26 results about "HRAS" patented technology

Disclosed is an isolated or purified T cell receptor (TCR) having antigenic specificity for an HLA-A11-restricted epitope of mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) (KRAS7-16), Neuroblastoma RAS Viral (V-Ras) Oncogene Homolog (NRAS), or Harvey Rat Sarcoma Viral Oncogene Homolog (HRAS). Related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions are also provided. Also disclosed are methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal.

The present invention relates to the use of compounds of formula (I) as RAS inhibitors and as a medicament, in particular for use in treating proliferative disorders, inflammatory diseases and / or genetic disorders. The present invention relates further to a pharmaceutical composition comprising the compounds of formula (I). Moreover, the present invention relates to a method of inhibiting growth, proliferation or metastasis of cancer cells in a subject in need thereof, in particular which may encompass subsets of patients defined by their mutational status of the RAS oncogene or patients who might have developed resistance to the standard of care or treatment with RAS mutation specific inhibitors. The present invention also relates to a method of inhibiting RAS molecules in treating genetic disorders like RASopathies or inflammatory disorders like Adenomyosis where KRAS gene is mutationally activated. In addition, the present invention relates to a method of inhibiting proliferation and or secretion of factors from a cell population sensitive towards inhibiting RAS activation in vitro, in particular sensitive towards inhibiting KRAS. HRAS and NRAS activation in vitro. Furthermore, the present invention relates to a kit containing a formulation comprising a pharmaceutical composition comprising a compound of formula (I).

The invention relates to kinase inhibitors, and specifically to inhibitors of the kinase c-RAF, comprising a cyclic peptide component capable of inhibiting complex formation between c-RAF and phosphodiesterase-8A (PDE8A). The inhibitors find use in various medical applications including the treatment of cancer, and in particular cancers which carry gain-of-function mutations in Ras (e.g. KRAS, NRAS or HRAS) and / or RAF mutations (e.g. mutations in A-RAF, B-RAF or c-RAF / RAF1).

The present invention relates to the use of compounds of formula (I) as RAS inhibitors and as a medicament, in particular for use in treating proliferative disorders, inflammatory diseases and / or genetic disorders. The present invention relates further to a pharmaceutical composition comprising the compounds of formula (I). Moreover, the present invention relates to a method of inhibiting growth, proliferation or metastasis of cancer cells in a subject in need thereof, in particular which may encompass subsets of patients defined by their mutational status of the RAS oncogene or patients who might have developed resistance to the standard of care or treatment with RAS mutation specific inhibitors. The present invention also relates to a method of inhibiting RAS molecules in treating genetic disorders like RASopathies or inflammatory disorders like Adenomyosis where KRAS gene is mutationally activated. In addition, the present invention relates to a method of inhibiting proliferation and / or secretion of factors from a cell population sensitive towards inhibiting RAS activation in vitro, in particular sensitive towards inhibiting KRAS, HRAS and NRAS activation in vitro. Furthermore, the present invention relates to a kit containing a formulation comprising a pharmaceutical composition comprising a compound of formula (I).

Disclosed herein are compounds, and salts thereof, which inhibit targeted Ras mutants, pharmaceutical formulations, and methods of treatment of NRAS-, KRAS, or HRAS-mediated diseases, such as certain cancers.

The invention relates to a high-sensitivity multi-gene joint detection kit. The kit is used for detecting mutation conditions of human BRAF, KRAS, NRAS, HRAS, RET, TERT, TP53 and PIK3CA genes. The primer probe and the amplification system are unique, the 37 mutation types of the 8 genes can be specifically and highly sensitively detected only through 5 ng DNA, and the detection sensitivity is as low as 1%-5%. Compared with the defects that the traditional Sanger sequencing detection sensitivity is low, the number of detection sites of a PCR method is small, NGS operation is complex, and the price is high, the method has obvious advantages in clinical application.

