comprises BRD4, CDK9, and / or p300.

Disclosed herein are heterobifunctional compounds that include a moiety that binds to the Y220C mutant of the p53 protein, a moiety that binds to the effector protein BRD4, and a linker. Also disclosed herein are pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., to treat proliferative diseases such as cancers.

The invention provides a BRD4 protein degradation agent and application thereof, and particularly provides a compound with a structure as shown in a formula (I) or pharmaceutically acceptable salt thereof, or a stereoisomer or a prodrug molecule thereof. The compound can degrade BRD4 protein in a targeted manner through a ubiquitin-proteasome way, so that the compound can be used for treating indications mediated by abnormal expression of the BRD4 protein. Wherein each group in the formula (I) is defined in the specification.

The purpose of the present invention is to provide a compound that has an excellent effect of inducing BRD4 protein degradation and is useful as a cancer therapeutic agent, or a pharmaceutically acceptable salt thereof. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof. [In the formula, each symbol is as defined in the description.]

The present technology relates to compositions and methods for modulating expression of genes, which include a target oligonucleotide sequence, such as repeats of a particular oligonucleotide sequence containing 3 to 10 nucleotides. In particular aspects, the present technology relates to agents having a formula A-L-B, wherein -L- is a linker; A- is a Brd4 binding moiety; and —B is a nucleic acid binding moiety, such as a polyamide or complementary oligonucleotide, that specifically binds to the target oligonucleotide sequence.

The invention provides a pyrimidine derivative and application thereof, and belongs to the field of medicinal chemistry. The pyrimidine derivative is a compound as shown in a formula I, a salt, a stereoisomer, a solvate, a hydrate or a prodrug thereof. The pyrimidine derivative disclosed by the invention has a good inhibition effect on BRD4-BD1 and HDAC1 proteins, can be used as a novel BET-HDAC bifunctional inhibitor, is used for preventing and / or treating various diseases related to BET and HDAC, such as cancers, has an excellent effect, and has a good application prospect.

The invention discloses a tumor neoantigen polypeptide aiming at BRD4: NUTM1 gene fusion mutation and an application of the tumor neoantigen polypeptide in NUT cancer treatment. The tumor neoantigen polypeptide comprises: (1) a tumor neoantigen polypeptide with an amino acid sequence represented by SEQ ID No.2; and (2) polypeptides with the same or similar functions obtained by substitution and / or deletion and / or addition of at least one amino acid in the amino acid sequence. The antigen peptide disclosed by the invention can stimulate and activate T cells specifically aiming at BRD4:: NUTM1 gene fusion mutation of a human body in vitro and perform mass amplification for adoptive reinfusion treatment of a patient; the polypeptide has obvious immunogenicity, and the killing ability of T cells on NUT cancer cells with BRD4: NUTM1 gene fusion mutation is improved; meanwhile, the BRD4: NUTM1 fusion mutant tumor antibody can be synthesized on a large scale and is used for subsequent standardized and individualized immunotherapy of BRD4:: NUTM1 fusion mutant tumor patients.

The application provides application of a VISTA gene as an early diagnosis marker of primary liver cancer, and belongs to the technical field of biological medicine. The application finds that inhibition of VISTA gene expression can effectively inhibit the proliferation and clone formation of liver cancer, and overexpression of the VISTA gene can significantly enhance the proliferation and clone formation of liver cancer. BRD4 is an upstream regulator of VISTA, and after overexpression of BRD4, the VISTA protein level is obviously increased, and after knockdown of BRD4, the VISTA protein level is obviously decreased. MMP11 is a downstream substrate of VISTA, and VISTA regulates MMP11 at the transcriptional level and the protein level, and after overexpression of VISTA, the expression level of MMP11 is obviously increased, and after knockdown of VISTA, the expression level of MMP11 is obviously decreased. BRD4 regulates the mRNA transcription of MMP11 by regulating the expression of VISTA, and then affects the occurrence of primary liver cancer.

