49 results about "ABL" patented technology

The invention discloses application of an SUMO inhibitor 2-D08 in preparation of drugs for treating chronic myelogenous leukemia (CML) and drug resistance of a tyrosine kinase inhibitor (TKI) of the SUMO inhibitor 2-D08. It is revealed for the first time that SUMOylation modification drives disease progression by stabilizing BCR-ABL protein, 2-D08 promotes BCR-ABL protein degradation by inhibiting the modification, and leukemia cell proliferation is remarkably inhibited. In-vitro experiments prove that the compound effectively inhibits the activity of TKI drug-resistant cells, and in-vivo experiments show that 5 mg / kg of the compound can improve liver and spleen infiltration of CML mice. The inhibitor provides a new scheme for overcoming drug resistance, and fills the application blank of SUMOylation modification in CML treatment.

A human chronic myeloid leukemia cell line and the use thereof. The human chronic myeloid leukemia cell line is the first cell line internationally established from chronic-phase leukemia cells of chronic myeloid leukemia, and was named human chronic myeloid leukemia cell YYXY-M6, which was deposited at the China Center for Type Culture Collection (Wuhan University, Wuhan, China) on July 24, 2023, under the deposit number of CCTCC NO: C2023219. The leukemia cell line exhibits primitive cell morphology and has three karyotypes, i.e. t(6:11)(q25:q23), del(11)(q23) and normal karyotype (46, XX); is BCR-ABL gene-negative; has good in-vitro proliferation ability; can be used as cellular material for the study of the mechanism of occurrence and development of the chronic phase of chronic myeloid leukemia, from the chronic phase thereof to the blastic phase thereof, and of BCR-ABL gene-negative chronic myeloid leukemia, and for the in-vitro study of individualized treatment; and can also be used for both in-vitro and in-vivo studies of drug screening and evaluation for the chronic phase of chronic myeloid leukemia, from the chronic phase thereof to the blastic phase thereof, and BCR-ABL gene-negative chronic myeloid leukemia, providing guidance for clinical medication.

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.

A splice variant of bcr-abl mRNA that produces BCR-ABL protein with a truncated C-terminus and its role in resistance to treatment with kinase inhibitors is disclosed. Vectors for expressing the truncated gene product are provided as well as recombinant cells that express the truncated gene product from a cDNA construct. Also provided are methods compositions and kits for detecting the BCR-ABL splice variant. Additionally, methods for screening BCR-ABL kinase domain inhibitors which rely on the recombinant cells and methods of predicting likelihood for resistance of a CML patient with a BCR / ABL translocation respond to treatment with one or more BCR-ABL kinase inhibitors are also disclosed.

The invention relates to a use of combinations of PD-1 inhibitor therapy with certain kinase inhibitors, in particular inhibitors of protein kinases including the SIK-family, CSF1R, ABL / BCR-ABL, SRC, HCK, PDGFR, KIT and / or their mutants, to overcome resistance to PD-1 / PDL1 inhibitor therapy in tumours. A preferred tumour disease treatable in accordance with the invention is a squamous cell lung cancer with a PD-1 inhibitor therapy resistance phenotype.

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 discloses a target BCR-ABL degradation agent and application thereof. The degradation agent has a structure as shown in a general formula (I) in the specification. The degradation agent disclosed by the invention can effectively reduce the BCR-ABL protein level in K562 cells to cause apoptosis, so that the degradation agent can be used for treating neoplastic diseases caused by abnormal expression of various wild-type and mutant BCR-ABL including chronic granulocytic leukemia and acute lymphocytic leukemia. # imgabs0 #

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 present disclosure relates to compounds for the use of treating neurodegenerative diseases and, in particular, to compounds targeting the Abelson non-tyrosine kinase (c-Abl) protein for such treatment. The neurological disorders and conditions include Parkinson's disease, Alzheimer's disease and the like. It also relates to pharmaceutical compositions and methods of treatment of such neurological disorders involving the c-Abl protein kinase.

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 primer set for detecting the leukemia BCR-ABL fusion gene and its application, belonging to the technical field of medical detection. The primer set includes amplification primer pairs, and each amplification primer pair includes an upstream primer and a downstream primer. The upstream primer is selected from a sequence complementary to the exon region e1 to b3 of the BCR gene of the BCR-ABL fusion gene, and the downstream primer is selected from a sequence complementary to the exon region a2 to a3 of the ABL gene of the BCR-ABL fusion gene. The primer set for detecting the leukemia BCR-ABL fusion gene of the present invention can be used in the CRISPR / Cas detection system, can achieve the detection of the BCR-ABL fusion gene, and has the advantages of simple and rapid detection process, high detection sensitivity, and does not depend on complex instrument equipment and professional operators, etc.

The present invention provides compounds of formula (I) wherein X is selected from the group consisting of ethyl, vinyl, ethynyl and triazinyl; r1 is selected from the group consisting of alkyl, alkoxy, cycloalkyl,-CH2-cycloalkyl,-O-cycloalkyl, halogen, haloalkyl, OH and CN; and R2 is a ring moiety selected from the group consisting of an imidazolyl group, a pyrazolyl group, a 1, 2, 3-triazolyl group, a thiazolyl group, a phenyl group and a pyridyl group, each optionally substituted; the compounds of formula (I) are useful as inhibitors against native BCR-ABL kinase proteins and clinically important BCR-ABL mutations such as T315I, F317L, E255K and Y253F for the treatment of diseases including chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML). # imgabs0 #

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.

The present invention relates to a biomarker composition for diagnosing resistance to BCR-ABL-independent tyrosine kinase inhibitors (TKIs), including FAM167A, and a composition for preventing or treating chronic myeloid leukemia that targets FAM167A. More specifically, the present invention provides a composition, kit, and method for diagnosing BCR-ABL-independent TKI resistance in chronic myeloid leukemia patients by confirming the mRNA expression level of the FAM167A protein, a fragment thereof, or a gene encoding the protein, as well as a pharmaceutical composition for preventing or treating chronic myeloid leukemia exhibiting BCR-ABL-independent TKI resistance that targets FAM167A, and a pharmaceutical composition for inhibiting BCR-ABL-independent TKI resistance in chronic myeloid leukemia patients.

The present disclosure relates to an [¹⁸F]-labeled imidazopyridine derivative or a salt thereof, as a positron emission tomography (PET) radiotracer, which is suitable for imaging of the stress signal non-receptor tyrosine kinase c-abl, and its use in in vivo diagnosis, pre-clinical and clinical imaging, patient stratification based on the c-abl mutation status, and assessment of response to treatment. The present disclosure also relates to the use of an [¹⁸F]-labeled imidazopyridine derivative as a PET radiotracer. The present disclosure also provides a method for radiosynthesizing an [¹⁸F]-labeled imidazopyridine derivative.

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 present disclosure provides for methods, systems, and compositions of nucleic acid and peptide sequences. The present disclosure provides for a composition comprising one or more polynucleotides encoding at least one amino acid sequence, wherein the at least one amino acid sequence is selected from the group consisting of SEQ ID NOs: 1 to 8, SEQ ID NOs: 10 to 17, and SEQ ID NOs: 19 to 44. The present disclosure also provides for a method of treating or preventing cancer, the method comprising administering to a subject an effective amount of a composition comprising one or more polynucleotides encoding at least one amino acid sequence, wherein the at least one amino acid sequence is selected from the group consisting of SEQ ID NOs: 1 to 8, SEQ ID NOs: 10 to 17, and SEQ ID NOs: 19 to 44.

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.

The present disclosure provides for methods, systems, and compositions of nucleic acid and peptide sequences. The present disclosure provides for a nucleic acid sequence encoding two or more amino acid sequences selected from the group consisting of SEQ ID NOs: 1 to 44. The present disclosure also provides for an immunogenic peptide composition comprising two or more peptides selected from the group consisting of SEQ ID NOs: 1 to 44. The present disclosure further provides for a nucleic acid sequence encoding one or more amino acid sequences selected from the group consisting of SEQ ID NOs: 46 to 112. The present disclosure additionally provides for an immunogenic peptide composition comprising one or more peptides selected from the group consisting of SEQ ID NOs: 46 to 112.

The invention discloses oligonucleotide for screening and identifying FGFR1 rearrangement by a multiplex fluorescent PCR (Polymerase Chain Reaction) technology, the oligonucleotide comprises an upstream primer, a downstream primer and a probe for detecting a ZNF198-FGFR1 fusion gene, and a kit and a detection method based on a Taqman probe real-time fluorescent quantitative PCR technology. The kit is used for rapidly and accurately detecting the expression level of the ZNF198-FGFR1 fusion gene in a patient with 8p11 myeloproliferative syndrome (EMS). A brand new oligonucleotide sequence is designed for a ZNF198-FGFR1 fusion site, and the amplification efficiency and the detection sensitivity are remarkably improved by optimizing the molar ratio of the primer to the probe; a double-standard curve quantitative technology is adopted, and a reference gene ABL and a target gene are synchronously detected, so that relative quantitative analysis of a fusion gene is realized, and variation interference among samples is avoided; due to the design of the integrated kit, sample treatment steps are simplified; the kit contains positive / negative / blank reference substances, ensures the reliability of a detection result, and is suitable for clinical trace residue monitoring and early targeted treatment guidance.

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.