67 results about "Kras mutation" patented technology

The present invention belongs to the technical field of medicinal chemistry, and particularly relates to a pyrimidine macrocyclic compound. The compound has a good inhibitory effect on KRAS mutations, has a good inhibitory effect on the G12V mutation and other types of mutations of the KRAS gene, can be used as a general KRAS inhibitor, and can be used for the treatment of tumors driven by KRASG12V and other types of gene mutations.

The present application provides guide RNAs and genome-editing complexes or nanoparticles that are useful for specifically targeting a mutated KRAS. Exemplary genome-editing complexes or nanoparticles comprise cell-penetrating peptides, and optionally a DNA nuclease (such as Cas9) or a polynucleotide encoding the DNA nuclease.

The invention provides a specific T cell receptor targeting KRAS G12V mutant epitope peptide (such as an amino acid sequence as shown in SEQ ID NO: 2) and anti-tumor application of the specific T cell receptor. The specific T cell receptor is composed of two peptide chains alpha and beta and can be specifically combined with a VVGAVGVGK-HLA-A * 11: 01 compound. The invention also provides an antigen binding fragment of the specific T cell receptor, a nucleic acid sequence for coding the T cell receptor, a vector containing the nucleic acid sequence, an engineered cell for expressing the T cell receptor, a composition containing the T cell receptor and application thereof. In addition, the invention also provides a method for screening the KRAS G12V specific T cell receptor. The specific T cell receptor and the antigen binding fragment thereof provided by the invention can be used as an immune effect activator to stimulate the immune response of a body, so that the effect of resisting diseases such as tumors and the like is achieved.

The invention relates to an amido-substituted aromatic heterocycle inhibitor as well as a preparation method and application thereof. Specifically, the compound disclosed by the invention has a structure as shown in a formula (I), and each group is defined in the specification. The invention further discloses a preparation method of the compound and application of the compound as a KRAS mutation inhibitor. The compound has a very good inhibition effect on KRAS mutation and has better pharmacodynamic and pharmacokinetic performance and lower toxic and side effects. # imgabs0 #

The present application relates to a novel tricyclic derivative compound as a KRAS mutant protein inhibitor, and use thereof. The compound according to one embodiment of the present application inhibits the activity of a KRAS mutant protein and thus can be used in the prevention or treatment of diseases induced by KRAS mutation.

The invention relates to the field of biomedicine, and discloses a method for screening KRAS mutant interacting proteins, an HEK293T cell line for continuously expressing an HA-Turbo ID-KRAS variant is established by utilizing lentivirus transduction, the stability of transgene expression is ensured through puromycin screening, and variation caused by transient transfection is reduced as much as possible. After a Turbo ID mediated proximity marker is activated by biotin treatment, KRAS proximity binding proteins are covalently biotinylated, captured by NeutrAvidin bead purification, and analyzed by quantitative mass spectrometry. According to the invention, two potential KRAS mutation treatment target proteins of LZTR1 and LAMTOR1 can simultaneously inhibit activation and efficacy exertion of three different mutants of G12C, G12D and G12V of the G12 mutant, compared with drugs on the market that a single target of G12C directly targets the KRAS mutant, a brand new KRAS mutation targeting intervention strategy is provided, the clinical curative effect can be further improved, and the occurrence rate of secondary drug resistance can be effectively reduced.

The present invention relates to a substituted pyrimidine-fused ring inhibitor, a method for preparing same, and use thereof. Specifically, the compound of the present invention has a structure represented by formula (I). Further disclosed are a method for preparing the compound, and use of the compound as a KRAS mutation inhibitor. The compound has a good selective inhibition effect on KRAS mutation and has better pharmacodynamic and pharmacokinetic performance and lower toxic and side effects.

The invention relates to a Pan KRAS protein degradation agent as well as a preparation method and application thereof. Specifically, the compound provided by the invention has a structure as shown in a formula I. The invention also discloses a preparation method of the compound and application of the compound in prevention and / or treatment of KRAS mutation related diseases.

Lung cancer is the leading cause of cancer deaths worldwide. Metastatic non-small-cell lung cancer (NSCLC) has recently benefited from two consecutive breakthroughs: the identification of oncogene drivers, such as KRAS mutations, leading to the development of targeted therapies, and the understanding of the cancer immunity cycle leading to the development of immune checkpoint inhibitors. KRASG12C mutations can be found in approximately 13% of patients with non-small-cell lung cancer (NSCLC) and historically have been associated with a poor prognosis. Now, data from a phase II trial demonstrate the efficacy of the novel KRASG12C-specific inhibitor sotorasib for patients with advanced-stage NSCLC harbouring this alteration with disease progression on at least one standard-of-care therapy. However one could expect that resistance to Ras inhibitors could occur and that there is a need for identifying new therapeutic avenues for limiting said resistance. The inventors now show that when use alone, sotorasib and tipifarnib did not show a significant anti-tumor effect on lung cancer cells harboring the G12C KRAS mutation, whereas the combination potently induced cell death, suggesting a synergism between these drugs. The present invention thus relates to the combination of Ras inhibitors and famesyltransferase inhibitors for the treatment of cancers.

The invention discloses a heterocyclic compound as well as a pharmaceutical composition and application thereof. Specifically, the present invention discloses a heterocyclic compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof. The compound provided by the invention has inhibitory activity on proliferation of one or more of stably transfected cells Ba / F3 KRAS G12C, Ba / F3 KRAS G12D, Ba / F3 KRAS G12V, human pancreatic cancer cells Capan-1, human non-small cell lung cancer cells NCI-H358 (KRAS G12C mutation) and human metastatic pancreatic adenocarcinoma cells AsPC-1 (KRAS G12D mutation) containing KRAS mutation, or the compound provided by the invention has relatively weak inhibitory activity on proliferation of wild PC-9 cells of KRAS. # imgabs0 #

The present application provides methods of treating a cancer in subjects who have been subjected to a KRAS inhibitor and / or harbor a KRAS secondary mutation by administering complexes (e.g., genome-editing complexes or complexes having RNAi) or nanoparticles specifically targeting a mutated KRAS. Exemplary genome-editing complexes or nanoparticles comprise cell-penetrating peptides and a guide RNA, and optionally a DNA nuclease (such as Cas9) or a polynucleotide encoding the DNA nuclease.

The invention discloses a tetra-heterocyclic compound as well as a preparation method and application thereof, and particularly discloses a compound as shown in a formula I, and a stereoisomer or pharmaceutically acceptable salt thereof. The tetra-heterocyclic compound provided by the invention has good proliferation inhibition activity on at least one of NCI-H358 cells, Capan-1 cells and AsPC-1 cells containing KRAS mutation, has relatively weak proliferation inhibition activity on KRAS wild type PC-9 cells, and is expected to treat and / or prevent KRAS mediated diseases.

The invention discloses a fused ring compound, a pharmaceutical composition containing the fused ring compound and application. The compound has a structure as shown in a formula (I) or a tautomer, a meso-mer, a raceme, an enantiomer, a diastereoisomer or a mixture form, a metabolite, a metabolism precursor, an isotope substitution form, a pharmaceutically acceptable salt, a hydrate, a solvate, a polymorphic substance or an eutectic substance thereof, the compound can be used for treating one or more cancers caused by KRAS mutation.

The invention discloses a fused ring compound, a pharmaceutical composition containing the fused ring compound and application. The compound has a structure as shown in a formula (I) or a tautomer, a meso-mer, a raceme, an enantiomer, a diastereoisomer or a mixture form, a metabolite, a metabolism precursor, an isotope substitution form, a pharmaceutically acceptable salt, a hydrate, a solvate, a polymorphic substance or an eutectic substance thereof. The compound can be used for treating cancers caused by KRAS mutation, the cancers caused by KRAS mutation are selected from one or more of cancers caused by KRASG12C, KRASG12V, KRASG12A and G12D mutation, and particularly, the compound can be used as a G12D inhibitor and has relatively high inhibitory activity.

The invention discloses a compound of a targeted KRAS protein degradation agent and application of the compound, and belongs to the technical field of medicines. Provided is a compound having an F-L-M structure, or a tautomer, a raceme, an enantiomer, a diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the F being a KRAS protein binding fragment; l is a connecting unit for connecting F and M; m is a VHL binding fragment; the compound can be used for treating diseases caused by KRAS mutation or amplification.

The invention relates to an AKR1C3 enzyme expression level and medical application through KRAS mutation. According to the AKR1C3 enzyme activated anticancer prodrug, KRAS gene mutation can be directly used as a detection target before medication, namely, a KRAS mutation patient is a patient with high expression of the AKR1C3 enzyme and does not need to be subjected to AKR1C3 enzyme expression level or AKR1C3RNA detection, that is to say, KRAS mutation detection positive can be used as a screening index to screen the patient with high expression of the AKR1C3 enzyme.