This disclosure provides compounds of Formula (I) or (II) (e.g., Formula (II-a), (Il-b), or (II-c)), or pharmaceutically acceptable salts thereof, that inhibit a Ras GTPase (e.g., a KRas, NRas, and / or HRas GTPase). In some embodiments, the Ras protein is a dysregulated Ras protein that has a mutation (referred to herein as a mutant Ras protein). These compounds are useful, for example, for treating a disease, disorder, or condition in which increased and / or sustained (e.g., excessive) Ras activation, such as Ras activation associated with a mutant Ras protein, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (I) or (II) (e.g., Formula (II-a), (Il-b), or (II- c)), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

The invention discloses a construction method and application of an HRAS humanized mouse for carcinogenicity evaluation, and the construction method comprises the following steps: construction of a Tg-HRAS mouse: injecting a constructed vector into a mouse fertilized egg in a prokaryotic injection manner, randomly inserting a human HRAS gene segment containing an HRAS gene regulatory sequence and an expression sequence into a mouse genome, and constructing the Tg-HRAS mouse; the sequence fragment of the human HRAS gene is as shown in SEQ ID NO. 1; construction of a PMD18-T skeleton vector: taking the PMD18-T vector as a template, carrying out high-fidelity PCR (Polymerase Chain Reaction) amplification to obtain a 2.7 kb linearized PMD18-T vector, and carrying out gel recovery to serve as a skeleton of SLIC reaction; according to the construction method and application of the HRAS humanized mouse for carcinogenicity evaluation, by constructing the HRAS humanized mouse, carcinogenicity verification of the mouse is more efficient, the passing incidence rate is high, quick discovery can be achieved in the verification process, the purpose of shortening the verification period is achieved, the test cost is reduced, and the spontaneous tumor probability is high.

The application discloses a method for detecting thyroid cancer driving gene mutations based on multiplex fluorescence PCR, and belongs to the technical field of molecular biology detection. The method simultaneously detects nine mutation sites, namely BRAF V600E, NRAS Q61R, NRAS Q61K, HRAS Q61R, HRAS Q61K, KRAS G12V, KRAS G12D, TERT C228T and TERT C250T in a single tube reaction. The method enhances the distinguishing ability of wild type and mutant types by using a locked nucleic acid modified allele-specific primer, suppresses wild type amplification by using a peptide nucleic acid clamp, introduces a competitive internal reference probe to correct amplification efficiency difference, and reduces the sample usage to one fifth of that of a traditional multi-tube scheme. The mutation detection lower limit reaches 0.5% allele frequency, and the total time consumption is not more than 2.5 h.

The invention relates to a selection of verified targets for T-cell receptors (TCR) against mutated human rat sarcoma (RAS) peptides as well as to several new T-cell receptors (TCR), which are isolated and / or expressed in an engineered cell, and which specifically recognize a G12V mutated human rat sarcoma (RAS) peptide, wherein the peptide is a mutated human Kirsten RAS (KRAS) peptide, a mutated human Harvey RAS (HRAS) peptide, or a human neuroblastoma RAS (NRAS) peptide, which consists of VVVGAVGVGK (SEQ ID NO: 1) or VVGAVGVGK (SEQ ID NO:2) presented in a HLA- A*11 complex, and wherein the individual TCR comprises a paired TCR alpha- and TCR beta-chain. The invention further relates to engineered cells and vectors expressing said TCRs and medical uses of the same for treating cancer patients.

The application belongs to the field of biological medicine, and particularly relates to a group of gene mutations and application thereof in diagnosis of pancreaticobiliary duct cancer. Specifically, the application provides a group of gene mutations for detecting pancreaticobiliary duct cancer, wherein the gene mutations include one or more of AKT1, KRAS, APC, NRAS, ARID1A, PIK3CA, AXIN1, PPP2R1A, BAP1, PTEN, BRAF, SMAD4, CDKN2A, TERT, TP53, EGFR, FBXW7, FGFR2, HRAS, IDH1 and IDH2.

