28 results about "ABL" patented technology

The invention discloses a positive charge fluorescent nanoprobe targeting BCR-ABL fusion protein and application of the positive charge fluorescent nanoprobe in leukemia single cell drug resistance detection, and relates to the field of biological medicine. According to the invention, the surface of the nanoprobe is subjected to specific modification of a polyethylene glycol hydrophilic polymer chain-bridged targeting molecule, so that the functionalized fluorescent nanoprobe with leukemia subcellular oncogenic fusion protein targeting property is successfully constructed. The probe realizes efficient and accurate targeting of the BCR-ABL fusion protein by regulating a subcellular transport pathway, completes diagnosis and quantitative analysis of drug resistance of the leukemia single-cell BCR-ABL fusion protein by utilizing an endocytosis-transport-exocytosis process of cells, can more comprehensively reveal heterogeneity and drug resistance conditions of BCR-ABL positive cells, and has a good application prospect. And a new technical means is provided for accurate diagnosis and treatment of chronic myelogenous leukemia.

The present application relates to the technical field of biological medicines. Specially, disclosed are a 2-arylbenzimidazole compound, and a preparation method therefor and the use thereof. The 2-arylbenzimidazole compound provided by the present application is a compound as shown in general formula I, or a pharmaceutically acceptable salt, isomer, solvate, hydrate, prodrug or isotope derivative thereof. The general formula I has a structural formula as follows: in the general formula I, R represents 1, 2, 3 or 4 identical or different substituents present on a benzene ring, and R is independently selected from the following groups: hydrogen, halogen, cyano, hydroxyl, optionally substituted C1-6 alkoxy, optionally substituted amino, optionally substituted formyl, optionally substituted sulfonyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. The 2-arylbenzimidazole compound of the present application exhibits an excellent inhibitory activity against BCR-ABL kinase, and is expected to be developed into a drug for treating and / or preventing BCR-ABL-related diseases.

The invention belongs to the technical field of disease model construction, and particularly relates to a construction method of a chronic myelogenous leukemia mouse model with conditional human EZH2 overexpression and RUNX1 knockout. According to the invention, a chronic myelogenous leukemia mouse transgenic mouse model with conditional human EZH2 overexpression and RUNX1 knockout is successfully constructed, the model is induced to be converted from a chronic stage to a sudden change stage, and particularly, the model is a transgenic mouse model which is positive in Lyz2-CreERT2 / EZH2 / RUNX1 and carries BCR-ABL and SCL-tTA. It is proved that a human EZH2 conditional overexpression and RUNX1 knockout chronic myelogenous leukemia mouse transgenic mouse model has feasibility and importance for research on conversion from CML CP to BC samples, and a molecular mechanism for conversion from chronic myelogenous leukemia to a sudden change stage is revealed for research. And a new animal model and a new research idea are provided for understanding of disease progression and development of a new treatment strategy.

The invention discloses an application of a disulfide bond isomerase single-domain antibody in preparation of a product for treating and / or preventing leukemia, the disulfide bond isomerase single-domain antibody comprises a variable region, and the variable region comprises CDR1, CDR2 and CDR3; the amino acid sequences of CDR1-CDR3 of the disulfide bond isomerase single-domain antibody are sequentially as shown in SEQ ID NO: 15, SEQ ID NO: 16 and SEQ ID NO: 17, and the CDR1-CDR3 are defined according to an IMGT definition scheme. The single-domain antibody provided by the invention can be used for remarkably inhibiting the growth of subcutaneous transplanted tumors of Ba / F3BCR-ABLT315I cells in nude mice, and has an obvious inhibiting effect on drug-resistant chronic granulocytic leukemia.

This invention discloses a quantitative genomic RNA standard for the BCR-ABL1 fusion gene and its preparation method. The method involves extracting genomic RNA containing two mutant forms of the BCR-ABL1P210 fusion gene, b2a2 and b3a2. RNA storage buffer and quantitative standard solutions are prepared, and corresponding primers and probes are designed. A one-step reverse transcription digital PCR method is used, with the BCR-ABL1P210 fusion mutant genomic RNA as a template for PCR amplification. Fluorescence signals are collected to detect the expression of the BCR-ABL1P210 fusion genes b2a2 and b3a2, thereby obtaining the copy number content of the BCR-ABL1P210 fusion genes b2a2 and b3a2 and the abundance of the mutant gene in ABL-WT as quantitative values.