The present disclosure relates to compounds which inhibit bromodomain testis (BRDT). In certain embodiments, the compound is a bromodomain and extra-terminal (BET) subfamily bromodomain 1 (BD1) selective compound. In certain embodiments, the compound selectively inhibits BD-1 over bromodomain 2 (BD2). The present disclosure further provides a method of inhibiting BRDT in a male subject, the method comprising administering to the male subject a therapeutically effective amount of a compound of the disclosure, whereby the male subject is provided a contraceptive effect. The present disclosure further provides a method of inhibiting BRD2, BRD3, BRD4, and / or BRDT in a subject with a cancer, inflammatory condition, infectious disease, and / or metabolic disorder in which one or more of BET proteins are regulators, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, thereby treating, preventing, and / or ameliorating the condition, disease, and / or disorder.

The application discloses a phthalocyanine-based photo-PROTAC drug and a preparation method and application thereof, and mainly adopts a chemical synthesis method of amino and carboxyl coupling, takes photosensitizer ZnPc and BRD4 ligand JQ1 (a BRD4 inhibitor) as a structural main body, selects a polyethylene glycol (PEG) chain with different lengths as a linker of ZnPc and JQ1, and constructs a photo-PROTAC drug with BRD4 as a target point. The raw material of the application has a wide source, and the preparation method is simple. The drug utilizes the expression of BRD4 in bladder cancer tumor tissues, and realizes efficient degradation of PROTAC independent of E3 ubiquitinase by combining selective tumor site light. Meanwhile, BRD4 degradation destroys the antioxidant and hypoxic inhibition barrier of PDT, and realizes synergistic effect of PDT and PROTAC.

The application discloses a degradation agent based on inhibitor fusion covalent fragments and application, and belongs to the technical field of medicines. Specifically, the degradation agent is obtained by fusing covalent fragments of an inhibitor (+) JQ-1 of BRD4 protein. The degradation agent can target BRD4 protein and degrade BRD4 protein. The degradation activity of the degradation agent is screened through two experiments of high-content screening technology and Western blotting, and the best compound M4 in degradation activity is obtained. The compound M4 can induce significant degradation of BRD4 protein within 6 hours, and presents dose dependence; the mechanism of action is to degrade BRD4 protein through an ubiquitin-proteasome pathway mediated by E3 ubiquitin ligase DCAF11. Cell experiments prove that the compound M4 has a broad-spectrum anticancer ability.

Provided in the present invention are a heterobifunctional compound for targeted degradation of BRD4 based on HSP70, preparation, and use, belonging to the technical fields of pharmaceutical synthesis and chemical engineering. In the present application, an HSP70 inhibitor is selected as a ligand moiety A that binds to HSP70, a BRD4 inhibitor is selected as a ligand moiety B that binds to BRD4, and the ligand A of HSP70 and the ligand B of BRD4 are linked by means of a linking chain, Linker, to obtain a series of bifunctional degradation agents that can degrade BRD4 to different degrees. The obtained degradation agents have the characteristics of high selectivity and strong activity, and can overcome the disadvantages of BRD4 inhibitors, such as poor selectivity for tumor tissues and strong toxic and side effects.

The present disclosure provides a use of a substance targeting BRD4 in the preparation of a product related to diabetes. In the present disclosure, it is found that the expression of BRD4 in human diabetic beta cells is significantly reduced, and BRD4 plays an important role in maintaining beta cell maturation and differentiation, and long-term and acute BRD4 deficiency can lead to reduced insulin secretion and down-regulation of differentiation markers, highlighting the key role of BRD4 in pancreatic beta cells, providing a target BRD4 that has a significant impact on diabetes, so that substances targeting BRD4 can help to assess the susceptibility of diabetes, screening, prevention, intervention and treatment of diabetes.

Disclosed in the present invention are a compound having a BRD4 inhibitory activity, a preparation method therefor and the use thereof. The structure of the compound having the BRD4 inhibitory activity of the present invention is as shown in formula I, and the definition of each substituent is as described in the description and claims. The compound of the present invention has a high bromodomain protein inhibitory activity, in particular a BRD4-targeting inhibitory activity, and can be used for the treatment and / or prevention of related diseases mediated by bromodomain proteins.

