94 results about "Anaplastic lymphoma kinase" patented technology

The present disclosure relates to the field of tyrosine kinase enzyme inhibition, in particular anaplastic lymphoma kinase (ALK) inhibition using novel small molecules. Provided are compounds capable to modulate ALK activity, compositions that comprise the compounds, and methods of using the compounds for the treatment or prevention of diseases or conditions that are characterized by ALK activity or expression.

In accordance with the invention, novel gene deletions and translocations involving chromosome 2 resulting in fusion proteins combining part of Anaplastic Lymphoma Kinase (ALK) kinase with part of a secondary protein have now been identified in human solid tumors, e.g. non-small cell lung carcinoma (NSCLC). Secondary proteins include Echinoderm Microtubule-Associated Protein-Like 4 (EML-4) and TRK-Fusion Gene (TFG). The EML4-ALK fusion protein, which retains ALK tyrosine kinase activity, was confirmed to drive the proliferation and survival of NSCLC characterized by this mutation. The invention therefore provides, in part, isolated polynucleotides and vectors encoding the disclosed mutant ALK kinase polypeptides, probes for detecting it, isolated mutant polypeptides, recombinant polypeptides, and reagents for detecting the fusion and truncated polypeptides. The disclosed identification of this new fusion protein enables new methods for determining the presence of these mutant ALK kinase polypeptides in a biological sample, methods for screening for compounds that inhibit the proteins, and methods for inhibiting the progression of a cancer characterized by the mutant polynucleotides or polypeptides, which are also provided by the invention.

The invention discloses a compound in a formula (I) and an anti-tumor application thereof. The compound in the formula (I) has degradation and inhabitation functions on ALK target protein and mainly comprises four parts, the first part ALK-TKIs is a compound with ALK tyrosine kinase inhabitation activity; the second part LIN is different linkers; the third part ULM (ubiquitin ligase binding moiety) of VHL, CRBN or other protease micromolecular ligand with a ubiquitination function; the fourth part group A is carboxyl or deficiency and covalently binds ALK-TKIs with LIN and covalently binds LINwith ULM. A series of designed and synthesized compounds have wide pharmacological activity, have functions of degrading ALK protein and inhibiting ALK activity and can be applied to related tumor therapy.

The invention relates to a pyridine chemical shown as the following general formula and having c-Met and / or ALK inhibitory activity and its pharmaceutically-acceptable salt or pharmaceutically-acceptable solvate, a preparation method thereof, a pharmaceutical composition containing the chemicals, and applications of the chemicals in preparation of medicines for preventing and treating abnormal proliferation and morphological change of cells and related diseases, such as hyperkiesis, related to hepatocyte growth factor receptor (HGFR) and / or anaplastic lymphoma kinase (ALK) in organism and diseases related to vascularization or cancerometastasis, especially application in preparation of medicines for treating and preventing growth and metastasis of tumor.

The invention discloses a nitrogen-containing heterogeneous ring compound, a preparation method thereof and an application of the nitrogen-containing heterogeneous ring compound in inhibition of kinase activity. The general formula of the nitrogen-containing heterogeneous ring compound is represented as a formula I or a formula I', wherein R1, R2, R3 and R4 in the formula I or the formula I' are selected from any one of hydrogen, halogen, cyanogroup, hydroxyl, amidogen and substituted or unsubstituted C1-C6 alkyl groups independently, and a 3-10-membered ring system can be formed by any two groups in R1, R2, R3 and R4; M1, M2 and M3 are selected from CRa or N independently, and at least one of M1, M2 and M3 is N; W is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl, unsubstituted or halogenated 4-8-membered alkine groups, substituted or unsubstituted C3-C8 naphthenic base, substituted or unsubstituted 4-8-membered heterocyclic groups, 5-10-membered aromatic or heteroaryl groups, substituted carbonyl, substituted sulfonyl and substituted or unsubstituted amidogen. The nitrogen-containing heterogeneous ring compound can inhibit EGFR (epidermal growth factor receptor) mutant kinase activity or ALK (anaplastic lymphoma kinase) activity and is a multi-target tumor therapeutic drug with a brand-new action mechanism.

The present invention concerns an antibody specific for human ALK (Anaplastic Lymphoma Kinase), in particular a scFv, a nucleic acid sequence encoding it, its production and its use as a pharmaceutical or for diagnostic purposes. Said antibody is suitable for the local treatment of tumors, in particular glioblastoma.