The present invention relates to the use of compounds of formula (I) as RAS inhibitors and as a medicament, in particular for use in treating proliferative disorders, inflammatory diseases and / or genetic disorders. The present invention relates further to a pharmaceutical composition comprising the compounds of formula (I). Moreover, the present invention relates to a method of inhibiting growth, proliferation or metastasis of cancer cells in a subject in need thereof, in particular which may encompass subsets of patients defined by their mutational status of the RAS oncogene or patients who might have developed resistance to the standard of care or treatment with RAS mutation specific inhibitors. The present invention also relates to a method of inhibiting RAS molecules in treating genetic disorders like RASopathies or inflammatory disorders like Adenomyosis where KRAS gene is mutationally activated. In addition, the present invention relates to a method of inhibiting proliferation and / or secretion of factors from a cell population sensitive towards inhibiting RAS activation in vitro, in particular sensitive towards inhibiting KRAS, HRAS and NRAS activation in vitro. Furthermore, the present invention relates to a kit containing a formulation comprising a pharmaceutical composition comprising a compound of formula (I).

The present invention relates to the use of compounds of formula (I) as RAS inhibitors and as a medicament, in particular for use in treating proliferative disorders inflammatory diseases and / or genetic disorders. The present invention relates further to a pharmaceutical composition comprising the compounds of formula (I). Moreover, the present invention relates to a method of inhibiting growth, proliferation or metastasis of cancer cells in a subject in need thereof, in particular which may encompass subsets of patients defined by their mutational status of the RAS oncogene or patients who might have developed resistance to the standard of care or treatment with RAS mutation specific inhibitors. The present invention also relates to a method of inhibiting RAS molecules in treating genetic disorders like RASopathies or inflammatory disorders like Adenomyosis where KRAS gene is mutationally activated. In addition, the present invention relates to a method of inhibiting proliferation and or secretion of factors from a cell population sensitive towards inhibiting RAS activation in vitro, in particular sensitive towards inhibiting KRAS, HRAS and NRAS activation in vitro. Furthermore, the present invention relates to a kit containing a formulation comprising a pharmaceutical composition comprising a compound of formula (I).

The present application relates to a kind of molecular marker for diagnosing cancer, kit and its application, belong to biotechnology field.The present application provides the m 6 A modification as a molecular marker for diagnosing cancer, the m 6 A modification site is A923, A930 and A955, 3 m 6 A modification site is regulated by demethylase FTO and ALKBH5, promotes HRAS protein expression and the proliferation and metastasis of cancer cell.The present application first identifies the epigenetic transcription modification of HRAS and clarifies relevant molecular mechanism, provides new single / combination targeting treatment theoretical basis for RAS this "difficult drug target".

The invention relates to a selection of verified targets for T-cell receptors (TCR) against mutated human rat sarcoma (RAS) peptides as well as to several new T-cell receptors (TCR), which are isolated and / or expressed in an engineered cell, and which specifically recognize a G12V mutated human rat sarcoma (RAS) peptide, wherein the peptide is a mutated human Kirsten RAS (KRAS) peptide, a mutated human Harvey RAS (HRAS) peptide, or a human neuroblastoma RAS (NRAS) peptide, which consists of VVVGAVGVGK (SEQ ID NO: 1) or VVGAVGVGK (SEQ ID NO:2) presented in a HLA- A*11 complex, and wherein the individual TCR comprises a paired TCR alpha- and TCR beta-chain. The invention further relates to engineered cells and vectors expressing said TCRs and medical uses of the same for treating cancer patients.

Provided is an analysis means that can be quickly applied to more cancers. A library consisting of a plurality of probes and / or primers for detecting cancer-related mutations in a gene selected from the group consisting of ARID1A, BRAF, EGFR, FGFR2, FGFR3, HRAS, KRAS and PIK3CA or a promoter region thereof, in which the plurality of probes and / or primers comprise: for ARID1A, for detecting c.5965Cgt; t, c.5548dup, and c.3826Cgt; a probe and / or primer for T; for the BRAF, the BRAF is used for detecting c.1799Tgt; a probe and / or primer of A; for EGFR (epidermal growth factor receptor), c.2573Tgt is detected; the kit comprises a probe and / or a primer of c.2236250del, a probe and / or a primer of c.2236250del, c. For the FGFR2, the FGFR2 is used for detecting c.755Cgt; g, c, 1650Tgt, c, 1650Tgt; a, c.1147Tgt, c.1147Tgt A probe and / or primer of C; for the FGFR3, the FGFR3 is used for detecting c.746Cgt; g, c, 1124Agt; g, c, 742Cgt; a probe and / or primer for T; for HRAS, the HRAS is used for detecting c.37Ggt; c, c, 182Agt, c, 182Agt; g, c.35 Ggt; t, c.182Agt, c. 182Agt; 181Cgt, T, c.181Cgt; a, c, 34Ggt; a, c.35 Ggt; a probe and / or primer of A; the KRAS is used for detecting c.35Ggt; a, c.35 Ggt; t, c.38Ggt; a, c, 34Ggt; a probe and / or primer for T; for PIK3CA, the PIK3CA is used for detecting c.3140Agt; g, c, 1633Ggt; a, c, 1624Ggt, c, 1624Ggt; a is a probe and / or a primer.

