77 results about "Venetoclax" patented technology

Purinostat mesylate (PM) for preventing and treating diffuse large B-cell lymphoma (DLBCL), an analogue thereof, a drug for combined use, and the use. PM exhibits excellent in-vivo and in-vitro anti-tumor therapeutic effects on DLBCL (DEL and DHL) subtypes with poor prognosis, DLBCL subtypes having TP53 deletion and mutation combined with a plurality of poor prognosis gene mutations, and DLBCL having TP53 mutation with double expressors, which are superior to that of most existing DLBCL clinical therapy plans. A doublet or triplet therapy of PM with rituximab, R-CHOP, venetoclax and R-CHP also exhibits excellent in-vivo therapeutic effects against DLBCL and a plurality of subtypes. Thus, PM and the drug for combined use have an important clinical significance for the DLBCL and a plurality of subtypes.

The invention discloses a novel application of adapalene and vinca in preparation of a medicine for treating acute myelogenous leukemia by combination, and finds that the adapalene and the vinca have a synergistic inhibition effect on proliferation of an acute myelogenous leukemia cell line, namely the adapalene and the vinca have a remarkable synergistic effect by combination for the first time, so that the application of the adapalene and the vinca in preparation of the medicine for treating the acute myelogenous leukemia is realized; the invention provides an effective drug combination strategy for treatment of acute myelogenous leukemia, and has good clinical application prospects and important transformation significance in the technical field of development of drugs for treating acute myelogenous leukemia.

The invention discloses a combined treatment medicine for acute myelogenous leukemia. The combined treatment medicine is prepared from vinaclaria, azacitidine and aclarithromycin. The medicine is applied to preparation of an acute myelogenous leukemia cell proliferation inhibitor; the medicine is applied to preparation of an acute myelogenous leukemia cell apoptosis inducer. The three medicines are combined to achieve a synergistic effect: the three medicines have a synergistic anti-tumor effect instead of a simple superposition effect, and a new combined medication mechanism is a result obtained through laboratory research and an initial effect of clinical application. The subsequent consolidation treatment scheme may also be used for part of initially treated patients with acute myelogenous leukemia, which are not suitable for enhanced chemotherapy or intense intense treatment by using targeted drugs, and relapse / refractory patients with acute myelogenous leukemia, and a better treatment scheme can also bring new hope and dawn to more patients.

This invention discloses a method for synthesizing a venetum intermediate, specifically as follows: Step 1: In an organic solvent, 2,4-difluorobenzoic acid and 5-hydroxy-7-azaindole undergo an etherification reaction under the action of an acid-binding agent. After the reaction, post-treatment yields 2-((1h-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid; Step 2: 2-((1h-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid reacts with 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexene-1-)methyl)piperazine in… An amination reaction occurs under the action of a base. After the reaction, post-treatment yields 2-(7-azaindole-5-oxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexene-1-)methyl)piperazine-1-)benzoic acid, i.e., Venetantora intermediate III. The synthetic process provided by this invention avoids Grignard reactions and subsequent hydrolysis reactions, shortens the operation steps, simplifies the synthetic process, and provides a simple and easy-to-operate synthetic process. The raw materials are inexpensive and readily available, while avoiding the use of highly toxic raw materials. The production process is green and environmentally friendly, and suitable for industrial production.

The invention discloses a synthesis method of a Vinetoram key intermediate and Vinetoram, and relates to the technical field of organic synthesis.The synthesis method comprises the steps that 1-((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro-[1, 1'-biphenyl]-2-yl) methyl) piperazine hydrochloride and 2-((1H-pyrrolo [2, 3-b] pyridine-5-yl) oxy)-4-bromobenzoic acid methyl ester are used as reaction raw materials, a reaction is carried out, and the Vinetoram key intermediate and the synthesis method of the Vinetoram key intermediate are synthesized; the method comprises the following steps: carrying out a substitution reaction and a hydrolysis reaction to obtain a key intermediate of the Venotocork, and carrying out a condensation reaction on the intermediate and 3-nitro-4-((tetrahydro-2H-pyran-4-yl) methylamino) benzenesulfonamide to obtain the Venotocork. The synthesis method has the advantages of short process route, easily available raw materials, mild reaction conditions, high yield and purity of the intermediate and the Vinetoram, facilitation of the improvement of the yield and quality of the Vinetoram, and reduction of the production cost of the Vinetoram.

