78 results about "Kras mutation" patented technology

A fused ring compound, a pharmaceutical composition comprising same, and the use thereof. The compound has a structure as represented by formula (I), or is a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, a metabolite, a metabolic precursor, an isotope-substituted form, a pharmaceutically acceptable salt, a hydrate, a solvate, a polymorph or a co-crystal thereof. The compound can be used for treating one or more cancers caused by KRAS mutation.

The invention provides a pyridopyrimidine derivative as a small GTP enzyme KRAS mutation inhibitor, and particularly provides a pyridopyrimidine derivative with a structural formula as shown in a general formula (A) and pharmaceutically acceptable salts thereof, and the pyridopyrimidine derivative has inhibitory activity on mutants such as KRAS G12D and the like. The invention also provides a preparation method of the derivative, a pharmaceutical composition and a salifying compound of the derivative, and medical application of the derivative as a small GTP enzyme KRAS mutation inhibitor in treatment of different types of tumors.

A fused ring compound, a pharmaceutical composition comprising same, and a use. The compound has a structure represented by formula (I) or a tautomer, mesomere, racemate, enantiomer, diastereomer or mixture thereof, metabolite, metabolic precursor, isotope substitution form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or eutectic thereof. The compound can be used for treating a cancer caused by KRAS mutations, and said cancer is 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.

A compound targeting a KRAS protein degradation agent, and a use thereof. The compound is a compound having an F-L-M structure, or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein F is a KRAS protein binding fragment, L is a linking unit for linking F and M, and M is a VHL binding fragment. The compound can be used for treating diseases caused by KRAS mutation or amplification.

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 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 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 invention belongs to the technical field of biological medicines, and particularly discloses application of CK2 in analysis of cold and hot attributes of lung cancer, total survival of KRAS mutation lung cancer patients and screening of lung cancer patients suitable for immunotherapy. The invention relates to application of a reagent for detecting KRAS mutation in preparation of a product for diagnosing whether lung cancer is a hot tumor or not. The invention also discloses application of the reagent for detecting the expression level of the CK2 protein in preparation of products for screening KRAS mutation lung cancer patients suitable for immunotherapy. The invention also discloses an application of the CK2 protein expression inhibitor in preparation of KRAS mutation lung cancer PD-1 / PD-L1 immunotherapy adjuvant drugs. The invention also relates to application of the reagent for detecting the interaction between the CK2 and the FASN protein in preparation of a product for analyzing the immunotherapy effect of the KRAS mutation lung cancer. The immunotherapy effect of the KRAS mutation lung cancer patient can be predicted, and meanwhile a new target spot can be provided for immunotherapy of the KRAS mutation lung cancer.

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.