98 results about "PARP inhibitor" patented technology

The invention discloses an application of a composition of a polypeptide and a PARP inhibitor in preparation of a medicine for treating breast cancer, the sequence of the polypeptide is as shown in SEQ ID NO: 1, and the PARP inhibitor is Olaparil or taprazopalil. The polypeptide can down-regulate the expression of the DNA damage repair gene FANCD2 protein and block the cross-linking damage repair between DNA chains. The PARP inhibitor blocks DNA single-stranded fracture damage repair by inhibiting the catalytic activity of PARP, and is mainly used for breast cancer treatment of BRCA mutation. DNA damage caused by the polypeptide and the PARP inhibitor in two different modes jointly destroys a cell replication fork protection mechanism, so that a DNA replication fork of a breast cancer cell is prone to stagnation and collapse, and cell death is caused. The invention shows synergistic cancer suppression activity in both BRCA wild type and BRCA mutant breast cancer subtypes, and is expected to provide a new treatment strategy for clinical treatment of breast cancer.

The disclosure provides substituted nitrogen containing tricyclic compounds as PARP inhibitors and the use thereof. This disclosure provides compounds represented by Formula (I) as below, wherein, the ring Z, Z1, Z2, Z3, Z4, Z5, A1, A2, A3, L, m, n, ring B and Cy are defined herein. The compounds of Formula I of the present disclosure are PARP inhibitors and thus are useful in the treatment of diseases, disorders and conditions, such as cancer, responsive to the inhibition of PARP activity. The present disclosure also relates to a pharmaceutical composition comprising the compound of Formula I and the use of the compound of Formula I in the preparation of a medicament for the treatment or prevention of diseases or conditions responsive to the inhibition of PARP activity.

The invention discloses a PARP inhibitor containing a beta-carboline structure, a synthesis method of the PARP inhibitor and application of the PARP inhibitor in preparation of a medicine for resisting triple negative breast cancer. The structural formula of the PARP inhibitor containing the beta-carboline structure is shown in the specification. The invention further specifically discloses the synthesis method of the PARP inhibitor containing the beta-carboline structure and application of the PARP inhibitor containing the beta-carboline structure in preparation of the medicine for resisting triple negative breast cancer. The synthesized PARP inhibitor containing the beta-carboline structure has relatively high inhibitory activity on the triple negative breast cancer and PARP, and a new way is provided for treatment of the triple negative breast cancer. The synthesis method of the PARP inhibitor containing the carboline structure is simple, raw materials are cheap and easy to obtain, and industrial production and clinical conversion are easy.

The present disclosure relates to compounds according to Formula I or a pharmaceutically acceptable salt and / or solvate thereof, wherein X 1 is H, F, or CI; R 1 is H, alkyl, or cycloalkyl; R 2 is H, alkyl, or cycloalkyl; R 3 is H, halo, alkyl, cycloalkyl, heterocyclyl, heteroaryl, or N(R 4 )(R 5 ); and one of R 4 and R 5 is H, alkyl, cycloalkyl, heterocyclyl, or heteroaryl, and the remaining one of R 1 and R 2 is H or alkyl, or R 4 and R 5 together with the nitrogen atom to which they are bound are heterocyclyl or heteroaryl. Furthermore, the present disclosure demonstrates that the compounds of the present disclosure penetrate the central nervous system, thereby allowing for the treatment of central nervous system cancers.

This invention belongs to the field of antitumor drug technology, specifically relating to PARP inhibitor-quinoline carboxylic acid coupled derivative compounds, their preparation methods, and uses. This invention synthesizes a novel polyADP-ribose polymerase (PARP) inhibitor derivative, the structure of which includes: a first structural unit with the clinical PARP inhibitor olaparib as the core backbone, a linker arm L, and a quinoline carboxylic acid fragment R; wherein the structural types and substituents of the linker arm L and the quinoline carboxylic acid fragment R are adjustable. This invention also provides a method for preparing the compound, which is characterized by simple steps, strong versatility, and ease of structural expansion, suitable for constructing compound libraries with different combinations of linker arms and different quinoline carboxylic acid fragments. The compound can be used to prepare drugs or drug compositions for inhibiting tumor cell proliferation and treating tumor-related diseases, showing excellent application prospects.

The present invention relates to a pharmaceutical combination comprising a PARP inhibitor and a compound of formula (I), or a stereoisomer, solvate, tautomer or pharmaceutically acceptable salt thereof, for use in a method of treating HR-functioning cancer, the pharmaceutical combination comprising a PARP inhibitor and a compound of formula (I): or a stereoisomer, solvate, tautomer or pharmaceutically acceptable salt thereof;

The invention relates to application of a PARP inhibitor in cancer treatment, in particular to application of the PARP inhibitor in ovarian cancer maintenance treatment. More specifically, the present invention provides a maintenance therapy for an ovarian cancer patient comprising administering an effective amount of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H)-dione, a hydrate or a pharmaceutically acceptable salt thereof, to an ovarian cancer patient who has undergone a first-line platinum-containing regimen treatment and achieves complete or partial remission, or a pharmaceutical composition containing 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H)-dione, a hydrate thereof, or a pharmaceutically acceptable salt thereof, or a medicament containing the pharmaceutical composition.

Provided are methods and compositions, for treating prostate cancer by administering to a patient in need thereof a therapeutically effective amount of a PARP inhibitor, e.g., niraparib; a therapeutically effective amount of a CYP17 inhibitor, e.g., abiraterone acetate, and a therapeutically effective amount of a glucocorticoid, e.g., prednisone.

The invention relates to an application of aloe-emodin. The invention provides an application of aloe-emodin in preparation of a PARP (poly-ADP-ribose polymerase) inhibitor. The aloe-emodin provided by the invention has relatively good inhibitory activity on PARP (Poly ADP-ribose Polymerase Chain Reaction).

Described herein are methods for treating cancer in a patient, the methods comprising administering to the patient a PRMT5 inhibitor and a PARP inhibitor, a KRAS inhibitor, or a kinase-like protein 18A (KIF18A) inhibitor, or a kinase inhibitor.

To provide a therapeutic agent for PARP inhibitor-resistant cancer.SOLUTION: The present invention relates to a pharmaceutical composition for treating or preventing a solid cancer patient having resistance to a PARP inhibitor, and the pharmaceutical composition according to the present invention can effectively reduce the size of a tumor in a patient having resistance to a PARP inhibitor.SELECTED DRAWING: Figure 4

The present invention relates to a PARP inhibitor, a combination of Omomyc, a functionally equivalent variant thereof, a conjugate comprising Omomyc or the functionally equivalent variant, a polynucleotide encoding the polypeptide, a vector comprising the polynucleotide, and a combination of cells capable of secreting the polypeptide or conjugate. The present invention also relates to pharmaceutical compositions containing the combinations of the present invention, and their medical use, specifically their use in the treatment of cancer.

Provided in the present application are an antibody-drug conjugate, and a preparation method therefor and the use thereof. The antibody-drug conjugate has a structure as represented by the following formula (III) or formula (IV). The drug is selected from a DNA topoisomerase inhibitor, a DNA intercalator, an RNA polymerase inhibitor, and a PARP inhibitor. The prepared antibody-drug conjugate exhibits a relatively good drug-to-antibody ratio and good targeted killing effects on breast cancer, gastric cancer, and lung cancer (e.g., non-small cell lung cancer, specifically lung adenocarcinoma).

The present invention provides an anti-cancer vaccine comprising: (i) at least one peptide comprising the amino acid sequence of a neoantigen encoded by a mutant homologous recombination (HR) DNA repair gene selected from the group: BRCA1, BRCA2, PALB2, CDK12, RAD51B, RAD51C and RAD51D, wherein the mutant gene comprises a reversion mutation; and / or (ii) at least one polynucleotide encoding the at least one peptide of (i). Also provided are engineered T cells that recognise said neoantigen. Related methods and medical uses of the vaccine and / or engineered T cell are provided, including for the treatment of cancers, such as homologous recombination (HR) deficient cancers that acquire PARP inhibitor resistance or platinum resistance by development of reversion mutations in an HR DNA repair gene selected from the group: BRCA1, BRCA2, PALB2, CDK12, RAD51B, RAD51C and RAD51D.

A method for treating a homologous recombination (HR)-deficient cancer, a homologous recombination (HR)-proficient cancer or a cancer that is resistant to DNA repair and DNA damage response (DDR) inhibitor therapy, such as Poly (ADP-Ribose) Polymerase (PARP) inhibitor therapy, is provided, the method comprising administering to a subject an RNA-binding motif protein 39 (RBM39) degrader, such as an aryl sulfonamide. A DDR inhibitor, such as a PARP inhibitor, may also be administered. A composition comprising a RBM39 degrader, such as an aryl sulfonamide, e.g., E7820 or Compound A, and a DDR inhibitor, such as a PARP inhibitor, is also provided.