The invention relates to a selection of verified targets for T-cell receptors (TCR) against mutated human rat sarcoma (RAS) peptides as well as to several new T-cell receptors (TCR), which are isolated and / or expressed in an engineered cell, and which specifically recognize a G12V mutated human rat sarcoma (RAS) peptide, wherein the peptide is a mutated human Kirsten RAS (KRAS) peptide, a mutated human Harvey RAS (HRAS) peptide, or a human neuroblastoma RAS (NRAS) peptide, which consists of VWGAVGVGK (SEQ ID NO: 1) or VVGAVGVGK (SEQ ID NO:2) presented in a HLA-A*11 complex, and wherein the individual TCR comprises a paired TCR alpha- and TCR beta-chain. The invention further relates to engineered cells and vectors expressing said TCRs and medical uses of the same for treating cancer patients.

The present invention relates to the use of compounds of formula (I) as RAS inhibitors and as pharmaceutical agents, particularly for the treatment of proliferative, inflammatory, and / or genetic disorders. The present invention also relates to pharmaceutical compositions comprising the compounds of formula (I). Furthermore, the present invention relates to methods for inhibiting the growth, proliferation, or metastasis of cancer cells in a subject in need thereof, which may include, in particular, a subset of patients defined by their RAS oncogene mutation status, or patients who have developed resistance to standard treatment or treatment with RAS mutation-specific inhibitors. The present invention also relates to methods for inhibiting RAS molecules in the treatment of genetic disorders such as RAS syndromes or inflammatory diseases such as adenomyosis in which the KRAS gene is activated by mutations. The present invention also relates to methods for inhibiting the proliferation and / or secretion of factors from cell populations sensitive to in vitro inhibition of RAS activation, particularly cell populations sensitive to in vitro inhibition of KRAS, HRAS, and NRAS activation. Furthermore, the present invention relates to kits containing formulations of pharmaceutical compositions containing compounds of formula (I).

The invention discloses application of an NASH-HCC mouse model, and belongs to the technical field of drug evaluation. The NASH-HCC mouse model can be applied to screening and / or evaluation of drugs and / or equipment for treating and / or preventing liver diseases, the NASH-HCC mouse model is an inducible Cre mouse, the HRAS protein is specifically and highly expressed in the liver under the induction of an inducer, and the liver diseases are NAFLD, NASH or HCC. The model can comprehensively evaluate the curative effect of a drug treatment scheme through multiple aspects such as mouse liver weight, blood biochemical indexes, total ROS (reactive oxygen species) amount of liver and spleen tissues, immune cell change conditions and the like, and provides support and assistance for clinical application.

This disclosure provides compounds of Formula ( I ) (e.g., Formula ( I-a )), ( II ), ( III ), or ( IV ), or pharmaceutically acceptable salts thereof, that inhibit a Ras GTPase (e.g., a KRas, NRas, and / or HRas GTPase). In some embodiments, the Ras protein is a dysregulated Ras protein that has a mutation (referred to herein as a mutant Ras protein). These compounds are useful, for example, for treating a disease, disorder, or condition in which increased and / or sustained (e.g., excessive) Ras activation, such as Ras activation associated with a mutant Ras protein, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula ( I ) (e.g., Formula ( I-a )), ( II ), ( III ), or ( IV ), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

The invention belongs to the technical field of gene detection, particularly discloses a thyroid cancer six-gene mutation detection kit based on digital PCR and application thereof, and provides a 4-hole combined primer probe mixed solution for detecting 13 mutation sites of six genes BRAF, TERT, PIK3CA, KRAS, NRAS and HRAS, and the multi-gene and multi-site detection coverage is wide; the kit has the advantages of simplicity in operation, short time consumption, high sensitivity and high specificity; the thyroid cancer related mutant genes can be rapidly and accurately quantified, so that clinical diagnosis of thyroid cancer is assisted.