The invention relates to BRD4 and p300 / CBP double-target PROTAC molecules as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The compound has a general formula shown in the specification, wherein L is preferably selected from one of the group; and E is preferably selected from one of the group. The compound disclosed by the invention has remarkable anti-tumor activity on human prostatic cancer cell strains PC-3, DU145 and 22Rv1 in vitro, the IC50 values are all lower than 20nM, and particularly, the IC50 values are all lower than 10nM in the cells PC-3 and DU145. The compound I-c shows the optimal activity, the IC50 values of the compound I-c in PC-3 and DU145 cells are 2.80 nM and 6.62 nM respectively, and the IC50 values of the compound I-c are obviously superior to those of positive control drugs NEO2734, paclitaxel and ARV-771. As a novel BRD4 and p300 / CBP double-target PROTAC molecule, the compound disclosed by the invention has a definite action mechanism and excellent anti-tumor activity, and can be used as a candidate or lead compound for research and development of anti-tumor drugs; the synthesis method is simple and convenient, and has good popularization and application prospects.

The present application relates to crystalline solid forms of an inhibitor of BET proteins such as BRD2, BRD3, BRD4, and BRD-t, including methods of preparation thereof, and intermediates in the preparation thereof, where the compound is useful in the treatment of diseases such as cancer.

The application relates to the technical field of pharmaceutical chemistry, in particular to a kind of azaphen compounds with BRD4 protein inhibition effect and preparation method and application thereof, these compounds can inhibit the interaction between BRD4 and p53 tumor suppressor, can be used for preparing BRD4 protein inhibitor, for preventing and treating the disease related to BRD4 protein inhibitor, good anti-tumor activity, with wide application prospect, structural formula is as shown in formula (I): wherein R1 is selected from hydrogen or methoxy;R2 is selected from hydrogen, methoxy or dimethylamino;R3 is selected from hydrogen or methoxy;R4 is selected from hydrogen or alkyl;R5 is selected from substituted benzene ring or naphthalene.

The application discloses a degrading agent based on an indole group fused covalent warhead, and a preparation method and application thereof, relates to the technical field of drug development, and the structural formula of the degrading agent is as follows: R is a single bond or -NH-; is a single bond,,,,,,,,, or ; is -NH-,,, or ; is or ; R 1 and R 2 Each is independently -H, -F, -Cl, -Br, -CH3, -OCH3, -NO2, -CH2-O-Ph or -CN; Ph is a phenyl group; represents a connection site. The application uses an indole skeleton and an acrylic ester to construct an E3 ubiquitin ligase ligand, and then connects the BRD4 protein inhibitor JQ1 through a linker, so that a series of degrading agents based on an indole group fused covalent warhead are obtained, E3 ubiquitin ligase ligand library and protein degradation targeting chimera molecule library are enriched, and the targeted degradation of BRD4 protein is realized.

The application discloses a molecular marker and a kit for assisting in diagnosing cancer. The application provides application of a substance for detecting a BRD4 gene methylation level in preparation of a product; the product is used in at least one of the following aspects: assisting in diagnosing cancer or predicting a cancer disease risk; assisting in distinguishing a benign nodule and cancer; assisting in distinguishing different subtypes of cancer; assisting in distinguishing different stages of cancer; assisting in distinguishing different cancers; determining whether a to-be-detected substance hinders or promotes occurrence of cancer; and the cancer can be lung cancer or breast cancer. The application finds a low methylation phenomenon of the BRD4 gene in blood of lung cancer and breast cancer patients, and has important scientific significance and clinical application value for improving early diagnosis and treatment effect of lung cancer and breast cancer and reducing a death rate.

Provided herein are methods of treating cancer using a combination of a compound provided herein (e.g., Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or Compound 7, or a stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a tautomer, a prodrug, a solvate, a hydrate, a co-crystal, a clathrate, or a polymorph thereof) and a second active agent. The second active agent is one or more of a PLK1 inhibitor, a BRD4 inhibitor, a BET inhibitor, a NEK2 inhibitor, a AURKB inhibitor, a MEK inhibitor, a PHF19 inhibitor, a BTK inhibitor, a mTOR inhibitor, a PIM inhibitor, an IGF-1R inhibitor, an XPO1 inhibitor, a DOT1L inhibitor, an EZH2 inhibitor, a JAK2 inhibitor, a BIRC5 inhibitor, or a DNA methyltransferase inhibitor.