328 results about "KRAS" patented technology

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof as a KRAS mutant inhibitor. The present invention also provides a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a use in treating cancer.

Provided in the present invention is a compound of formula (X), or an isotopic variant, a tautomer or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as a KRAS mutant inhibitor. Further provided in the present invention are a pharmaceutical composition containing the compound, or the isotopic variant, the tautomer or the stereoisomer thereof, or the pharmaceutically acceptable salt thereof, and the use thereof in the treatment of cancers.

The present disclosure provides compounds having activity as inhibitors of the G12C mutant KRAS protein, pharmaceutical compositions comprising the compounds, and methods of treating certain disorders, such as cancer, including but not limited to lung cancer, pancreatic cancer, colorectal cancer, and solid tumors. In particular, the disclosure provides compounds of Formula (I):, and pharmaceutically acceptable salts thereof, wherein the substituents are as described.

Disclosed herein is use of a combination of Compound (A) (azenosertib), or a pharmaceutically acceptable salt thereof, and a KRAS G12C inhibitor, such as sotorasib or adagrasib, or a pharmaceutically acceptable salt thereof, for treating a disease or condition, such as a colorectal, pancreatic and / or non-small cell lung cancer.

The present disclosure relates to an improved, efficient, scalable process to prepare intermediate compounds, such as 2-isopropyl-4-methylpyridin-3-amine, useful for the synthesis of compounds, such as Compound 9, for the treatment of KRAS G12C mutated cancers.

The invention discloses a coumarin KRAS-G12C inhibitor as well as preparation and application of the coumarin KRAS-G12C inhibitor. The coumarin compound disclosed by the invention has a remarkable inhibition effect on non-small cell lung cancer cells (NCI-H23 and NCI-H358) with high expression of KRAS-G12C and pancreatic cancer cells (MIAPaCa-2), is particularly used for preparing medicines for treating and / or preventing non-small cell lung cancer and pancreatic cancer, and has a good prospect of development and application of antitumor medicines.

The present invention pertains to the technical field of drug application and particularly relates to clinical use of a KRAS G12D inhibitor. The inhibitor can be clinically used to effectively treat patients with advanced solid tumors carrying the KRAS G12D mutation and can produce beneficial effects.

The present disclosure relates to an improved, efficient, scalable process to prepare intermediate compounds, such as 2-isopropyl-4-methylpyridin-3-amine, useful for the synthesis of compounds, such as Compound 9, for the treatment of KRAS G12C mutated cancers.

The invention relates to the technical field of biomedicine, in particular to a mouse intrahepatic bile duct cancer cell strain and a construction method and application thereof, the cell strain is named as mouse intrahepatic bile duct cancer cell strain KP-ICC and preserved in China Center for Type Culture Collection (CCTCC), and the preservation number is CCTCC NO: C202574; the cell strain is derived from a KrasG12D / Tp53flox / flox C57BL / 6J mouse, a spontaneous tumor model is constructed through high-pressure hydrodynamic tail vein injection of pT3-Cre and a sleep beauty transposase plasmid, and the spontaneous tumor model is obtained through in-vitro culture, passage, monoclonal screening and tumorigenicity verification. The KP-ICC cell strain naturally has chemotherapy-immune combined treatment drug resistance and ferroptosis resistance characteristics, and can be widely applied to the fields of intrahepatic cholangiocarcinoma drug resistance mechanism research, drug resistance reversing, combined treatment drug development, drug resistance animal model establishment and the like.

The present disclosure relates to an improved, efficient, scalable process to prepare intermediate compounds, such as 2,2′,2″-(1,3,5,2,4,6-trioxatriborinane-2,4,6-triyl)tris (3-fluorophenol), useful for the synthesis of compounds, such as Compound 9, for the treatment of KRAS G12C mutated cancers.

A multi-targeted siRNA for treating cancers is disclosed. Specifically, an siRNA composition is provided, comprising: a first siRNA molecule that reduces the expression of the first target gene; optionally, a coding sequence targeting a peptide element; and optionally, a second siRNA molecule that reduces the expression of the second target gene, wherein the first target gene is selected from the group consisting of EGFR, KRAS, or a combination thereof, and the siRNA composition reduces the expression of two or more genes. The siRNA or vector provided can be directly injected into the body to treat cancers.

Provided herein are KRAS G12C inhibitors, composition of the same, and methods of using the same. These inhibitors are useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers.

The invention discloses application of an ENOPH1 gene, and relates to the technical field of biological medicines. According to the application, a key metabolic gene closely related to CRC prognosis is analyzed and identified by adopting bioinformatics, and the expression of ENOPH1 in KRAS mutant CRC tissues and cell lines is evaluated. The function of the ENOPH1 in the KRASG12D / G13D mutant CRC is verified through CCK8, a wound healing experiment, an in-vivo subcutaneous xenotransplantation tumor model and other in-vitro experiments. The result shows that the ENOPH1 is highly expressed in the KRAS mutant CRC and is subjected to MEK / ERK signal cascade regulation and control. The ENOPH1 is knocked down through shRNA, so that CRC cell proliferation, migration and tumorigenesis can be inhibited, cell apoptosis is induced, and the reaction to chemotherapy is enhanced. The application provides a new strategy and direction for treatment of colorectal cancer, has extremely high clinical application value, and can bring a better treatment effect for patients with colorectal cancer.

A compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, a preparation method therefor, and a use thereof. The compound has one or more of the following effects: (1) good KRAS G12C inhibitory activity; (2) good KRAS G12D inhibitory activity; (3) good KRAS G12V inhibitory activity; (4) optimal exposure dose; (5) good bioavailability; and (6) good in vivo efficacy.

This disclosure provides compounds of Formula ( AA ) Formula ( A ), Formula ( I ) (e.g., Formula ( I-a1 )), Formula ( II ) (e.g., Formula ( II-1 ), ( II-a ), ( II-a1 ), ( II-a2 ), or ( II-a3 )), Formula ( III ) (e.g., Formula ( III-1 )), Formula ( IV ) (e.g., Formula ( IV-a ), ( IV-a1 ), ( IV-b ), ( IV-b1 ), or ( IV-c )), or Formula ( B ) (e.g., Formula ( B-1 )), or pharmaceutically acceptable salts thereof, that inhibit a KRas protein. In some embodiments, the KRas protein has a dysregulation (e.g., the KRas protein is mutated or amplified). These compounds are useful, for example, for treating a disease, disorder, or condition in which increased and / or sustained (e.g., excessive) KRas activation, for example, KRas activation associated with a mutant KRas 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 as disclosed herein, or pharmaceutically acceptable salts thereof, and methods of using and making the same.

The present disclosure relates to an improved, efficient, scalable process to prepare intermediate compounds, such as 2,2′,2″-(1,3,5,2,4,6-trioxatriborinane-2,4,6-triyl)tris(3-fluorophenol), useful for the synthesis of compounds, such as Compound 9, for the treatment of KRAS G12C mutated cancers.

Disclosed are a nitrogen-containing heterocyclic compound, a preparation method therefor and a use thereof. Specifically disclosed is a compound represented by formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The nitrogen-containing heterocyclic compound provided by the present invention has proliferation inhibitory activity against at least one of KRAS-mutant NCI-H358, Capan-1 and AsPC-1 cancer cells, and exhibits relatively weak proliferation inhibitory activity against KRAS wild-type PC-9 cells, thereby demonstrating favorable selectivity, and showing potential in treatment and / or prevention of KRAS-mediated diseases.

of KRAS G12C mutated cancers. O N F oH N N N N F O M iPr N 20 26 20 48 47 23 J un 2 02 6 A B S T R A C T 2 0 2 6 2 0 4 8 4 7 2 3 J u n 2 0 2 6 o f K R A S G 1 2 C m u t a t e d c a n c e r s . 0 N F O H N N N N F N

The invention discloses a novel pyrimidine KRAS-G12C inhibitor as well as a preparation method and application of the novel pyrimidine KRAS-G12C inhibitor. The pyrimidine compound disclosed by the invention has a remarkable inhibition effect on non-small cell lung cancer cells (NCI-H23 and NCI-H358) with high expression of KRAS-G12C, is particularly used as a medicine for treating and / or preventing the non-small cell lung cancer, is simple and efficient in preparation route, and has a good antitumor medicine development and application prospect.

Provided is a compound useful as an active ingredient in a pharmaceutical composition for treating cancer.　The present inventors have examined a compound useful as an active ingredient in a pharmaceutical composition for cancer treatment, and have completed the present invention by finding that: a heterocyclic compound represented by formula (I) and formula (I-I) has excellent an action of inducing degradation of a mutant KRAS protein and a wild-type KRAS protein, and in particular, an action of inducing degradation of a KRAS protein having a G12C mutation, G12D mutation, G12V mutation, or G13D mutation; and said heterocyclic compound has mutant KRAS inhibition and the inhibitory activity of KRAS amplified by a wild-type KRAS gene, and in particular, inhibitory activity of KRAS having a G12C mutation, G12D mutation, G12V mutation, or G13D mutation. The heterocyclic compound according to the present invention or a salt thereof can be used as a therapeutic agent for cancer.

