21 results about "Activating mutation" patented technology

The invention relates to the technical field of medicines and biology, in particular to a mouse EGFR (Epidermal Growth Factor Receptor) mutant lung adenocarcinoma cell line (EP Mus musculus) as well as preparation and application thereof. The invention provides an EP cell line ([EGFRE19delta (mutation); trp53 (deletion), EP] is derived from a lung adenocarcinoma model of a C57BL / 6 strain mouse, carries the most common EGFRE19del mutation in lung adenocarcinoma, is a first lung adenocarcinoma mouse cell line carrying EGFR mutation known in the world at present, has the in-vivo tumorigenesis ability of the C57BL / 6 strain mouse, and fills the blank of the mouse EGFR mutant cell line. The cell line provided by the invention has the background of EGFRE19del homozygous activation mutation and Trp53 homozygous deletion mutation, is sensitive to EGFR-TKI targeted therapy, can be used for in-situ tumor formation in subcutaneous and lung of an immune normal mouse C57BL / 6, and is suitable for immunotherapy and targeted therapy research of EGFR mutation lung adenocarcinoma.

A method of treating a cancer in a subject in need thereof is disclosed. The cancer can be an esophageal cancer, a uterine cancer, a liver cancer, or a cholangiocarcinoma. The method comprises administering to the subject an effective amount of an anti-Dkk-1 antibody or antigen binding-fragment thereof, wherein the subject is determined to have a constitutively activating mutation of the beta-catenin protein.

The application discloses application of Pemigatinib or a salt thereof in preparation of a medicine, and the compound is used for treating seborrheic keratosis, preferably seborrheic keratosis related to abnormal activation of a fibroblast growth factor receptor (FGFR) signal pathway, but is not limited to the above mechanism, and specifically, the medicine can inhibit or improve skin hyperplasia and hyperkeratosis lesions driven by FGFR3 gene activating mutation.

Hypomelanosis of Ito is a clinical term for patients with mosaic syndromes characterized by skin hypopigmentation and developmental disorders. The genetic causes of these rare diseases remain largely unclear. Here, we report that GNA13 is a new gene that causes Hypomelanosis of Ito. We identified an identical mutation in this gene in four unrelated patients exhibiting pigmentary mosaicism. In depth functional investigations revealed that this is an activatory mutation that alters the cytoskeleton and morphology of melanocytes via a hyperactivation of the RHOA / ROCK signalling pathway. Our results also indicate that this pathology does not necessarily originate from a decreased production of melanin, but can originate from a defect in melanosome transfer to keratinocytes due to cell shape alterations. Thus, our findings suggest for the first time a mechanism by which the clinical symptoms of patients with Hypomelanosis of Ito appear, and pave the path for new therapeutic approaches. Altogether, the present invention relates to a method for treating a patient suffering from hypomelanosis of Ito by administering a ROCK inhibitor and / or RHOA inhibitor.

A compound for use in treating a disease associated with activating mutations in RAS, or for use in treating a disease treatable by a reduction in RAS activity, is selected from a compound of Formula (I), salts and esters thereof. The compounds are particularly useful in treating cancer.

The present disclosure provides the use of an antigen-binding molecule that binds to HERS for the treatment or prevention of cancers comprising (i) at least one gene encoding a positive regulator of HERS-mediated signalling that does not comprise an activating mutation; or (ii) at least one gene encoding a negative regulator of HERS-mediated signalling that does not comprise an inactivating mutation.

To provide compounds for effective treatment of diseases and disorders related to LRRK2, which are idiopathic PD, LRRK2 mutation associated PD (e.g., PD associated with one or more LRRK2 activated mutations), primary tauopathy (e.g., progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD)), Lewy body dementia, Crohn's disease, Hansen's disease (e.g., Hansen's disease associated with type 1 inflammatory reactions), and / or neuroinflammation, for example.SOLUTION: Provided are bifunctional compounds useful as modulators of leucine-rich repeat kinase 2 (LRRK2). Particularly, the hetero-bifunctional compounds of the present disclosure contain on one end a moiety that binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds LRRK2, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The hetero-bifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation / inhibition of target protein. Diseases or disorders that result from aberrant regulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.SELECTED DRAWING: None

The present invention relates to the use of neocuproine, elesclomol, disulfiram and / or dithiocarbamate for use in treatment of cancer, optionally in combination with MAPK-pathway inhibitors in cancers carrying mutations that are recognized as MAPK-pathway activating mutations.