The present invention relates to the use of compounds of formula (I) as RAS inhibitors and as a medicament, in particular for use in treating proliferative disorders, inflammatory diseases and / or genetic disorders and / or genetic disorders. The present invention relates further to a pharmaceutical composition comprising the compounds of formula (I). Moreover, the present invention relates to a method of inhibiting growth, proliferation or metastasis of cancer cells in a subject in need thereof, in particular which may encompass subsets of patients defined by their mutational status of the RAS oncogene or patients who might have developed resistance to the standard of care or treatment with RAS mutation specific inhibitors. The present invention also relates to a method of inhibiting RAS molecules in treating genetic disorders like RASopathies or inflammatory disorders like Adenomyosis where KRAS gene is mutationally activated. In addition, the present invention relates to a method of inhibiting proliferation and / or secretion of factors from a cell population sensitive towards inhibiting RAS activation in vitro, in particular sensitive towards inhibiting KRAS, HRAS and NRAS activation in vitro. Furthermore, the present invention relates to a kit containing a formulation comprising a pharmaceutical composition comprising a compound of formula (I).

This disclosure provides compounds of Formula (I), or pharmaceutically acceptable salts thereof, that inhibit a Ras GTPase (e.g., a KRas, NRas, and / or HRas GTPase). In some embodiments, the Ras protein is a dysregulated Ras protein that has a mutation (referred to herein as a mutant Ras protein). These compounds are useful, for example, for treating a disease, disorder, or condition in which increased and / or sustained (e.g., excessive) Ras activation, such as Ras activation associated with a mutant Ras protein, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (I) (e.g., Formula (I-a) or Formula (I-b)), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

The invention discloses a construction method of an NASH-HCC mouse model, and belongs to the technical field of gene editing animal models. The construction method comprises the following steps: constructing a targeting vector containing a target sequence fragment of LoxP-Stop-LoxP-HRAS, transfecting the targeting vector into a mouse ES cell, injecting the targeting vector into a receptor embryo sac, transplanting an embryo to the uterus of a pseudopregnant mouse, screening out a chimeric mouse, mating the chimeric mouse with an inbred strain laboratory mouse to obtain a heterozygous mouse, selfing the heterozygous mouse to obtain a positive homozygous mouse, and screening the positive homozygous mouse to obtain the target sequence fragment of the LoxP-Stop-LoxP-HRAS. And mating a homozygote mouse with an inducible Cre mouse to obtain a double-heterozygous NASH-HCC mouse model containing the gene sequence of the targeting vector and the inducible Cre sequence, thereby obtaining the double-heterozygous NASH-HCC mouse model. The NASH-HCC mouse model has the advantages of typical clinical characteristics, controllable disease process, high morbidity and the like.

This invention provides cyclic compounds effective against RAS-mutated cancers, as well as non-natural amino acids and peptide compounds useful for their production, particularly peptide compounds that exhibit sufficiently selective KRAS inhibitory activity against HRAS and NRAS. [Solution] The present invention provides a cyclic compound having a specific amino acid sequence that interacts with and selectively inhibits amino acid residues specific to KRAS, or a salt thereof, or a solvate thereof. The pharmacological effect of the cyclic compound is to inhibit the proliferation of tumor cells having RAS mutations.

Disclosed is an isolated or purified T cell receptor (TCR) having antigenic specificity for an HLA-A11-restricted epitope of mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) (KRAS7-16), Neuroblastoma RAS Viral (V-Ras) Oncogene Homolog (NRAS), or Harvey Rat Sarcoma Viral Oncogene Homolog (HRAS). Related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions are also provided. Also disclosed are methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal.