47 results about "ABL Tyrosine Kinase" patented technology

Truncation variants of BCR-ABL mRNA that produces BCR-ABL proteins with a truncated C-terminus and its role in resistance to treatment with kinase inhibitors is described. Vectors for expressing the truncated gene products are described as well as recombinant cells that express the truncated gene products from cDNA constructs. Also provided are methods compositions and kits for detecting the BCR-ABL truncation variants. Also provided are methods for determining the prognosis of a patient diagnosed as having myeloproliferative disease, and methods for predicting the likelihood for resistance to a treatment with tyrosine kinase inhibitor in a patient diagnosed as having myeloproliferative disease. Additionally, methods for screening BCR-ABL tyrosine kinase domain inhibitors which rely on the recombinant cells are also disclosed.

The invention described herein relates to novel genes and their encoded proteins, termed Mutants Associated with Resistance to STI-571 (e.g., T315I Bcr-Abl), and to diagnostic and therapeutic methods and compositions useful in the management of various cancers that express MARS. The invention further provides methods for identifying molecules that bind to and / or modulate the functional activity of MARS.

The present invention relates to a method of treating chronic myelogenous leukemia in a subject comprising administering to the subject a compound, such as N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide, that inhibits the T315I mutation in BCR-ABL tyrosine kinase, or a pharmaceutically acceptable salt thereof. The present invention also relates to a pharmaceutical composition comprising a compound such as N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide, that inhibits the T315I mutation in BCR-ABL tyrosine kinase, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

An oral pharmaceutical formulation containing an effective amount of NRC-AN-019 including its pharmaceutically acceptable salts and polymorphs such as Form I, Form II and Form III thereof to improve the bioavailability intended for self-emulsification upon its contact with the gastro-intestinal fluid. The invention also relates to a process for the preparation of oral solution containing NRC-AN-019 in an effective concentration for the better therapy against Chronic Myeloid Leukemia as BCR-ABL tyrosine kinase inhibitor and against other tumors such as head and neck cancer, prostate cancer and the like.

The invention provides a protein degradation targeting BCR-ABL compound as shown in a formula (I) and an application thereof to resisting tumors. The compound as shown in the formula (I) has the effects of degrading and restraining BCR-ABL targeting protein, and mainly consists of four parts of a first part: BCR-ABL-TKIs which is a compound having BCR-ABL tyrosine kinase restraining activity, a second part: LIN which is a link unit, a third part: ULM which is a VHL or CRBN protease micromolecule ligand having a ubiquitination function, and a fourth part: a group A which is carbonyl and is used for performing covalent bonding on the BCR-ABL-TKIs and the LIN and covalent bonding on the LIN and the ULM. A series of compounds designed and synthesized by the invention have broad pharmacological activity, have the functions of degrading BCR-ABL protein and restraining BCR-ABL activity, and can be used for pertinent tumor treatment. (As shown in the description)

Disclosed are a hydroxyproline peptoid derivative and a preparation method and application thereof. With biphenyl pyridine as a hinge region binding fragment, by adopting a design strategy of a fragment drug and introducing L-hydroxyproline as a flexible Linker, a peptoid micromolecule-like compound library with kinase inhibition activity is constructed, and through screening of ADP-Glo and otheractivity tests, a peptoid tyrosine-like kinase inhibitor which has Bcr-Abl kinase inhibition activity and prevents the proliferation of tumor cells is found. The compound can be used for preparing anti-tumor drugs and has the activity of inhibiting Bcr-Abl and Bcr-AblT315I kinases and activity of inhibiting the cell proliferation of K562 cells. By introducing the L-hydroxyproline, the structural diversity of the Bcr-Abl inhibitor is expanded, the activity result shows that the introduction of proline has a certain effect on the inhibition activity of the compound, and the proline can serve asa novel pharmacological-effect fragment of the Bcr-Abl tyrosine kinase inhibitor.

The invention discloses a Bcr / Abl tyrosine kinase inhibitor capable of treating chronic granulocytic leukemia and a preparation method thereof. The Bcr / Abl tyrosine kinase inhibitor capable of treating chronic granulocytic leukemia obtained by a large number of experimental screenings not only can effectively inhibit Bcr / Abl tyrosine kinase, and still has a good inhibitory effect to mutated Bcr / Abl tyrosine kinase, so that the Bcr / Abl tyrosine kinase inhibitor is a novel Bcr / Abl tyrosine kinase inhibitor for effectively treating chronic granulocytic leukemia.

Methods of diagnosing a tauopathy and predicting whether a subject will develop a tauopathy are provided. Also provided are antibody preparations that specifically bind to tau phosphorylated at tyr394 and / or tyr310. Methods of inhibiting tau phosphorylation in a cell and methods of treating a subject having a tauopathy are additionally provided. Methods of treating a subject at risk for a tauopathy are also provided. Additionally, non-human mammals comprising a transgene encoding an abl tyrosine kinase are provided. Also provided are methods of evaluating whether a compound inhibits development of a tauopathy.