This application relates to the field of molecular pathology diagnostic technology, specifically disclosing a bone marrow smear FISH detection kit and its application. The kit includes a rapid hybridization buffer, a stabilization pretreatment solution, room temperature hybridization probes, probe dilution buffer, low-salt washing buffer, high-salt washing buffer, counterstaining solution, positive control samples, and negative control samples. The room temperature hybridization probes include broken probe pairs targeting the BCR-ABL, PML-RARA fusion genes, and IgH gene rearrangements. The detection method of this kit includes sample pretreatment, probe denaturation, room temperature hybridization, washing and counterstaining, and signal interpretation. Through the synergistic effect of the rapid hybridization buffer and the short-chain low-Tm value probes, rapid hybridization at room temperature is achieved, eliminating the need for a dedicated isothermal hybridization instrument. The stabilization pretreatment solution can complete cell permeation and RNA removal in one step, resulting in a high degree of operational standardization.

The invention relates to the treatment of chronic myeloid leukemia (CML). In particular it relates to the treatment of CML with inhibitors of mitochondrial pyruvate transport, which are able to target leukemic stem cells (LSCs) which are resistant to therapy with tyrosine kinase inhibitors (TKIs). Combination therapies with BCR-ABL kinase inhibitors are also described.

The invention discloses a targeted protein degradation agent utilizing a ubiquitin-proteasome pathway as well as a preparation method and application of the targeted protein degradation agent, and belongs to the technical field of biological medicines. On the basis of a PROTAC (protein targeted degradation chimera) strategy and on the basis of imatinib, different Linkers are introduced to be connected with an E3 ubiquitin enzyme ligand Nutlin-3 derivative, a degradation tag is labeled on BCR-ABL cancer protein, and the degradation agent with the Bcr-Abl protein targeting capacity is constructed. A Western blot experiment shows that the targeted protein degradation agent shows a good degradation effect on the Bcr-Abl protein in K562 cells, and the compound WP shows a degradation effect on concentration dependence and time dependence of the Bcr-Abl protein. Tumor cell proliferation experiments show that the compound has certain inhibitory activity on K562 cells. Wherein when the Linker is dodecane-1, 12-diketone, the anti-proliferative activity is the best. An apoptosis experiment and a period experiment show that the targeted protein degradation agent can realize concentration-dependent promotion of cell apoptosis and retard cells in S and G1 / G0 periods.

This invention provides primers and a kit for detecting the BCR / ABL fusion gene in chronic myeloid leukemia, including LCR primers CP, SP, T1, and T2, whose nucleotide sequences are shown in SEQ ID NO:1-SEQ ID NO:4 or SEQ ID NO:5-SEQ ID NO:8. These primers have a low detection limit and strong ability to distinguish single-base mismatches.

The present invention relates to a 3-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-phenylbenzamide derivative, a method for preparing the same, and a pharmaceutical composition comprising the same as an active ingredient for preventing or treating cancer. The derivative can significantly inhibit the proliferation of cancer cells by inhibiting kinases, particularly Bcr-Abl kinase or Bcr-Abl (T315I) kinase. Therefore, the derivative can be effectively used as a pharmaceutical composition for the prevention or treatment of cancer.

Methods for treating leukemia are disclosed based on detecting specific cell states and transcriptional programs within leukemic cells. This disclosure presents a novel therapeutic method for treating acute lymphoblastic leukemia (ALL), including BCR-ABL positive and BCR-ABL1-like ALL subtypes. The method involves detecting specific cell states and transcriptional programs in patient samples and administering targeted therapies based on these characteristics. For a pre-B cell-like state or pre-BCR signaling program, a combination of tyrosine kinase inhibitor (TKI) and SYK inhibitor is used. Conversely, a progenitor-like state or stress-autophagy program is treated with a TKI and a p38 MAPK inhibitor. This approach aims to improve treatment efficacy by tailoring therapy to the leukemia's unique molecular and cellular features, particularly in relapsed cases or when minimal residual disease is present.

