35 results about "FGFR Inhibition" patented technology

Described herein are inhibitors of FGFR, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions to inhibit the activity of tyrosine kinases.

The present invention relates generally to methods of in vitro diagnostics, in particular the use of a compound selected from the group consisting of fibroblast growth factor 23 (FGF23), inorganic phosphorus (P), the product of inorganic phosphorus and total calcium (P×tCa), osteopontin (OPN) and parathyroid hormone (PTH) as biomarker. Said biomarkers can be used to monitor the modulation of fibroblast growth factor receptor (FGFR) kinase activity, in particular its inhibition, and / or the occurrence of secondary effects of FGFR inhibition. The invention further provides methods and kits relating to these uses.

Provided is an isolated human naive pluripotent stem cell (PSC), wherein: (i) when the naive PSC is a female PSC, then said naive female PSC has two unmethylated alleles of an X-inactive specific transcript (XIST) gene; and (ii) when said naive PSC is a male PSC, then said naive male PSC has an unmethylated allele of said XIST gene. Also provided is a culture medium which comprises an ERK1 / 2 inhibitor, a GSK3beta inhibitor, a p38 inhibitor, a JNK inhibitor, a STAT3 activator and at least one agent selected from the group consisting of: bFGF, TGFbeta 1, a PKC inhibitor, a ROCK inhibitor and a NOTCH inhibitor; or at least agent selected from the group consisting of: a TGFR inhibitor, a FGFR inhibitor, a PKC inhibitor, a ROCK inhibitor and a NOTCH inhibitor.

The invention relates to a combination of a FGFR inhibitor and an IGF1R inhibitor. The combination is for use in the treatment of a proliferative disorder, in particular for the treatment of cancer. The FGFR inhibitor and the IGFR inhibitor can be administered simultaneously, separately or sequentially. The invention further relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a combination according to the invention.

The present invention relates to tricyclic compounds, and pharmaceutical compositions of the same, that are inhibitors of one or more FGFR enzymes and are useful in the treatment of FGFR-associated diseases such as cancer.

A method of predicting a lung cancer patient's response to FGFR inhibitors is disclosed herein, particularly in patients with squamous cell lung cancer.

The invention relates to a human intrahepatic duct cancer cell line and an application thereof. The human intrahepatic duct cancer cell line LICCF is established according to the invention, is clear and definite in algebra, does not have cross contamination, shows unique sensitivity to an inhibitor of a PI3K / mTOR passage and an inhibitor of an MEK1 / 2 passage, has high drug resistance to 5-FU, cis-platinum and FGFR inhibitors, and can be used for establishing in vivo and in vitro tumor drug experiment and drug resistance models, so that an experimental basis is provided for revealing a human intrahepatic duct cancer drug resistance mechanism, reversing the appearance of drug resistance, developing new anticancer drugs and screening human intrahepatic duct cancer related biological markers.

The present invention relates to a method for predicting the responsiveness of cancer cells to FGFR1 inhibitors, which comprises the evaluation of the status of FGFR1 gene and the status of MYC. A kit useful for carrying out the method is also provided. In addition, a method of treating cancer such as lung cancer is also provided which includes determining the status of FGFR1 gene and the status of MYC gene, and administering to the cancer patient an FGFR1 inhibitor if the tumor tissue or cells exhibit an increased expression or amplification of the FGFR1 gene, as well as an increased expression or amplification of the MYC gene.

The present invention relates to an alkynyl-substituted heterocyclic compound acting as an FGFR inhibitor, a preparation method therefor and a medical use thereof. In particular, the present invention relates to a compound as shown in general formula (I) and a pharmaceutically acceptable salt thereof; a pharmaceutical composition including the compound or a pharmaceutically acceptable salt thereof; a method for treating and / or preventing FGFR-associated diseases, particularly tumors, by using the compound or a pharmaceutically acceptable salt thereof; and a preparation method for the compound or a pharmaceutically acceptable salt thereof. The present invention also relates to the use of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition including the compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing FGFR-associated diseases, particularly tumors, wherein the definition of each substituent group in general formula (I) is the same as that in the description.

Disclosed herein are methods of identifying a cancer patient that will be responsive to treatment with a fibroblast growth factor receptor (FGFR) inhibitor and methods of treating cancer patients. The methods involve evaluating a biological sample from the patient for the presence of one or more FGFR mutants from a FGFR mutant gene panel. Kits and primers for identifying the presence of one or more FGFR mutant genes in a biological sample are also disclosed herein.

The invention discloses a 1-(2,6-dichlorophenyl)-3-(substituted pyrimidine-4-yl)urea compound and preparation and application thereof. The structure of the compound is shown in a formula (I). The compound has no toxicity function on the proliferation of BEAS-2B cells (lung normal cells), but has certain inhibiting functions on the selected five types of non-small cell lung cancer cell lines, suchas A549 cells (WT EGFR), PC-9 cells (EGFRdel E746-A75), H520 cells (FGFR amplification), H1581 cells (FGFR amplification), and H226 cells; the certain anti-tumor activity is realized, and the compoundis an effective EGFR / FGFR (epidermal growth factor receptor / fibroblast growth factor receptor) inhibitor. The formula (I) is shown in the attached figure.