The invention discloses a compound shown in a formula I, and pharmaceutically acceptable salts, stereoisomers, solvates or predrugs. The symptoms are defined in claim requirements. The compound shownin the formula I has good inhibiting activity on ALK (anaplastic lymphoma kinase), and can be used for preparing medicines for adjusting the activity of the ALK activity or treating the ALK-related diseases, especially nonsmall-cell lung cancer drugs. (The formula I is shown in the attached figure.).

The invention relates to the fields of biotechnologies and medicines, particularly discloses a detection primer for EML4-ALK (anaplastic lymphoma kinase) fused gene mutation, a probe and a detection kit, and aims to detect the EML4-ALK fused gene mutation. The detection primer comprises sequences as shown in SEQ ID NO: 1 to SEQ ID NO: 14. The sequence of the probe is as shown in SEQ ID NO: 15, of which the end 5' is modified with FAM or VIC (vasoactive intestinal contractor), and the end 3' is modified with NFQ-MGB (non-fluorescent quencher-myohemoglobin). The kit comprises the detection primer, the probe and a quality control system. The detection primer can specifically identify 13 EML4-ALK fusion mutation types, is high in sensitivity and can detect 5-copied mutations; the whole reverse transcription PCR (polymerase chain reaction) and fluorescence PCR detection process can be completed only by 80 minutes.

The present invention concerns an antibody specific for human ALK (Anaplastic Lymphoma Kinase), in particular a scFv, a nucleic acid sequence encoding it, its production and its use as a pharmaceutical or for diagnostic purposes. Said antibody is suitable for the local treatment of tumors, in particular glioblastoma.

The present invention relates to a pyrimidine-2,4-diamine derivative or pharmaceutically acceptable salts thereof, and a pharmaceutical composition for preventing or treating cancer, which contains a pyrimidine-2,4-diamine derivative as an active ingredient. A compound according to the present invention is very effective in suppressing anaplastic lymphoma kinase (ALK) activity, and as a result, can improve the effectiveness of treatment on cancer cells having anaplastic lymphoma kinase (ALK) fusion proteins, such as EML4-ALK and NPM-ALK, and is expected to effectively prevent recurrence of cancer, thus being useful as a composition for preventing or treating cancer.

The invention discloses a compound being able to adjust the activity of protein kinase and used for treating or preventing protein kinase related diseases, concretely relates to a 4-saturated cyclosubstituted aniline protein kinase inhibitor belonging to a compound for adjusting the activity of anaplastic lymphoma kinase (ALK), and provides a preparation method of the compound and a pharmaceutical use of the compound in treatment or prevention of ALK related diseases.

Disclosed herein are a new N2,N4-bis(4-(piperazin-1-yl)phenyl)pyrimidin-2,4-diamine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical composition for the prevention or treatment of cancers containing the same as an active ingredient. The compound of the present invention has excellent inhibitory effects against the activities of anaplastic lymphoma kinase (ALK) and activated cdc42-associated kinase (ACK1) and thus can improve the therapeutic effects on the treatment of cancer cells having anaplastic lymphoma kinase fusion proteins such as EML4-ALK and NPM-ALK, and also effectively prevent the recurrence of cancers thus being useful as a pharmaceutical composition for the prevention and treatment of cancers.

The invention provides a pyrimidine derivative and application thereof. The pyrimidine derivative is a compound as shown in formula I or pharmaceutically acceptable salt, a hydrate, a solvate, a metabolite or a prodrug of the compound as shown in formula I, wherein R1, R2, R3, R4 and R5 are as defined in the specification. The compound can be used as an ALK (Anaplastic Lymphoma Kinase) inhibitor for preparing an anti-tumor treatment medicine for inhibiting ALK.