The invention provides a kit for detecting the concentration of Venoclarias and a Venoclarias concentration detection method, and belongs to the technical field of in-vitro diagnos.The kit comprises a calibrator, an internal standard mother solution, a quality control product, an internal standard-sample releasing agent, a sample dilution treating fluid and a mobile phase. And the detection of low-concentration Venokacrah can be realized. The kit provided by the invention also has the advantages of high sensitivity, strong anti-interference capability and high accuracy.

This invention provides the application of IGF2BP3 as a target in the preparation of therapeutic drugs for fusion gene leukemia, specifically in the preparation of mRNA-highly stable fusion gene leukemia. The highly stable mRNA fusion genes include, but are not limited to, PAX5-ETV6 and STK38-PXT1 fusion genes. The drugs include IGF2BP3 gene-specific interfering RNA and IGF2BP3 inhibitors, including but not limited to venetoclax. This invention is the first to propose the use of IGF2BP3-targeted drugs for the treatment of mRNA-highly stable fusion gene leukemia; it not only reveals the role of IGF2BP3 in the oncogenic function of fusion genes but also provides a new therapeutic target and effective drug for this type of fusion gene leukemia, offering the possibility of further improving the clinical efficacy, prognosis, and survival of leukemia patients.

The invention provides a preparation method of a Vickaclara intermediate 2-(7-azaindole-5-oxy)-4-(4-((2-(4-chlorphenyl)-4, 4-dimethyl cyclohexene-1-) methyl) piperazine-1-) benzoic acid, which comprises the following steps: by taking a compound II, namely 1-((2-(4-chlorphenyl)-4, 4-dimethyl cyclohexene-1-) methyl) piperazine hydrochloride as an initial raw material, reacting at the temperature of 60-80 DEG C under the protection of nitrogen, thereby obtaining the Vickaclara intermediate 2-(7-azaindole-5-oxy)-4-(4-(2-(4-chlorphenyl)-4, 4-dimethyl cyclohexene-1-) methyl) piperazine-1-) benzoic acid. The key intermediate 2-(7-azaindole-5-oxyl)-4-(4-((2-(4-chlorphenyl)-4, 4-dimethylcyclohexene-1-) methyl) piperazine-1-) benzoic acid of the Venoclara bulk drug is prepared by taking 2-(7-azaindole-5-oxyl)-4-(4-(2-(4-chlorphenyl)-4, 4-dimethylcyclohexene-1-) methyl) piperazine-1-) benzoic acid as a raw material through hydrochloric acid removal, nucleophilic reaction, hydrochloride formation and deprotection reaction and adopting a proper purification method. The method does not need a noble metal catalyst, does not need column chromatography purification, is simple and convenient to operate and is suitable for industrial production.

Therapeutic combinations of kapasitinib and vonetog are described. The combination can be used for treating B-cell malignancies. In some embodiments, reducing the dosage (e.g., reducing the frequency and / or reducing the amount) of Venatog may mitigate or eliminate effects such as weight loss that may be experienced in an initial dosing regimen.

Therapeutic combinations of capivasertib and venetoclax are described. The combinations can be useful in the treatment of B-cell malignancies. In some embodiments, reduced dosing (e.g., reduced frequency and / or reduced amount) of venetoclax can mitigate or abrogate effects such as body weight loss that may be experienced with an initial dosage regime.

The invention relates to combination and combination therapies, particularly for the treatment of a myeloid malignancy, such as acute myeloid leukemia (AML) or a myelodysplastic syndrome (MDS). The combination therapies include (i) a recombinant binding protein comprising (a) an ankyrin repeat domain specifically binding CD3 and (b) at least one, at least two, or at least three further ankyrin repeat domains, wherein each of the at least one, at least two, or at least three further ankyrin repeat domains specifically binds one tumor-associated antigen, suitably one selected from the group consisting of CD123, CD33 and CD70, and (ii) a Bcl-2 inhibitor, e.g., venetoclax, or a pharmaceutically acceptable salt thereof and / or (iii) a hypomethylating agent, e.g., azacitidine or decitabine.

Therapeutic combinations of an AKT inhibitor, a BCL-2 inhibitor and an anti-CD20 antibody are described. Preferably, the combination comprises capivasertib, venetoclax and rituximab. The combinations can be useful in the treatment of B-cell malignancies.

In netrin-1 expressing tumor cells, netrin-1 interference triggers Mcl-1 degradation, restricted to these netrin-1 expressing tumor cells. It is proposed a netrin-1 interference to trigger tumor-specific Mcl-1 degradation. In addition, netrin-1 interference may be combined with BH3-mimetics, especially a Bcl-2 inhibitor. Netrin-1 interference is made using anti-netrin-1 antibodies. The invention proposes an anti-netrin-1 antibody for use as a tumor-specific Mcl-1 inhibitor in the treatment of a Mcl-1+ tumor, more particularly a Mcl-1+, netrin-1+ and netrin-1 receptor+, especially UNC5B+, tumor. Also provided is a combination of an anti-netrin-1 antibody and a Bcl-2 inhibitor, such as Venetoclax.

This disclosure provides methods of treating a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in a subject in need thereof, wherein the subject treated is classified as having an intermediate-2 or high IPSS risk MDS or AML; or has MDS or AML relapsed, refractory, or intolerant to HMA, venetoclax, or a combination thereof. The method includes administering to the subject an effective amount of a telomerase inhibitor or a pharmaceutically acceptable salt thereof, such as e.g. imetelstat or imetelstat sodium.

Compositions and method of prevention and treatment for a subject in need comprising drug-resistant natural killer (NK) cells, which are effective for treating cancer when administered in conjunction with cytotoxic therapies. A method of treatment comprising administering to a subject in need thereof an effective amount of modified NK cells and a cytotoxic therapy. A purified cell composition comprising modified NK cells. A pharmaceutical composition comprising an effective amount of G101V mutated NK cells and venetoclax.

Provided are pharmaceutical compositions which include an amorphous solid dispersion comprising i) a lipophilic active pharmaceutical ingredient such as abiraterone, alectinib, pazopanib, cabozantinib, venetoclax, lurasidone, or vilazodone or a salt thereof, ii) a hydrophilic polymer, iii) optionally a surfactant, iv) optionally an adsorbent, and v) optionally an acid. Also described are methods for preparing such pharmaceutical compositions and treating a subject in need thereof. In one aspect, disclosed herein is an amorphous solid dispersion comprising an active pharmaceutical ingredient.

The present invention concerns novel methods of treatment for venetoclax-resistant acute myeloid leukemia, particularly in subjects with a low expression of TP53 protein or expression of TP53 protein associated with a mutation of the TP53 gene, the methods comprising administering to the subject in need thereof a therapeutically effective amount of a NTRK / ALK / ROS1 inhibitor, or a pharmaceutically acceptable salt thereof.

Therapeutic combinations of capivasertib and venetoclax are described. This combination may be useful for treating B-cell malignancies. In some embodiments, reduced dosing (e.g., reduced frequency and / or reduced amount) of venetoclax can reduce or prevent effects, such as weight loss, that may be experienced with initial dosing regimens.

The invention belongs to the field of molecular targeted therapy, and discloses a small-molecule inhibitor CTPI3 of a targeted mitochondrial citric acid transporter SLC25A1 and application of the small-molecule inhibitor CTPI3 in tumor therapy. On the basis of an existing inhibitor CTPI2 structure, molecular design is carried out through an induced fit docking (IFD) module of Schrdinger software, and CTPI3 is obtained. Experiments show that the median inhibitory concentration (IC50) of CTPI3 on acute myelogenous leukemia (AML) cell lines (such as Kasumi-1 and THP1) and primary AML cells is obviously lower than that of CTPI2, the synergistic effect of CTPI3 and Venetoclax is enhanced, the mitochondrial ATP yield is reduced, and the TCA cycle metabolite level is affected. Animal experiments prove that CTPI3 can significantly prolong the lifetime of AML model mice and reduce leukemia load (spleen weight is reduced, and bone marrow and peripheral blood GFPcells are reduced), and has no significant toxicity (liver, kidney and brain histopathology is normal). The invention provides an efficient and safe new candidate drug for SLC25A1 targeted therapy.

The present invention concerns assessment of therapies for cancer and, in particular, hematopoietic cancers. In particular, it relates to a method for assessing and, preferably predicting response to a BCL-family inhibitor therapy in a subject suffering from cancer, preferably a hematopoietic cancer, comprising the steps of determining the amounts of the biomarkers BCL-2, BCL-xL, and MCL-1 in a tumor driving cell population, preferably leukemic stem cell (LSC) population, in a sample of said subject and comparing the amounts of the said biomarkers to a reference, whereby the response to a BCL-family inhibitor therapy is assessed. Furthermore, the present invention relates to a BCL-2 inhibitor, preferably Venetoclax, a BCL-xL and / or MCL-1 inhibitor, preferably Navitoclax, or a BCL-2 inhibitor in combination with at least one MCL-1 inhibitor or use in treating cancer, preferably a hematopoietic cancer, in a subject that has been assessed to benefit from a therapy using said inhibitors by using the method of the invention.

The disclosure describes T cells that express chimeric antigen receptors (CARs), as well as pharmaceutical compositions comprising T cells and methods of making and using such T cells. Particularly, this disclosure describes T cells expressing a CAR that binds to CD64, and methods of use in treating acute myeloid leukemia.

Methods and uses of immunoconjugates that bind to CD123 (e.g., pivekimab sunirine) in patients with acute myeloid leukemia (AML) are provided. Such immunoconjugates can be used as monotherapies or can be used in combination with BCL-2 inhibitors (e.g., venetoclax), and / or hypomethylating agents (e.g., azacitidine or decitabine) to prepare patients with AML for hematopoietic stem cell transplant and / or to achieve complete remissions in patients with AML, including those with poor prognostic markers.

The invention discloses an application of brucein D and Vinetoram in preparation of a medicine for treating acute or drug-resistant myelogenous leukemia. Through a large number of experimental screening, the brucein D and the Venotocork are combined for medication, and the test result shows that the brucein D and the Venotocork act on different targets and different signal channels of AML cells to generate a remarkable synergistic anti-tumor effect, and after the brucein D and the Venotocork are combined, the proliferation inhibition and apoptosis induction effects on the AML cells can be directly enhanced, and the anti-tumor effect of the Venotocork D and the AML cells can be improved. The compound can also reverse the drug resistance possibly occurring when the Vinetoram is singly used, and also has a remarkable killing effect on chemotherapy drug-resistant AML cells at the same time. The composition provided by the invention can reduce the dosage of antitumor drugs, reduce drug resistance, reduce adverse reactions and improve the life quality of patients, and has important application prospects.

The invention relates to the technical field of clinical molecular diagnosis and individualized tumor medicine, in particular to a group of children leukemia prognosis biomarkers based on mitochondrial activity and application of the children leukemia prognosis biomarkers. The invention aims to provide a group of children leukemia prognosis biomarkers based on mitochondrial activity, the children leukemia prognosis biomarkers are used for quantifying mitochondrial metabolic activity of children B-ALL patients, and the biomarkers can be used for early prediction of recurrence risk, evaluation of early curative effect and long-term outcome and guidance of application of a BCL-2 inhibitor or an OXPHOS inhibitor. The marker can be used as an accompanying diagnostic marker for predicting the chemotherapy recurrence risk and the reaction of a targeted drug (such as venetoclax); meanwhile, the children leukemia prognosis biomarker provided by the invention can be used as an accompanying diagnostic tool for ALL risk stratification and metabolism targeted therapy (such as a BCL-2 inhibitor) reaction prediction, and the consistency is verified in multiple queues in the specific embodiment of the invention, so that the children leukemia prognosis biomarker is high in clinical generalization performance.