The invention discloses a thiazol-aminobenzamide acetate derivative with anti-tumor activity. The thiazol-aminobenzamide acetate derivative with the anti-tumor activity can be applied to preparing anti-cancer drugs and is particularly applicable to serving as a Bcr-Abl tyrosine kinase inhibitor, especially as a Bcr-Abl tyrosine kinase inhibitor for T3151 mutation.

Truncation variants of BCR-ABL mRNA that produces BCR-ABL proteins with a truncated C-terminus and its role in resistance to treatment with kinase inhibitors is described. Vectors for expressing the truncated gene products are described as well as recombinant cells that express the truncated gene products from cDNA constructs. Also provided are methods compositions and kits for detecting the BCR-ABL truncation variants. Also provided are methods for determining the prognosis of a patient diagnosed as having myeloproliferative disease, and methods for predicting the likelihood for resistance to a treatment with tyrosine kinase inhibitor in a patient diagnosed as having myeloproliferative disease. Additionally, methods for screening BCR-ABL tyrosine kinase domain inhibitors which rely on the recombinant cells are also disclosed.

The present invention provides machine readable media embedded with the three-dimensional molecular structure coordinates of AblKD and variants and subsets thereof, including binding pockets, methods of using the structure to identify and design affecters, including inhibitors and activator AblKD crystals and compounds and compositions that affect Abl activity.

The invention described herein relates to novel genes and their encoded proteins, termed Mutants Associated with Resistance to STI-571 (e.g., T315I Bcr-Abl), and to diagnostic and therapeutic methods and compositions useful in the management of various cancers that express MARS. The invention further provides methods for identifying molecules that bind to and / or modulate the functional activity of MARS.

The invention relates to succinyl hydrazine compounds derivative and medical compound containing them; and the application of it in preparing medicine that resists leukemia. The succinyl hydrazine compounds derivative shows inhibiting action to BCR-Ab1 tyrosine kinase activity through pharmacological test. It is characterized by high effecivity and low toxicity, and can be widly used to prepare medicine that treats chronic granulocytic leukemia (CML) and philadelphia chromosome positive acute lymphoblastic leukemia, especially medicine treating patient that generates drug resistance to Gleevec.

In the field of pharmaceutical chemistry compounds of general formula I having heteroaryl alkynyl moiety or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, and pharmaceutical compositions including these compounds, as well as uses of these compounds and compositions thereof in the manufacture of a medicament. The compounds have a strong inhibitory effect on BCR-ABL tyrosine kinase and are useful for treating diseases, such as tumors.

An oral pharmaceutical formulation containing an effective amount of NRC-AN-019 including its pharmaceutically acceptable salts and polymorphs such as Form I, Form II and Form III thereof to improve the bioavailability intended for self-emulsification upon its contact with the gastro-intestinal fluid. The invention also relates to a process for the preparation of oral solution containing NRC-AN-019 in an effective concentration for the better therapy against Chronic Myeloid Leukemia as BCR-ABL tyrosine kinase inhibitor and against other tumors such as head and neck cancer, prostate cancer and the like.

The invention discloses application of a substance for inhibiting phosphorylation of a 357 tyrosine residue of a YAP protein to prevention of atherosclerosis. The substance for inhibiting phosphorylation of the 357 tyrosine residue of the YAP protein is an Src / c-Abl tyrosine kinase double inhibitor or a c-Abl inhibitor or an Src inhibitor; bosutinib is adopted as the Src / c-Abl tyrosine kinase double inhibitor; and experiments prove that the bosutinib prevents atherosclerosis, treats atherosclerosis, decreases the area of plaques of atherosclerosis, reduces lipid deposition, decreases the collagen content, inhibits forming of the plaques of atherosclerosis, inhibits activation of vascular endothelial cells and inhibits the expression level of adherence factors by inhibiting phosphorylation of the 357 tyrosine residue of the YAP protein. The substance has significant application value.

According to the present invention, there is provided a pharmaceutical composition for treating Philadelphia chromosome positive lymphocytic leukemia, including a thalidomide derivative and BCR-ABL tyrosine kinase inhibitor. According to the present invention there is also provided a method of treating Philadelphia chromosome positive lymphocytic leukemia, including administering a thalidomide derivative and a BCR-ABL tyrosine kinase inhibitor to a patient suffering from Philadelphia chromosome positive lymphocytic leukemia.

The present disclosure provides a compound of formula (I) targeting and degrading BCR-ABL protein and its use in the field of antitumor. The compound of formula (I) shows degradation and inhibitory effects on BCR-ABL target protein, which is mainly comprised of four moieties, wherein the first moiety (BCR-ABL-TKIs) is compound moiety with BCR-ABL tyrosine kinase inhibited activity; the second moiety (the LIN) is link units; the third moiety (the ULM) is a small molecule ligand for VHL or CRBN proteases with ubiquitination; and the four moiety (the group A) is carbonyl group that covalently binds to BCR-ABL-TKIs and LIN, and the LIN is further covalently bonded to ULM. A series of compounds designed and synthesized by the present disclosure shows extensive pharmacological effective, which function to degrade BCR-ABL protein and inhibit BCR-ABL effective, and can be utilized for treating relevant tumor.