The invention discloses a detection chip for a tumor driving gene and application thereof. The detection chip for the tumor driving gene comprises an ALK (anaplastic lymphoma kinase) fusion detection agent, an EGFR (epidermal growth factor receptor) fusion detection agent, an RET (reticulocyte) fusion detection agent and an ROS1 (reactive oxygen species 1) fusion detection agent. Proofed by the results of clinical detect, after fusion probes corresponding to the ALK, the EGFR, the RET and the ROS1 are specifically designed, the detection chip has the advantages that the sensitivity is high, and the gene fusion between a particular site area of the ALK, the EGFR, the RET and the ROS1 and fusion segments is specifically detected. The invention further discloses a detection chip for detecting a second sequence group of the gene mutation and a third sequence group of the gene amplification; after detecting once, the gene fusion, gene mutation and gene amplification of the multiple tumor driving genes, such as the ALK, BRAF (aserine / theroninespecific kinases), DDR2 (discordin domain receptor 2), the EGFR, ERBB2 (receptor tyrosine kinase 2), FGFR1 (fibroblast growth factor receptor 1), KRAS (kirstenrat sarcoma viral oncogene), MET (methionine), NRAS, PIK3CA (phosphatidylino-sitol 3-kinases), the RET and the ROS1.

The invention provides a method for detecting gene fusion, and in particular provides a RACE-like PCR (polymerase chain reaction) joint sequencing detection method (RACE-like PCR joint sequencing method for short) for detecting fusion genes such as anaplastic lymphoma kinase (ALK) fusion gene and the like. By the method, different ALK fusion genes can be detected simultaneously, and unknown ALK fusion genes are detected under the condition of not knowing genes fused with ALK and the fusion modes of the ALK fusion genes in advance, so that the sensitivity, practicability and universality of the detection method are improved.

The invention discloses a method for preparing a compound as shown in a formula (I), an intermediate compound as shown in a formula (II) and used for preparing the compound as shown in the formula (I), a compound as shown in a formula (III) and a preparation method of the compound as shown in the formula (III). The compound as shown in the formula (I) is the anaplastic lymphoma kinase inhibitor, and it has proved that the anaplastic lymphoma kinase inhibitor can inhibit related diseases such as a non-small cell lung cancer.

The invention discloses primer, a probe and a kit for detecting ALK (anaplastic lymphoma kinase) gene expression difference. The primer mainly comprises the following sequences: SEQ ID NO1-SEQ ID NO12. The primer and the probe disclosed by the invention can specifically detect the ALK gene expression difference, so as to determine whether ALK gene fusion exists. A real-time fluorescent PCR (polymerase chain reaction) system for detecting the ALK gene expression difference is built; qualitative evaluation of an ALK gene expression difference exon is provided by detecting the difference of 5'-end and 3'-end gene expression quantities; and the primer and the probe are suitable for a patient with a non-small cell lung cancer before entering personalized targeted therapy. The method has the advantages that (1) sensitivity is high, wherein five copies of positive plasmids can be detected; (2) operation is simple, detection is cheap, and clinical application range is wide; (3) sample detection range is wide, wherein the sample can be used as a fresh pathological tissue, a paraffin-embedded tissue (slice) or a frozen pathological slice; (4) fast detection speed is fast, wherein the detection process can be finished just by 160 minutes.

The invention provides methods to identify, diagnose, and treat kidney cancer through the detection of expression and / or activity of anaplastic lymphoma kinase (ALK). The detection of the presence of a polypeptide with ALK kinase activity (e.g., by detecting expression and / or activity of the polypeptide), identify those kidney cancers that are likely to respond to an ALK-inhibiting therapeutic.

The present disclosure relates to the field of tyrosine kinase enzyme inhibition, in particular anaplastic lymphoma kinase (ALK) inhibition using novel small molecules. Provided are compounds capable to modulate ALK activity, compositions that comprise the compounds, and methods of using the compounds for the treatment or prevention of diseases or conditions that are characterized by ALK activity or expression.

Disclosed herein are a new N2,N4-bis(4-(piperazin-1-yl)phenyl)pyrimidin-2,4-diamine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical composition for the prevention or treatment of cancers containing the same as an active ingredient. The compound of the present invention has excellent inhibitory effects against the activities of anaplastic lymphoma kinase (ALK) and activated cdc42-associated kinase (ACK1) and thus can improve the therapeutic effects on the treatment of cancer cells having anaplastic lymphoma kinase fusion proteins such as EML4-ALK and NPM-ALK, and also effectively prevent the recurrence of cancers thus being useful as a pharmaceutical composition for the prevention and treatment of cancers.

The compounds and salts of the present invention inhibit kinases, especially the anaplastic lymphoma kinase (ALK) and the HGF receptor tyrosine kinase (RTK) c-Met, and are useful for treating or ameliorating abnormal cell proliferative disorders, such as cancer.