The present disclosure relates to [18F]-labeled imidazopyridine derivatives or salts thereof as positron emission tomography (PET) radiotracers suitable for imaging the stress-signaling non-receptor tyrosine kinase c-abl, and their use in in vivo diagnosis, preclinical and clinical imaging, patient stratification on the basis of mutational status of c-abl and assessing response to therapeutic treatments. The present disclosure further relates to the use of [18F]-labeled imidazopyridine derivatives as PET radiotracers. The disclosure also provides a process for the radiosynthesis of [18F]-labeled imidazopyridinederivatives.

The application belongs to the field of medicine, and particularly relates to a novel quinazoline ring and tetrahydronaphthalene ring PROTAC compound, a preparation method and application thereof. The quinazoline ring and tetrahydronaphthalene ring PROTAC compound has a structural formula shown in general formula (I), and has significant Bcr-Abl protein inhibitory activity as an antitumor drug. The application further provides a preparation method of the compound, a pharmaceutical composition containing the compound and use thereof. The PROTAC molecule obtained by the application has better antitumor activity and safety, and has great value as an antitumor agent in Bcr-Abl-mediated diseases.

The present application relates to a kind of arylamide compounds or its pharmaceutically acceptable salt or its stereoisomer with the structure shown in formula I, formula II, formula III or formula IV, and its application.The arylamide compound provided by the present application is a molecular glue degrader for Bcr-Abl T315I , which can effectively degrade wild-type Bcr-Abl kinase and mutant Bcr-Abl T315I Kinase, can effectively inhibit the kinase activity of Bcr-Abl and Bcr-Abl T315I Mutant, has good anti-proliferation effect on tumor cells carrying Bcr-Abl and Bcr-Abl T315I ;And selectivity is good, side effect is small, and safety is good.

The invention provides a novel micro PROTAC compound without a linker based on N-degree and application of the novel micro PROTAC compound without the linker based on the N-degree. The invention provides a novel and unique miniature PROTAC small molecule without a linker, and the BCR-ABL and EML4-ALK fusion protein can be specifically degraded by utilizing a degradation path of a cell. Different from a common PROTAC in which the spatial positions of a target protein and a specific E3 ubiquitin ligase are adjusted by using the length and the type of a linker, the miniature PROTAC provided by the invention respectively recruits different E3 ubiquitin ligase through nineteen different N-degron amino acids; therefore, an optimal 'E3-AA-mini PROTAC-POI' ternary complex which is beneficial to realizing ubiquitination labeling on the target protein in space can be formed, and further efficient degradation of the target protein is realized.

Provided are compounds of Formula (I) wherein X is selected from the group of ethanyl, ethenyl, ethynyl, and triazinyl; R1 is selected from the group of R1 is selected from the group of alkyl, alkoxy, cycloalkyl, —CH2-cycloalkyl, —O— cycloalkyl, halogen, haloalkyl, OH, and CN; and R2 is a ring moiety selected from the group of imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, phenyl, and pyridinyl, each optionally substituted; for use as inhibitors against native BCR-ABL kinase protein and clinically important BCR-ABL mutations such as T315I, F317L, E255K and Y253F for the treatment of diseases that include chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myelogenous leukemia (AML).

The invention belongs to the technical field of mouse model construction, and particularly relates to a construction method of a chronic myelogenous leukemia mouse model with RUNX1 gene conditional knockout. The method comprises the following steps: hybridizing a RUNX1 gene conditional knockout mouse and an LYZ2-CreERT2 mouse to obtain an F1 generation, and carrying out DNA (Deoxyribose Nucleic Acid) identification and screening to obtain a double-transgenic mouse with the genotype of LYZ2-CreERT2 / RUNX1; then hybridizing the LYZ2-CreERT2 / RUNX1 double-transgenic mouse of the F1 generation with the SCL-tTA / Bcr-abl double-transgenic mouse to obtain an F2 generation, and carrying out DNA (Deoxyribose Nucleic Acid) identification and screening to obtain a four-transgenic mouse of which the genotype is SCL-tTA / Bcr-abl / LYZ2-CreERT2 / RUNX1. The invention provides a solid research basis for deep research of the effect of the RUNX1 gene in chronic myelogenous leukemia and research and development of LSCs targeted drugs aiming at the RUNX1 gene.

Provided are novel proteolysis targeting chimera (PROTAC) compounds that exhibit improved efficacy and safety profiles over current inhibitor-based drugs, and pharmaceutical compositions and methods of preparation and use for treatment of certain diseases or conditions, in particular those mediated by BCR-ABL.

The invention relates to an aryl amide compound with a structure as shown in a formula I, a formula II, a formula III or a formula IV, or pharmaceutically acceptable salt or stereoisomer thereof, and application thereof. The aryl amide compound provided by the invention is a molecular glue degradation agent aiming at Bcr-AblT315I, can effectively degrade wild type Bcr-Abl kinase and mutant type Bcr-AblT315I kinase, can effectively inhibit the kinase activity of Bcr-Abl and Bcr-AblT315I mutants, and has a relatively good anti-proliferation effect on tumor cells carrying Bcr-Abl and Bcr-AblT315I; the selectivity is good, toxic and side effects are small, and the safety is good.

The disclosure provides compositions and methods for treating traumatic brain injury (TBI). The compositions comprise inhibitors of multiple protein tyrosine kinase families, including Src, Abl, and / or c-Kit protein tyrosine kinase families. The methods comprise administering a therapeutically effective amount of a composition comprising an inhibitor of multiple protein tyrosine kinase families to a subject, wherein the inhibitor is administered at a dose of less than about 20 mg / day to an adult human.

The invention discloses a straight-chain Bcr-Abl substrate binding site targeting peptide as well as a preparation method and application thereof, and belongs to the technical field of tumor targeted therapy. The straight-chain Bcr-Abl substrate binding site targeting peptide is obtained by carrying out single-point mutation, multi-point mutation or D-type amino acid substitution on glutamic acid at the first site, isoleucine at the third site, tyrosine at the fourth site and / or phenylalanine at the eighth site of Abltide. And connecting the straight chain type Bcr-Abl substrate binding site targeting peptide with a cell-penetrating peptide, so as to obtain the straight chain type Bcr-Abl substrate binding site targeting cell-penetrating peptide. The polypeptide has higher affinity with a substrate binding site, is small in molecular weight, easy to synthesize in a large scale, good in stability and good in safety, and has certain tumor cell targeting and membrane penetrating capabilities; the polypeptide has a good application prospect in preparation of therapeutic drugs targeting human chronic myelogenous leukemia cells, human peripheral blood basophilic leukemia cells or human acute T lymphocytic leukemia cells, and can be used in another important field of polypeptide development for leukemia new target treatment.

The application belongs to the field of pharmaceutical chemistry, and discloses a preparation method and application of a self-assembled nanomaterial targeting Bcr-Abl. The structure of the self-assembled nanomaterial targeting Bcr-Abl is shown in the specification. The self-assembled nanomaterial targeting BCR-ABL provided by the application can retain high toxicity of the drug to tumors, improve accumulation of the drug at the tumor site, reduce toxicity of the drug to normal tissues, and thus reduce the occurrence of side effects.

The invention discloses a Bcr-Abl protein degradation agent based on a hydrophobic label technology as well as a preparation method and application thereof, and belongs to the technical field of preparation of protein degradation agents. The preparation method comprises the following steps: coupling demethylated imatinib with alpha-bromo-carboxylic acid tert-butyl ester to obtain target protein ligands with connecting arms with different lengths; exposing carboxyl through a protecting group removing reaction to obtain a target protein ligand with carboxyl and a connecting arm; a target protein ligand with carboxyl and a connecting arm and 5-norbornene-2-methylamine are subjected to an amide condensation reaction, and the Bcr-Abl protein degradation agent based on the hydrophobic label technology is obtained. The preparation method of the protein degradation agent is simple, easy to implement and high in yield, and the protein degradation agent can be used for preparing drugs for treating or preventing cancers, especially for preparing anti-tumor drugs taking Bcr-Abl as a target spot.

The present invention belongs to the field of medicinal chemistry, and discloses a molecular glue degrader targeting Bcr-Abl protein, its preparation method and use. The structural formula of the molecular glue targeting BCR-ABL is as follows, wherein R1 is hydrogen or hydroxyl; R2 satisfies R2COOH and is selected from one of (2E)-4-(4-methoxyphenyl)-4-oxydibutyl-2-enoic acid, cyclopent-1-ene-1-carboxylic acid, (2E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoic acid, (2E)-3-[2-(trifluoromethyl)phenyl]prop-2-enoic acid and acrylic acid. Compared with the third-generation BCR-ABL inhibitor H0 in the clinical stage, the compound H0-mGlu and H1-mGlu inhibitory activity (IC 50 ) has shown a significant improvement (IC 50 The value can be reduced by 1-2 orders of magnitude), so it has good application prospects.

The invention discloses a polypeptide targeted degradation agent based on a Bcr-Abl protein substrate binding site as well as a preparation method and application of the polypeptide targeted degradation agent, and belongs to the technical field of tumor targeted therapy. From the C end to the N end, the novel polypeptide targeted degradation agent is obtained by connecting a targeted peptide (obtained by carrying out amino acid site mutation on Abltide) with high affinity of Bcr-Abl, a connecting peptide, a degradation peptide (polypeptide ligand PMI of E3 ubiquitin ligase MDM2 and a conserved sequence LIR in autophagy receptor protein respectively exert a degradation effect) and a cell-penetrating peptide (R6 or TAT). The polypeptide targeted degradation agent has the capability of remarkably inhibiting the activity of Bcr-Abl mutant strain cells, can degrade related proteins in K562 cells, can induce apoptosis of the K562 cells, can influence the cell cycles of the K562 cells, can be used for preparing anti-tumor drugs, and has a good application prospect. The compound has a good application prospect in preparation of drugs for targeting human chronic granulocytic leukemia cells or human peripheral blood basophilic leukemia cells.

The present application provides an N-degron-based novel linker-free mini-PROTAC compound, and a use thereof. The present application provides a novel and unique linker-free mini-PROTAC small molecule, which can utilize a cell's own degradation pathway to specifically degrade BCR-ABL and EML4-ALK fusion proteins. Unlike conventional PROTACs, which regulate the spatial position between a target protein and a specific E3 ubiquitin ligase by means of the length and type of a linker, the mini-PROTAC of the present application recruits different E3 ubiquitin ligases by means of nineteen different N-degron amino acids, respectively, so as to form an optimal "E3—AA-miniPROTAC—POI" ternary complex that is spatially favorable for the ubiquitination labeling of a target protein, thereby achieving efficient degradation of the target protein.

The invention discloses an application of an anti-malarial drug primaquine phosphate in preparation of drugs for treating BCR-ABL positive leukemia and breast cancer and a drug combination composition, and discovers that the anti-malarial drug primaquine phosphate has obvious effects of resisting BCR-ABL + leukemia and breast cancer, and has obvious anti-BCR-ABL + leukemia and breast cancer in the cellular level. The PRQ can significantly inhibit the growth of a BCR-ABL + leukemia cell line and an imatinib drug-resistant BCR-ABL + leukemia cell line, significantly inhibit the growth of breast cancer cells and induce ferroptosis of the breast cancer cells, and further researches find that the PRQ can degrade wild or mutant BCR-ABL proteins in a targeted manner. At the patient level, the PRQ is found to be capable of inhibiting the formation ability of primary cell colonies of wild-type or mutant patients with the BCR-ABL + leukemia, and at the animal level, the PRQ is found to have an obvious inhibiting effect on the progress of the BCR-ABL + leukemia.

The present invention relates to kinase inhibitors, particularly inhibitors of protein kinases, including the protein tyrosine kinases LCK, ABL, SRC, KIT, SIK family, and / or mutants thereof. Although structurally similar to dasatinib, the kinase inhibitors of the present invention may exhibit one or more properties that differ from dasatinib. Similarly, the present invention relates to pharmaceutical compositions comprising one or more kinase inhibitors. The kinase inhibitors or pharmaceutical compositions of the present invention can be used to treat diseases or conditions, such as proliferative diseases, such as leukemia or solid tumors. The kinase inhibitors or pharmaceutical compositions can be used in treatment regimens that are similar to, similar to, or different from the treatment regimens used for the corresponding diseases with dasatinib, and in particular can be used in combination treatment regimens with one or more other therapeutic agents (e.g., immune checkpoint inhibitors).