This invention discloses EGFR inhibitors, their preparation, and applications. Specifically, this invention relates to a 4-substituted-2-(N-(5-substituted allylamido)phenyl)amino)pyrimidine derivative of formula (I). This series of compounds exhibits activity against L858R EGFR mutants, T790M EGFR mutants, and exon 19 deletion activation mutants, and can be used to treat diseases mediated by EGFR mutant activity, either alone or in part. For example, they have wide applications in the prevention and treatment of cancer, especially non-small cell lung cancer, and hold promise for development into a new generation of EGFR inhibitors.

Activating mutations in CTNNB1 gene encoding β-catenin is encountered in approximately 30% of hepatocellular carcinoma (HCC) and in more than 80% of hepatoblastoma. In ApcΔhep model, the inventors unravel the biggest cluster of non-coding RNAs identified called the DLK1 / DIO3 locus as the most significantly induced region in response to β-catenin activation regarding transcription of coding and non-coding elements. Using in vivo Crispr / cas9 strategy, the inventors were able to demonstrate that β-catenin and its cofactor TCF-4 directly bind on a WRE-containing site located upstream of Meg3 to create an active enhancer regulatory region engaged in chromatin remodeling in the direct vicinity of this binding site but also at distance by long range DNA-DNA contacts to promote transcription of the entire locus. These Crispr / cas9 constructs have also proved to be a valuable strategy to impair the locus expression in the murine models mimicking HCC and hepatoblastoma (ApcΔhep and β-cateninΔExon3 tumors) but also in two cell lines with activating mutations in β-catenin encoding gene, the murine Hepa1-6 and human HuH6 cells. In transformed cells, it significantly impaired cell proliferation in vitro and HuH6 sternness capacities but also tumor progression in Hepa1-6 allografts. In mouse models, the locus editing during early steps of tumorigenesis decreased the proliferation of ApcΔhep preneoplastic hepatocytes but also those of ApcΔhep and β-cateninΔExon3 tumor cell resulting in impairment of tumor size. In conclusion, the results demonstrate that disrupting the β-catenin / TCF-4 binding site located upstream of Meg3 in the DLK1 / DIO3 locus represents a very interesting approach for the treatment of liver cancers.

A growing number of patients presenting severe combined immunodeficiencies associated with Rac2 mutations have been identified in newborns. These mutations are associated with high frequency of infection, leukopenia and more rarely autoinflammatory features. Here, the inventors show that the Rac2 activating mutations activates the NLRP3 inflammasome leading to the secretion of IL-1β from macrophages depending on their activation strength. Therefore, inhibiting GasderminD (GSDMD) pathway should be considered as a potential treatment for these patients. The present invention relates to a method of treating Rac2 monogenic disorders in a subject in need thereof comprising the administration of an inhibitor of GasderminD (GSDMD).

The present invention discloses a pyrimidine-piperidine-based FGFR inhibitor represented by Formula 1, and its preparation method and uses. The compounds according to the present invention, or pharmaceutically acceptable salts, stereoisomers, prodrug molecules or solvates thereof, exhibit high inhibitory activity against FGFR activating mutants or resistant mutant forms (one or more). The compounds of the present invention have good physicochemical properties and safety and toxicity parameters. Such compounds will have good clinical effects in the treatment of diseases (including cancer) mediated by FGFR activating mutations and / or drug-resistant mutations.

