47 results about "Venetoclax" patented technology

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.

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 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.

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.

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 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.

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 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.

Provided are pharmaceutical combinations, pharmaceutical compositions, and methods of treatment of cancer using combinations of BH3 mimetics such as venetoclax and navitoclax with 0MA1 activators such as BTM-3566.

This application relates to methods for treating patients with reduced sensitivity to BCL-2 inhibitors. An antibody or antigen-binding fragment thereof that binds to CD70 is provided for treating myeloid malignancies in human subjects resistant to BCL-2 inhibitor treatment, and a method for treating myeloid malignancies in a subject, the method comprising (a) selecting a human subject with myeloid malignancies who has reduced sensitivity to or is refractory to BCL-2 inhibitors; and (b) administering the CD70-binding antibody or antigen-binding fragment thereof to the subject. In some embodiments, the myeloid malignancy is acute myeloid leukemia (AML). In some embodiments, the CD70-binding antibody is Cusatuzumab. In some embodiments, the BCL-2 inhibitor is co-administered with the CD70-binding antibody or antigen-binding fragment thereof. In some embodiments, the BCL-2 inhibitor is Venetoc.

Methods for treating T cells with venetoc to enhance T cell-mediated cytotoxicity and / or T cell-mediated antitumor activity are described. Enhanced T cell populations and their related methods and uses in cancer treatment are also described.

The present invention provides a compound of Formula (I), or a salt thereof : (I) for use in the treatment or prophylaxis of a cancer, wherein the compound of Formula (I) is administered in combination with Azacitidine and Venetoclax wherein the three compounds are administered simultaneously, sequentially or separately.

Provided according to embodiments of the invention are methods of treating a disorder in a subject in need thereof that include administering to the subject an effective amount of cedazuridine, an effective amount of decitabine, and an effective amount of venetoclax, thereby treating the disorder in the subject. In some embodiments of the invention, the disorder is a hyperproliferative disorder such as a cancer. In some embodiments, the disorder is a hematological cancer such as myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), leukemia (e.g., acute myeloid leukemia), or lymphoma.

The present disclosure provides methods for treating leukemia (e.g., AML) using a CLK / DYRK inhibitor and a B-cell lymphoma 2 (BCL2) inhibitor (e.g., venetoclax). Kits for use in practicing the methods are also provided.

The invention relates to a pharmaceutical composition which is used for treating leukemia and contains poison carotene and vinca, and also provides application of the pharmaceutical composition containing poison carotene and vinca to preparation of a medicine for treating leukemia, and the leukemia is preferably leukemia with resistance to vinca. The pharmaceutical composition can synergistically kill leukemia cells and promote apoptosis, has low cytotoxicity, and can significantly reduce expression of Venokra drug resistance related proteins.

The present disclosure relates to Venetoclax oral drugs and uses thereof. In some aspects, the present disclosure provides for a pharmaceutical composition for oral administration, which comprises an effective amount of Venetoclax, or a pharmaceutically acceptable salt thereof; and an anionic surfactant, or a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable carrier or excipient. In some aspects, the present disclosure provides for uses of the above pharmaceutical compositions.

The present invention relates to the field of the treatment of cancer. In this study, the inventors found that VDAC2 is heterogeneously expressed in MM cells. VDAC2 protein expression correlated with BAK but not with BAX protein levels. Transient silencing of VDAC2, but not VDAC1 or VDAC3, sensitized MM cells to intrinsic mitochondrial apoptosis signals, alongside with the induction of pre-activated BAK and the increase of global, MCL1 and BCL2 mitochondrial priming. They also found a that a VDAC2 compound, efesevin recapitulated the sensitization effect of VDAC2 knock-down on BH3 mimetics apoptotic response. This novel VDAC2 modulator sensitized MM cells to BH3 mimetics targeting MCL1 (S63845) or BCL2 (Venetoclax) without modifying BAK or BAX protein expression. The efficiency of the VDAC2 modulator was directly correlated with the levels of VDAC2 protein. To better understand the VDAC2 / BAK interplay, The inventors generated VDAC2 KO myeloma cells. VDAC2 KO cells exhibited an important decrease of BAK protein expression while BAX remained unchanged. Accordingly, VDAC2 KO cells completely lost their mitochondrial priming. Interestingly, they also found that BAK KO myeloma cells displayed decreased levels of VDAC2. The reciprocal regulation between VDAC2 and BAK was dependent on both the proteasome and lysosome degradation pathways. Thus, the present invention relates to a combination of a VDAC2 modulator and a BH3- mimetics compound for use in the treatment of a cancer in a subject in need thereof.

Stapled BAD BH3 peptides and compositions comprising the same that are useful in overcoming venetoclax resistance are provided. Also provided are methods of using the stapled BAD BH3 peptides for treating a BCL-2 expressing and / or dependent cancer (e.g., a hematologic cancer or a solid tumor) in a human subject in need thereof. In some cases, the cancer is a venetoclax-resistant cancer due to acquired mutations in the BCL-2 protein. The methods involve administering to the human subject a stapled BAD BH3 peptide or pharmaceutical composition or delivery vehicle comprising the stapled BAD BH3 peptide disclosed herein.

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.