The application belongs to the technical field of biological medicine, and specifically discloses the use of CK2 in analyzing the cold and hot properties of lung cancer and the total survival of KRAS mutant lung cancer patients and screening lung cancer patients suitable for immunotherapy. It relates to the use of a reagent for detecting KRAS mutation in the preparation of a product for diagnosing whether lung cancer is a hot tumor; the use of a reagent for detecting the expression level of CK2 protein in the preparation of a product for screening KRAS mutant lung cancer patients suitable for immunotherapy; the use of a CK2 protein expression inhibitor in the preparation of a KRAS mutant lung cancer PD-1 / PD-L1 immunotherapy adjuvant drug; and the use of a reagent for detecting the interaction between CK2 and FASN protein in the preparation of a product for analyzing the immunotherapy effect of KRAS mutant lung cancer. The present disclosure can predict the immunotherapy effect of KRAS mutant lung cancer patients, and at the same time, can provide a new target for immunotherapy of KRAS mutant lung cancer.

The invention discloses a tetra-heterocyclic compound as well as a preparation method and application thereof. The invention provides a compound as shown in a formula I, and a stereoisomer or pharmaceutically acceptable salt thereof. The compound has good inhibitory activity on KRAS mutation, for example, the compound has good proliferation inhibitory activity on NCI-H358, AsPC-1 and Capan-1 cancer cells containing KRAS mutation, has relatively weak proliferation inhibitory activity on KRAS wild PC-9 cells, has good selectivity, and is expected to treat and / or prevent KRAS mediated diseases.

The invention belongs to the technical field of medicine. The invention particularly relates to application of statin combined with a KRAS inhibitor in preparation of a medicine for treating colorectal cancer. The invention provides a new effective strategy for treatment of the KRAS inhibitor drug-resistant colorectal cancer, namely a medication scheme of statin combined with the KRAS inhibitor, can significantly improve the treatment effect of the drug-resistant colorectal cancer, effectively inhibit the growth of tumor cells, inhibit the proliferation of tumors, and improve the treatment effect of the KRAS inhibitor drug-resistant colorectal cancer. The KRAS mutant colorectal cancer has an excellent treatment effect on the KRAS mutant colorectal cancer generating drug resistance to a first-line chemotherapy regimen, overcomes the clinical treatment difficulty caused by KRAS mutation, and has a very good application prospect.

The present application provides a kind of compound with inhibitory effect on KRAS mutation, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, as shown in formula (I), wherein the definition of each group is detailed in the specification.In addition, the present application also discloses a pharmaceutical composition comprising the compound, and its use in the preparation of a kit for treating cancer, immune diseases or cancer patient prognosis evaluation.

The invention discloses a generic KRAS mutation inhibitor and application thereof, and belongs to the technical field of biomedicine. The inhibitor disclosed by the invention is a triaromatic ring compound, can selectively inhibit the proliferation of KRAS mutant cells by blocking the function of REG gamma-20S proteasome, and is used for treating KRAS mutant tumors or cancers. The method has a wide application prospect.

A binding protein is provided comprising a binding domain having antigen specificity for an antigen peptide: HLA complex, the binding domain comprising a T cell receptor (TCR) alpha chain variable region and a TCR beta chain variable region. Also provided are uses of the binding protein and a pharmaceutical composition comprising the binding protein in the treatment of cancers associated with the antigen peptide.

The present invention relates to a combination of a PIM kinase inhibitor and a KRAS inhibitor for use in treating cancer in a subject in need of such treatment. Compositions or kits containing the same are also provided. The present invention also relates to a PIM kinase inhibitor for use in treating cancer with a KRAS mutation in a human subject in need of such treatment.

The application provides an antisense nucleic acid targeting a KRAS gene, a pharmaceutical preparation thereof and an application thereof, and belongs to the technical field of biological medicines.The nucleotide sequence of the antisense nucleic acid comprises at least one of SEQ ID NO:1 to SEQ ID NO:7; the nucleotide sequence of the antisense nucleic acid further comprises a modified nucleotide sequence of SEQ ID NO:1 and a modified nucleotide sequence of SEQ ID NO:8.The antisense nucleic acid can target the 3'-UTR region of mRNA of KRAS, down-regulate the corresponding mRNA and various mutants thereof, inhibit tumor cell growth, the pharmaceutical preparation thereof can deliver the target antisense nucleic acid to a tumor site and exert a significant inhibitory effect, and has great application potential in the field of tumor gene therapy of KRAS mutation.

The invention discloses a BRD4 and CDK4 / 6 double-target inhibitor and application of the BRD4 and CDK4 / 6 double-target inhibitor as a KRAS mutation non-small cell lung cancer treatment medicine. The inhibitor is a compound as shown in a structural general formula I or pharmaceutically acceptable salt, isomer, metabolite or prodrug thereof: # imgabs0. The double-target inhibitor can simultaneously inhibit the activity of BRD4 and CDK4 / 6 and is used for preparing a medicine for treating the KRAS mutant non-small cell lung cancer, and the double-target inhibitor effectively overcomes the problem of drug resistance of a single CDK4 / 6 inhibitor; the application prospect in the aspect of clinical treatment of KRAS mutant non-small cell lung cancer is relatively good.

The present invention relates to the technical field of medicines, and provides a fused ring compound, a pharmaceutical composition containing the same, and use of the fused ring compound. The compound has a structure as shown in formula (I), or a tautomer, a mesomer, a racemat, an enantiomer, a diastereoisomer or a mixture thereof, a metabolite, a metabolic precursor, an isotope substitution form, a pharmaceutically acceptable salt, a hydrate, a solvate, a polymorph or a eutectic substance thereof. The compound provided by the present invention can be used for treating cancers caused by KRAS mutation. The cancers caused by KRAS mutation are selected from one or more cancers caused by KRAS G12C, KRAS G12V, KRAS G12A and G12D mutations. In particular, the compound can serve as a G12D inhibitor and has relatively high inhibitory activity.

The invention relates to a KRAS mutant colorectal cancer treatment target and application thereof, and belongs to the technical field of biological medicine. The polypeptide for targeted blocking of TRIP6 S147 site phosphorylation is designed, it is found that the polypeptide can reverse abnormal glycolysis driven by KRAS mutation through targeted inhibition of TRIP6 phosphorylation, and the feasibility of blocking of TRIP6 S147 site phosphorylation in treatment of KRAS mutant colorectal cancer is proved. The polypeptide is combined with an immune checkpoint inhibitor, so that the anti-tumor curative effect of a PD-1 blocking therapy can be remarkably improved. The invention also finds that the KRAS mutant colorectal cancer promotes the generation of lactic acid by inducing TRIP6 phosphorylation so as to enhance CD44 lactic acid and finally inhibit the anti-tumor immune function of CD8 + T cells, and the CAR-T cells for targeted blocking of CD44 K158 lactic acid prepared on the basis also have a good anti-tumor effect.

The invention relates to a halogenated alkylene substituted naphthenic base or heterocyclic base inhibitor as well as a preparation method and application thereof. Specifically, the compound has a structure as shown in a formula (I), the invention further discloses a preparation method of the compound and application of the compound as a KRAS mutation inhibitor, and the compound has a very good inhibition effect on KRAS mutation and has better pharmacodynamic and pharmacokinetic performance and lower toxic and side effects.

The present invention relates to an inhibitor having a quinazoline-containing structure for the treatment of cancer. Specifically, the present invention relates to a derivative as represented by formula (I) having a quinazoline-containing structure, and a pharmaceutically acceptable salt thereof. The compound or the salt thereof can simultaneously inhibit a plurality of mutation types of the KRAS proteins, including KRAS G12C, G12D and G12V mutant proteins, and can be used as a KRAS small-molecule inhibitor for treating various diseases caused by KRAS mutations. The present invention relates to the structure of an inhibitor derivative having a quinazoline-containing structure and a preparation method therefor. The present invention further relates to a pharmaceutical composition containing the compound or the salt thereof, and a method for treating diseases related to KRAS mutations by means of using the compound and the salt thereof.

The application belongs to the technical field of biological medicine, and particularly relates to application of an imidazoquinazoline small-molecule compound or a pharmaceutically acceptable salt thereof shown in formula (I) in preparation of a drug for treating KRAS mutant gastrointestinal tumors, wherein R is as described in the claims and the specification. The imidazoquinazoline compound can selectively inhibit proliferation, migration and invasion of KRAS mutant gastrointestinal tumor cells, and induce cell cycle arrest and apoptosis. Specifically, the compound exerts an anti-tumor effect by inhibiting the binding of p-ERK2 and p53, restoring p53 transcriptional activity, and up-regulating the expression of a pro-apoptotic gene PUMA downstream of p53. The mechanism of action is different from that of traditional KRAS or MEK inhibitors, and provides a new treatment option for KRAS mutant gastrointestinal tumor patients.