The invention relates to a complex of biguanide and EGFR (Epidermal growth factor receptor)-TKI (Tyrosine kinase inhibitor) or ALK (anaplastic lymphoma kinase)-TKI and application of the complex. The complex can be used for preventing or relieving interstitial pneumonia and particularly the interstitial pneumonia caused by EGFR-TKI or ALK-TKI during treatment of NSCLC (Non-Small Cell Lung Cancer). The complex can prevent complications caused by EGFR-TKI or ALK-TKI during treatment of NSCLC, thereby effectively improving the treatment effect of EGFR-TKI or ALK-TKI and reducing the occurrence and development of complications of a patient.

The invention belongs to the field of a medical technology and specifically relates to a pyrimidine derivative type anaplastic lymphoma kinase inhibitor as shown in the general formula (I) or its stereisomer, or its pharmaceutically acceptable salt, ester or solvate, wherein R1, R2, R3, R4, R5 and A ring are as defined in the specification. The invention also relates to a preparation method of the compounds, a pharmaceutic preparation and a pharmaceutical composition containing the compounds and an application of the compound or its stereisomer, or its pharmaceutically acceptable salt, ester or solvate in the preparation of medicines for treating and / or preventing diseases related to anaplastic lymphoma kinase-mediated cancer.

Novel gene deletions and translocations involving chromosome 2 resulting in fusion proteins combining part of Anaplastic Lymphoma Kinase (ALK) kinase with part of a secondary protein have now been identified in human solid tumors, e.g. non-small cell lung carcinoma (NSCLC). Secondary proteins include Echinoderm Microtubule-Associated Protein-Like 4 (EML-4) and TRK-Fusion Gene (TFG). The EML4-ALK fusion protein, which retains ALK tyrosine kinase activity, was confirmed to drive the proliferation and survival of NSCLC characterized by this mutation. The invention therefore provides, in part, isolated polynucleotides and vectors encoding the disclosed mutant polypeptides, probes for detecting it, isolated mutant polypeptides, and reagents for detecting the fusion and truncated polypeptides. The invention also provides methods for determining the presence of these mutant polypeptides in a biological sample, methods for screening for compounds that inhibit the proteins, and methods for inhibiting the progression of a cancer characterized by the mutant polynucleotides or polypeptides.

The invention discloses a PCR (Polymerase Chain Reaction) primer, a kit and a liquid phase chip for detecting an ALK (Anaplastic Lymphoma Kinase) fusion gene. The liquid phase chip comprises a PCR amplification primer, ASPE (Allele Specific Primer Extension) primers and microspheres, wherein the ASPE primers consist of tag sequences and specific primers, wherein the sequences of the specific primers are SEQ ID NO.12 for K15; DEL15A20, SEQ ID NO.13 for K17; A20, SEQ IDNO.14 for K9; A20, SEQ ID NO.15 for T6; A20 and / or SEQ ID NO.16 for T3; A20. The liquid phase chip disclosed by the invention has a very good signal noise ratio and can amplify five fusion subtypes by a single step, and the specific primers have very good specificity.

Disclosed are methods and compositions for detecting the presence of a cancer in a subject and assessing the efficacy of treatments for the same. The disclosed method use reverse transcription polymerase chain reaction (RT-PCR) and multiplex polymerase chain reaction techniques as well as Template Exchange Extension Reaction (TEER) to detect the presence of point mutations, truncations, or fusions of anaplastic lymphoma kinase.

The invention relates to an ALK (Anaplastic Lymphoma Kinase) for gene deletion and a mutant in a human solid tumor. According to the invention, novel second chromosome related gene deletion and translocation are authenticated in the existing human solid tumor such as non-small cell lung cancer (NSCLC), thus a fusion protein which is combined with part of ALKs and part of secondary proteins is caused. Therefore, the invention partially provides separated polynucleotides and carriers, a mutant ALK polypeptide disclosed by codes of the separated polynucleotides and carriers, a probe for detecting the mutant ALK polypeptides, separated mutant polypeptides, recombined polypeptides and a reagent for detecting fused and truncated polypeptides. Due to the authentication for the disclosed novel fusion protein, the existence of the mutant ALK polypeptides in a biological sample can be determined by using a novel method. The invention also provides a method for screening a compound for inhibiting the protein and a method for inhibiting cancers which are characterized by the mutant polynucleotides or polypeptides.

This invention relates to novel pyrazole-substituted amino-heteroaryl compounds of Formula I:and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering an inhibitor of anaplastic lymphoma kinase (ALK).