The invention relates to a heterocyclic compound, a pharmaceutical composition containing the same, a preparation method of the same, and an application of the heterocyclic compound as a fibroblast growth factor receptor (FGFR) inhibitor. The inhibitor is a heterocyclic compound as shown in a formula I which is described in the specification, or pharmaceutically acceptable salts, prodrugs, solventcompounds, polymorphs, isomers, stable isotope derivatives thereof, or pharmaceutical compositions containing the same. The compounds provided by the invention can be used for treatment or preventment of related diseases mediated by FGFR, such as cancers.

The invention discloses a culture medium for rat embryonic stem cells. The culture medium comprises basal culture media and additives, wherein the additives comprise differentiation inhibitors and Pluripotin; and moreover, the differentiation inhibitors comprise GSK (Glycogen Synthase Kinase) inhibitors, FGFR (Fibroblast Growth Factor Receptor) inhibitors and MAPK (Mitogen-activated Protein Kinases) inhibitors. The invention also discloses a culture medium kit of the rat embryonic stem cells, a method for culturing the rat embryonic stem cells and applications of the culture medium and the kit, wherein the culture medium kit comprises the basal culture media, the differentiation inhibitors and the Pluripotin. With the adoption of the differentiation inhibitors and the Pluripotin, the culture medium for the rat embryonic stem cells can inhibit the differentiation of the rat embryonic stem cells and can further guarantee the stability of karyotype for reproductive potential.

The invention discloses a 1-(2,5-dimethoxyphenyl)-3-(substituted pyrimidine-4-yl)urea compound and preparation and application thereof. The compound has no toxicity function on the proliferation of BEAS-2B cells (lung normal cells), but has certain inhibiting functions on the selected five types of non-small cell lung cancer cell lines, such as A549 cells (WT EGFR), PC-9 cells (EGFRdel E746-A75),H520 cells (FGFR amplification), H1581 cells (FGFR amplification), and H226 cells; the certain anti-tumor activity is realized, and the compound is a relative effective EGFR / FGFR (epidermal growth factor receptor / fibroblast growth factor receptor) inhibitor. The formula is shown in the attached figure.

The present invention relates generally to 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition comprising 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl)-1-methyl-urea or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemia rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), tumor-induced osteomalacia, post-renal transplant hypophosphatemia, epidermal nevus syndrome, osteoglophonic dysplasia or McCune-Albright syndrome.

Provided is a method for prevention or treatment of a cancer, comprising co-administering (a) an FGFR inhibitor and (b) an anti-c-Met antibody or antigen-binding fragment thereof to a subject in need thereof, wherein the anti-c-Met antibody or the antigen-binding fragment thereof specifically binds to an epitope comprising 5 or more contiguous amino acids within the SEMA domain of c-Met protein.

The present inventors successfully identified novel gatekeeper mutations for FGFR. Further, they discovered that mutant FGFR having the mutations demonstrate resistance to known FGFR inhibitors such as AZD4547, and at the same time demonstrate sensitivity to specific compounds. Mutant polypeptides having the mutations may be used as biomarkers in cancer treatment by FGFR inhibitors to prevent the development of side effects in therapy by conventional FGFR inhibitors, and to control the therapeutic mode for receiving the best therapeutic effect, thus making individualized treatment possible.

To provide a pharmaceutical composition for treating FGFR4-related cancer, FGF19-related cancer, or FGF19 gene amplification positive liver cancer. The inventors perfected the present invention through study of compounds having FGFR4 inhibitory effect, verifying that specific pyrimidine compounds have FGFR4 inhibitory effect, and that pharmaceutical compositions having these compounds as active ingredients have therapeutic effect against FGFR4-related cancer, or in another mode against FGF19-related cancer, or in yet another mode against FGF19 gene amplification positive liver cancer.

A method of selecting a subject suffering from a cancer for a therapeutic regimen of administration of a pharmaceutical composition comprising an effective amount of an FGFR inhibitor is described, which method comprises (1) the taking of a tumor or liquid biopsy from the subject; (2) determination of the level of expression of any or all of FGFR1, FGFR2 and FGFR3, and (3) comparison of the determined level of expression of at least one of FGFR1, FGFR2 and FGFR3 with a pre-established threshold value, and declaring the subject eligible for the therapeutic regimen if the determined level exceeds the threshold value. The invention also relates to a method of personalized cancer therapy comprising selection of a subject by the above-described method and subjecting the subject to a therapeutic regimen that comprises administration of a pharmaceutical composition comprising an effective amount of an FGFR inhibitor.

The present inventors successfully identified novel gatekeeper mutations for FGFR. Further, they discovered that mutant FGFR having the mutations demonstrate resistance to known FGFR inhibitors such as AZD4547, and at the same time demonstrate sensitivity to specific compounds. Mutant polypeptides having the mutations may be used as biomarkers in cancer treatment by FGFR inhibitors to prevent the development of side effects in therapy by conventional FGFR inhibitors, and to control the therapeutic mode for receiving the best therapeutic effect, thus making individualized treatment possible.