The application discloses a kind of gastric adenocarcinoma transgenic mouse model construction method and its application, the construction method includes the following steps: using transgenic and hybridization technology, MYC gene expression quantity or MYC protein activity in mouse gastric mucosa layer epithelial cell is overexpressed or increased, KRAS gene mutant type in gastric mucosa layer epithelial cell is activated simultaneously, make Kras protein function abnormal, continuously in activated state, finally obtained mouse is gastric adenocarcinoma transgenic mouse model.The application constructs Myc gene overexpression and KRAS activation mutation double gene mutation mouse spontaneous gastric cancer animal model, method is simpler.This mouse model of gastric cancer tumorigenesis time is shortened, tumorigenic rate is as high as 100%, and tumorigenic effect is stable.And after induction, only in stomach tumorigenesis, tumorigenesis has high specificity.Pathological section and immunohistochemical staining determine that this animal model is adenocarcinoma in gastric cancer, has good clinical representativeness, can be applied to the application in later development or screening gastric cancer drug.

To provide methods and compositions for enhancing immune responses against cancer and pathogens.SOLUTION: The presently disclosed subject matter provides methods and compositions for enhancing immune responses against cancer and pathogens. The presently disclosed subject matter relates to cells comprising a c-Kit mutant, e.g., a c-Kit mutant comprising an activating mutation. The cell may further comprise an antigen recognizing receptor (e.g., a chimeric antigen receptor (CAR) or a T cell receptor (TCR)). The presently disclosed subject matter relates to the use of cells for treatment, e.g., treatment of cancer.SELECTED DRAWING: None

The invention discloses a nucleic acid inhibitor of a targeted thyroid stimulating hormone receptor and application. The nucleic acid inhibitor has high targeting property, and can accurately recognize TSHR and avoid off-target effect; the inhibition effect is strong, and the TSHR function can be obviously blocked under the micro-mole or even nano-mole concentration; as a nucleic acid molecule, the nucleic acid molecule does not cause obvious immune response and is suitable for long-term treatment; good biological stability: after chemical modification, excellent serum stability and tissue penetrating ability are achieved; the compound is suitable for various administration routes, is convenient for clinical transformation, and shows a wide clinical application prospect in treatment of various TSHR-mediated autoimmune and neoplastic diseases such as Graves diseases, thyroid-related eye diseases, TSHR activated mutation-driven thyroid cancer and the like. Especially for moderate and severe TED patients lacking effective specific targeted therapy means at present, the nucleic acid inhibitor is expected to become the first precise therapy for directly intervening the TSHR pathogenic core link.

The present invention provides polypeptides, polynucleotides, constructs and / or vectors comprising activating mutations in 53BP1. In particular, 53BP1 mutation at amino acid position 334 that makes the resulting protein resistant to phosphorylation and inactivation by GSK3β is provided. Also provided are lymphocytes comprising the mutant 53BP1 or a 53BP1 resistant to GSK3β phosphorylation and inactivation and methods of making and using the same.

The invention relates to a compound shown in a formula (I) and an isotope form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, a prodrug and a polymorph of the compound, the compound shown in the formula (I) can be used as an EGFR (epidermal growth factor receptor) inhibitor, can effectively inhibit EGFR with L858R mutation, exon 19 deletion mutation, C797S mutation, G724S mutation, L861Q and PACC mutation, and can be used for preparing an EGFR inhibitor. The compound has a good application prospect in the aspect of preparing medicines for treating cancers with EGFR activation mutation.

Methods for treating a B-cell malignancy in a human subject are described. The methods involve determining the presence or absence of a B-cell activating mutation in a gene(s) obtained from the subject. Methods include treatment with the compound of formula (I).

To provide methods for treating cancer in a patient determined to have an EGFR activating mutation.SOLUTION: The present disclosure provides methods for treating cancer in a patient determined to have an EGFR activating mutation by administering a CDK inhibitor and / or SAC component inhibitor.SELECTED DRAWING: None

The present disclosure provides compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 38, 39 JPEG2026500166000038.jpg48165 or a pharmaceutically acceptable salt thereof. The unit dosage forms described herein are suitable for oral administration. There remains a need for anti-estrogen agents that can completely inhibit estrogen receptors, including those encoded by both wild-type and mutant forms (e.g., those containing activating mutations) of the genes encoding estrogen receptor alpha (ERα) and estrogen receptor 1 (ESR1). Selective estrogen receptor modulators (SERMs) or degraders (SERDs) are particularly useful or promising tools for such treatment.