The present invention relates to compounds and compositions containing said compounds acting as PARP inhibitors (Poly (ADP-ribose) polymerase). Moreover, the present invention provides processes for the preparation of the disclosed compounds, as well as methods of using them, for instance as a medicine, in particular for the treatment of cell proliferative disorders, such as cancer.

Described herein are injectable or infusible formulations of PARP inhibitors. In one aspect, the formulation comprises a PARP inhibitor and a cyclodextrin. The injectable or infusible PARP inhibitor-cyclodextrin formulation improves drug solubility, bioavailability, and therapeutic effectiveness. Also described herein are methods for treating oncological and non-oncological indications with injectable or infusible formulations of PARP inhibitors.

The present invention relates to a crystal form of a compound N-cyclopropyl-5-(4-((7-ethyl-6-oxo-5.6-dihydro-1.5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridine carboxamide and a preparation method therefor, and the use thereof in the preparation of a related drug.

The application discloses an anticancer composition of combined medication, and application of the composition in preparation of an anticancer drug. The combined medication composition provided by the application comprises a PARP inhibitor, Olaparib, and a calcium ion antagonist, Amlodipine maleate, and the two components have a synergistic effect, have higher sensitivity to gastric cancer compared with a single PARP inhibitor, and significantly improve the effective rate, thereby having a wide application prospect. The Amlodipine in the combined medication composition provided by the application enhances the curative effect of the PARP inhibitor, Olaparib, on gastric cancer.

Biomarkers, systems, and methods for predicting a prognostic outcome of pancreatic duct adenocarcinoma (PDAC) and responsiveness of a cancer patient to a PARP inhibitor are provided. The metabolites biomarkers are used to predicting a prognostic outcome of PDAC, and includes one or more of LysoPC (14: 0), LysoPC (18: 2), LysoPC (18: 1), Androsterone sulfate, alpha-CEHC, Glycodeoxycholic acid sulfate, LysoPC (20: 5), LysoPE (22: 5), and LysoPE (16: 1). The gene biomarkers are used to identify cancer patients responsive to a PARP inhibitor, and includes one or more of CTNND1, THRAP3, BRAF, STAT5B, and EXT2.

The invention belongs to the technical field of biological medicine, and particularly relates to application of REXO4 interference polypeptide in tumor treatment. It is found for the first time that the REXO4 interference polypeptide can inhibit breast cancer tumor cell proliferation, promote chemotherapy drug-induced DNA damage and improve the breast cancer chemotherapy effect, in addition, through combination of the REXO4 interference polypeptide and Olaparib, the remarkable synergistic anti-tumor effect can be shown, and the effect is better than that of single medication. The invention also finds that the REXO4 interference polypeptide can reverse the drug resistance of breast cancer to chemotherapeutic drugs, and a brand new solution is provided for overcoming the drug resistance of PARP inhibitors.

The invention discloses application of an HDAC8 inhibitor in preparation of a medicine for enhancing the curative effect of a PARP inhibitor or reversing / improving the drug resistance of the PARP inhibitor, and relates to the technical field of biological medicine. According to the scheme of combining the HDAC8 inhibitor and the PARP inhibitor, the curative effect of the PARP inhibitor is remarkably enhanced, the drug resistance of the PARP inhibitor is reversed / improved, and the core problem in clinical application of the PARP inhibitor is effectively solved. Through combined inhibition of targeting HDAC8 and PARP, a new strategy capable of effectively overcoming drug resistance of a PARP inhibitor, improving treatment sensitivity and being good in safety is provided, the defects in the aspects of targeting, safety and curative effect stability in the prior art are overcome, and a new feasible path is provided for solving the technical defects existing in the field for a long time.

The invention discloses a PARP inhibitor sensitivity prediction method based on a specific cell cluster and application. The method comprises the following steps: acquiring an ovarian cancer tumor tissue sample of a subject; detecting whether a specific cell cluster exists in the sample or not, and determining the abundance of the specific cell cluster, wherein the specific cell cluster comprises an IFN epithelial cell cluster CN12 taking an IFN tumor cell as a center and / or a TAM enrichment cluster CN29 taking an M2 type tumor related macrophage as a center; according to the detection result, predicting according to at least one of the following rules: if the CN12 abundance before treatment is greater than 0.8%, the CN29 abundance before treatment is greater than 32.7%, the CN12 abundance after treatment is greater than 0.009%, the CN29 abundance after treatment is greater than 2.9%, or the SPP1 cell density before treatment is greater than 1.7%, predicting that the drug resistance is not sensitive or easily generated. The prediction model is established from a cell cluster space tissue level, and the method has the advantages of high prediction accuracy, flexible sample requirements, high operability and the like.

The invention provides a method of characterising a DNA sample obtained from a tumour, the method including the steps of: determining the presence or absence of a plurality of base substitution signatures, rearrangement signatures and indel signatures in the sample and copy number profiles for the sample; generating, from the presence or absence of said plurality of base substitution signatures, rearrangement signatures and indel signatures and the copy number profile for the sample, a probabilistic score; and based on said probabilistic score, identifying whether said sample has a high or low likelihood of being homologous recombination (HR)-deficient. Identification of a tumour as HR-deficient may be used to inform treatment choices, for example treatment with a PARP inhibitor or platinum therapy or an anthracycline.

The present invention addresses the problem of developing a drug for inhibiting the DNA damage restoration mechanism in a cancer which does not have a mutation in BRCA 1 / 2 and in which homologous recombination repair functions normally.　The inventors of the present invention have clarified that cell death can be induced by inhibiting PARP functions and mitochondrial respiration functions in cells, and indicated that the problem can be solved. In other words, the present invention provides: a method for inducing cell death by inhibiting PARP functions and mitochondrial respiration functions in cells; and a pharmaceutical composition for treating cancer, the pharmaceutical composition containing a PARP inhibitor and a mitochondrial respiration inhibitor.

The invention belongs to the technical field of nuclear medicine, and particularly relates to a PARP inhibitor, a radionuclide marker thereof, a preparation method and application. One purpose of the present invention is to provide a PARP inhibitor, which is a compound represented by a formula I or a salt thereof, and the structure of the compound represented by the formula I is shown in the specification. According to the technical scheme, diagnostic radionuclide (such as 68Ga) and therapeutic radionuclide (such as 177Lu) are compatible through optimal design of the precursor. The advantages fully show that the radionuclide-labeled DOTA-nirapalide has good feasibility and application potential in the aspect of tumor diagnosis and treatment integration.

The invention discloses a pharmaceutical composition for treating KRAS G12D mutation cancer and application of the pharmaceutical composition, and belongs to the technical field of biological medicine. The pharmaceutical composition comprises a KRAS G12D inhibitor and a PARP (poly-ADP-ribose polymerase) inhibitor. The core of the invention lies in that a KRAS G12D inhibitor (such as MRTX1133) can down-regulate expression of homologous recombination (HR) repair related proteins (such as BRCA1, RAD51 and RPA32) and induce HR defects, so that tumor cells carrying KRAS G12D mutation have high sensitivity to a PARP inhibitor (such as Olaparib), and a synthetic lethal effect is formed. The combined strategy not only shows synergistic anti-tumor activity in a model sensitive to the KRAS G12D inhibitor, but also is effective in a model resistant to the KRAS G12D inhibitor. The invention provides a new effective scheme for treating cancers such as pancreatic ductal adenocarcinoma with KRAS G12D mutation, and is expected to expand the applicable patient population of the PARP inhibitor.

The invention belongs to the field of anticancer drugs, and discloses application of a TACR3 inhibitor in preparation of drugs for treating BRCA1 defective breast cancer. In the research of the invention, it is found that TACR3 is significantly up-regulated in BRCA1-deficient tumors, deletion of TACR3 and BRCA1 causes cell death, TACR3 provides a necessary replication protection mechanism for survival of BRCA1-deficient breast cancer cells, and deletion of TACR3 can overcome drug resistance of PARP inhibitors, that is, TACR3 can be used for preventing and treating BRCA1-deficient breast cancer cells. The inhibition of TACR3 can cause the death of BRCA1 defective breast cancer cells and overcome the drug resistance of PARP inhibitors in the BRCA1 defective breast cancer cells.

Disclosed herein is a method of cell death using a CRISPR / Cas system having single chain cleavage activity and a PARP inhibitor, as a type of method of cell death using the CRISPR / Cas system. Compared with a method for death of cells by using a CRISPR / Cas system with double-chain breaking activity, the method is a safer cell death technology and hardly has unnecessary side effects. Disclosed herein is a method of treating cancer by using the cell death method, and specific configurations required to implement the method.