Disclosed herein are combination therapies for treating hematological malignancies (e.g., acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)) using an antibody that binds human galectin-9 (anti-Gal9 antibody, e.g., G9.2-17) and one or more chemotherapeutic agents, e.g., a Bcl2 inhibitor such as venetoclax, a hypomethylating agent (HMA), or a combination thereof.

The invention belongs to the technical field of medicines, and particularly relates to application of a pharmaceutical composition in treatment of diffuse large B-cell lymphoma. Specifically, two groups of pharmaceutical compositions, namely the magnolin and the vonacrah as well as the masitinib and the gemcitabine hydrochloride, are found, and the molar ratio of the magnolin to the vonacrah is (40-120): (0.2-0.8). The molar ratio of masitinib to gemcitabine hydrochloride is (1-10): (1-10). Research finds that the pharmaceutical composition can synergistically inhibit growth of DLBCL cells, provides a novel combined treatment scheme for clinical treatment of DLBCL, and has a wide clinical application prospect.

The present invention relates to a first composition comprising one of CD4+ T cells and CD8+ T cells for use with a second composition comprising the other of CD4+ T cells and CD8+ T cells in a method for treating a subject having chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), wherein the method comprises administering to the subject a dose of modified T cells comprising CD4+ and CD8+ T cells comprising a chimeric antigen receptor (CAR) that binds specifically to CD19, wherein: (i) the subject has relapsed following remission after treatment with, has become refractory to or has failed treatment with and / or has been intolerant to ibrutinib and venetoclax;(ii) administration comprises administering a plurality of separate compositions, wherein the plurality of separate compositions comprises the first composition comprising one of the CD4+ T cells and CD8+ T cells and the second composition comprising the other of the CD4+ T cells and CD8+ T cells, and (iii) the modified T cell dose comprises a defined ratio of CAR-expressing CD4+ cells to CAR-expressing CD8+ cells, optionally wherein the ratio is between approximately 1:3 and approximately 3:1;

The utility model relates to the technical field of plasma analysis, and discloses a plasma Vickers rapid analysis device which comprises detection analysis equipment, an inlet is formed in the detection analysis equipment, a placing frame is inserted into the inlet, a limiting mechanism is arranged on the placing frame, the limiting mechanism comprises a fixing block and a guide column, and the fixing block is connected with the guide column through a bolt. The guide column penetrates through the fixing block, a clamping block is fixedly connected to the guide column, a limiting block is fixedly connected to the guide column, and the guide column is sleeved with a spring. The test tube containing plasma is inserted into the insertion hole, the lower end of the test tube can separate the two clamping blocks along with continuous lowering of the test tube, the clamping blocks abut against and are attached to the outer wall of the test tube under the action of the spring, the test tube is clamped, the test tubes of different models and sizes can be conveniently placed, and the test tube placement efficiency is improved. And the plasma detection efficiency is improved.

A process for preparing Venetoclax, the compound of Formula I, or a salt or a solvate thereof (Formula I). The process allows to decrease the DMSO amount using a solvent mixture in compliance with the safety process requirements. Moreover, in step a) a certain percentage of DMSO in the reaction solvent mixture is necessary to obtain the desired degree of conversion and purity. The process of the present invention thus allows to combine process productivity with process safety, leading to compound VI with a very high overall yield and purity.

The invention discloses application of Venetoclax in preparation of a medicine for preventing and / or treating nasopharyngeal carcinoma, and particularly, the Venetoclax inhibits expression of ACSBG1 protein and can be used for treating the nasopharyngeal carcinoma. The anti-tumor mechanism of Venetoclax relates to regulation and control of fatty acid metabolism or mitochondrial functions, and can reverse the drug resistance of tumor cells to cis-platinum. According to the invention, Venetoclax is expanded from a BCL-2 inhibitor in hematologic tumor treatment to an ACSBG1 inhibitor for solid tumor nasopharyngeal carcinoma, belongs to a brand-new and expected'new use of old medicine ', and shows remarkable innovation potential.