The invention discloses a thiazolyl aminobenzoic acid derivative with antineoplastic activity, which can be used for preparing an anticancer drug, in particular as a Bcr-Abl tyrosine kinase inhibitor,especially as a Bcr-Abl tyrosine kinase inhibitor of a T315I mutation.

The invention discloses a kit for detecting an ABL tyrosine kinase inhibitor based on an HPLC-MS / MS method and a detection method. The ABL tyrosine kinase inhibitor comprises imatinib, dasatinib, nilotinib, panatinib and flumatinib. The kit comprises the following reagents: a sample treatment solution, a standard substance, a quality control substance, an internal standard solution and a mobile phase, wherein the mobile phase comprises a mobile phase A and a mobile phase B; the mobile phase A is a 0.1% formic acid methanol solution; the mobile phase B is a 2 mmol.L <-1 > ammonium acetate and -0.1% formic acid aqueous solution; according to the invention, the concentration of the ABL tyrosine kinase inhibitor in the blood plasma is quantitatively detected based on an HPLC-MS / MS technology; the detection result is not interfered by common drugs and combined drugs, and the accuracy of quantitative detection of the ABL tyrosine kinase inhibitor is greatly improved; the kit is helpful for improving the detection quality of the ABL tyrosine kinase inhibitor and promoting the standardization and normalization of a detection method, so that the blood concentration of the clinical ABL tyrosine kinase inhibitor can be monitored more quickly, accurately and reliably.

Provided herein are methods of treating a cancer in a patient comprising administration of an effective amount of a nuclease-resistant polynucleotide that hybridizes to the translation initiation site of a Grb2 nucleic acid in the patient and either a Bcr-Abl tyrosine kinase inhibitor (e.g., dasatinib) or a cytidine analogue (e.g., decitabine or cytarabine). The cancer may be Ph+ and / or Bcr-Abl positive chronic myelogenous leukemia or acute myeloid leukemia or myelodysplastic syndrome.

The invention provides low molecular weight compounds, namely 1H-thieno[2,3-c]pyrazoles, showing a high affinity for the ATP pocket of ABL tyrosine kinase. These compounds are thus ATP-competitive tyrosine kinase inhibitors displaying a significant inhibitory potency also, and in particular, towards BCR-ABL inhibitor-resistant T315I ABL mutants. The compounds of the invention find a useful application in the treatment of BCR-ABL inhibitor-resistant ABL-mediated diseases, such as Imatinib-resistant chronic myelogenous leukemia. Moreover, the invention provides a screening method for the identification of compounds capable of binding the ATP pocket of a kinase protein, in particular of the T315I mutant ABL kinase.

Provided herein are methods of treating a cancer in a patient comprising administration of an effective amount of a nuclease-resistant polynucleotide that hybridizes to the translation initiation site of a Grb2 nucleic acid in the patient and either a Bcr-Abl tyrosine kinase inhibitor (e.g., dasatinib) or a cytidine analogue (e.g., decitabine or cytarabine). The cancer may be Ph+ and / or Bcr-Abl positive chronic myelogenous leukemia or acute myeloid leukemia or myelodysplastic syndrome.

The present invention relates to a method of treating chronic myelogenous leukemia in a subject comprising administering to the subject a compound, such as N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide, that inhibits the T315I mutation in BCR-ABL tyrosine kinase, or a pharmaceutically acceptable salt thereof. The present invention also relates to a pharmaceutical composition comprising a compound such as N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide, that inhibits the T315I mutation in BCR-ABL tyrosine kinase, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

The invention discloses an indazole cyclotriazole compound as well as a preparation method and application thereof, a drug design strategy based on fragments is adopted, and a halogenated substituent group is introduced to an end benzene ring while amino acylation is performed on an indazole ring, so that an indazole cyclotriazole compound library with kinase inhibition activity is constructed; the tyrosine kinase inhibitor with Bcr-Abl kinase inhibition activity is found through kinase activity screening, and the tyrosine kinase inhibitor can be used for preparing antitumor drugs, has certain activity of inhibiting Bcr-AblWT and Bcr-AblT315I kinase, and has certain cell proliferation inhibition activity on K562 cells. Meanwhile, an activity test shows that indazoletriazole has an important effect on the inhibition activity of a compound, can improve the affinity between a receptor and the compound, and can be used as a pharmacological fragment of a Bcr-Abl tyrosine kinase inhibitor.

The invention discloses a class of protein kinase inhibitor aryne derivatives. The compound is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, R1, R2, R3, R4, ring A, ring B , L, m, n, p or q are defined in the specification. In addition, the invention also discloses a drug with the compound or its salt as active ingredient, which can be used for treating proliferative diseases such as cancer and inflammatory diseases, especially diseases related to Bcr-Abl tyrosine kinase.