The present invention relates to a polypeptide which has the function of regulating the cell proliferation and differentiation. The present invention provides a separated ERK2 combined polypeptide, which is the polypeptide or the conservative variation polypeptide which has an amino acid sequence of SEQIDNO: 1. the present invention further provides a preparation method of the polypeptide. The polypeptide can be combined with ERK2 (Extracellular signal-regulated kinase2) to regulate the cell proliferation and differentiation, and the disclosure of the polypeptide site provides a new targeted inhibition site for an FGFR inhibitor.

The invention relates to a human intrahepatic duct cancer cell line and an application thereof. The human intrahepatic duct cancer cell line LICCF is established according to the invention, is clear and definite in algebra, does not have cross contamination, shows unique sensitivity to an inhibitor of a PI3K / mTOR passage and an inhibitor of an MEK1 / 2 passage, has high drug resistance to 5-FU, cis-platinum and FGFR inhibitors, and can be used for establishing in vivo and in vitro tumor drug experiment and drug resistance models, so that an experimental basis is provided for revealing a human intrahepatic duct cancer drug resistance mechanism, reversing the appearance of drug resistance, developing new anticancer drugs and screening human intrahepatic duct cancer related biological markers.

The present invention relates generally to 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition comprising 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), tumor-induced osteomalacia, post-renal transplant hypophosphatemia, epidermal nevus syndrome, osteoglophonic dysplasia or McCune-Albright syndrome.

Provided is a compound useful as a prophylactic and / or therapeutic agent for bladder cancer.As a result of studies on compounds having FGFR inhibitory action, the present inventors have found that the nitrogen-containing aromatic heterocyclic compounds of the present invention have inhibitory action on FGFR1, FGFR2, and / or FGFR3, particularly, mutant FGFR3, and thus, the present invention has been accomplished. The nitrogen-containing aromatic heterocyclic compound of the present invention can be used as a therapeutic agent for various cancers related to FGFR1, FGFR2, and / or FGFR3, such as lung cancer and hormone therapy-resistant breast cancer, stomach cancer, triple negative breast cancer, endometrial cancer, bladder cancer, and glioblastoma, particularly as a prophylactic and / or therapeutic agent for mutant FGFR3-positive bladder cancer.

A method of selecting a subject suffering from a cancer for a therapeutic regimen of administration of a pharmaceutical composition comprising an effective amount of an FGFR inhibitor is described. The method comprises (1) the taking of a tumor or liquid biopsy from the subject; (2) determination of the level of expression of any or all of FGFR1, FGFR2 and FGFR3, and (3) comparison of the determined level of expression of at least one of FGFR1, FGFR2 and FGFR3 with a pre-established threshold value, and declaring the subject eligible for the therapeutic regimen if the determined level exceedsthe threshold value. The invention also relates to a method of personalized cancer therapy comprising selection of a subject by the above-described method and subjecting the subject to a therapeutic regimen that comprises administration of a pharmaceutical composition comprising an effective amount of an FGFR inhibitor.

The present invention relates to a polypeptide which has the function of regulating the cell proliferation and differentiation. The present invention provides a separated ERK2 combined polypeptide, which is the polypeptide or the conservative variation polypeptide which has an amino acid sequence of SEQIDNO: 1. the present invention further provides a preparation method of the polypeptide. The polypeptide can be combined with ERK2 (Extracellular signal-regulated kinase2) to regulate the cell proliferation and differentiation, and the disclosure of the polypeptide site provides a new targeted inhibition site for an FGFR inhibitor.

An indole derivative as expressed by Formula (I), a preparation method thereof, a pharmaceutical salt, and use thereof as a therapeutic agent, especially as a FGFR inhibitor. Each substituent in Formula (I) has identical definition as specified in the specification.

A heterocyclic compound is described, which is an inhibitor of FGFR (fibroblast growth factor receptor). Specifically, it is a compound represented by the following formula (I), including an isomer (enantiomer or diastereomer) which may be present, or a pharmaceutically acceptable salt thereof, prodrugs, deuterated derivatives, hydrates, solvates. The definition of each group in the formula (I) is as described in the specification. The compound of the present invention has FGFR inhibitory activity and can be used for preventing or treating a disease associated with FGFR activity or expression.

An indole derivative as expressed by Formula (I), a preparation method thereof, a pharmaceutical salt, and use thereof as a therapeutic agent, especially as a FGFR inhibitor. Each substituent in Formula (I) has identical definition as specified in the specification.

The present invention relates to a method for predicting the responsiveness of cancer cells to FGFR1 inhibitors, which comprises the evaluation of the status of FGFR1 gene and the status of MYC. A kit useful for carrying out the method is also provided. In addition, a method of treating cancer such as lung cancer is also provided which includes determining the status of FGFR1 gene and the status of MYC gene, and administering to the cancer patient an FGFR1 inhibitor if the tumor tissue or cells exhibit an increased expression or amplification of the FGFR1 gene, as well as an increased expression or amplification of the MYC gene.