The application discloses a five-heterocycle compound, a preparation method and application thereof. Specifically disclosed are a compound as shown in formula I, a pharmaceutically acceptable salt or solvate thereof, a composition containing the compound, and a pharmaceutical use of the compound for preparing a drug for treating a disease or disorder related to the mechanism of action of KRAS G12C mutant protein. The five-heterocycle compound in the application has the activity of inhibiting the proliferation of Ba / F3 KRAS-G12C cells, NCI-H358 cells and MIA PaCa-2 cells expressing KRAS G12C mutant protein, and has a good inhibitory effect on the growth of a subcutaneous transplanted tumor of a NCI-H358 nude mouse.

Provided herein are compounds, or salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers thereof, as well as pharmaceutical compositions comprising the same. Also provided herein are methods of using the same in modulating (e g., inhibiting) KRAS (e.g., KRAS having a G12D mutation) and treating diseases or disorders such as cancers in subjects in need thereof.

Provided herein are compounds of Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), (II-b2), (II-3), (II-a3), (II-4), (II-a4), (II-5), (II-a5), (II-6), (II-a6), (II-7), (II-a7), (II-7), or (II-a8)), Formula (III) (e.g., Formula (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), or (III-8)), Formula (IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), (IV-b2), (IV-a3), (IV-b3), (IV-a4), (IV-b4), (IV-a5), (IV-b5), (IV-a6), (IV-b6), (IV-a7), (IV-b7), (IV-a8), or (IV-b8)), Formula (V) (e.g., Formula (V-a) or (V-b), (V-a1), (V-c), (V-d), (V-b1), (V-a2), (V-b2), (V-a3), or (V-b3)), Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))), or Formula (A) (e.g., Formula (I-a1)), or pharmaceutically acceptable salts thereof, that inhibit a KRas protein (e.g., a dysregulated KRas protein (e.g., a mutated or amplified KRas protein)). This disclosure also provides compositions containing the compounds as provided herein, or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

Provided herein are combinations comprising a KRAS inhibitor and a SPH2 inhibitor and methods of treating cancer.

Pharmaceutical compositions and therapeutic methods are provided comprising a single-domain antibody consisting of SEQ ID NO:1 and a pharmaceutically acceptable carrier. The antibody inhibits KRAS GTPase activity and inhibits phosphorylation of STAT3. In certain embodiments, inhibition of KRAS results in decreased phosphorylation of ERK1 / 2. The antibody reduces tumor cell surface PD-L1 expression and reduces VEGF production. The antibody crosses the blood-brain barrier following systemic administration and may exhibit sustained biological activity in vivo. Methods are provided for treating KRAS-mutant cancers, including pancreatic cancer and triple negative breast cancer, and for enhancing anti-tumor immunity through reduction of PD-L1 expression.

The application discloses an inhibitor for inhibiting KRAS phase separation to play an anti-tumor role and application, and relates to the fields of tumor molecular biology and targeted therapy.The application aims at solving the problems of limited effect, strong drug resistance and limited application range of KRAS tumor treatment methods, and the inhibitor is a statin.The KRAS protein can form a liquid condensate in cells, and the application discloses the mechanism of the KRAS protein in promoting KRAS protein processing, transportation and downstream signal activation, and further provides a technical scheme for inhibiting tumor growth and enhancing the therapeutic effect of a KRAS inhibitor by inhibiting the formation of KRAS condensates, so as to provide a new target and intervention approach for tumor treatment.

Provided herein are compounds of Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), (II-b2), (II-3), (II-a3), (II-4), (II-a4), (II-5), (II-a5), (II-6), (II-a6), (II-7), (II-a7), (II-7), or (II-a8)), Formula (III) (e.g., Formula (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), or (III-8)), Formula (IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), (IV-b2), (IV-a3), (IV-b3), (IV-a4), (IV-b4), (IV-a5), (IV-b5), (IV-a6), (IV-b6), (IV-a7), (IV-b7), (IV-a8), or (IV-b8)), Formula (V) (e.g., Formula (V-a) or (V-b), (V-a1), (V-c), (V-d), (V-b1), (V-a2), (V-b2), (V-a3), or (V-b3)), Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))), or Formula (A) (e.g., Formula (I-a1)), or pharmaceutically acceptable salts thereof, that inhibit a KRas protein (e.g., a dysregulated KRas protein (e.g., a mutated or amplified KRas protein)). This disclosure also provides compositions containing the compounds as provided herein, or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

The present invention discloses a pentaperture heterocyclic compound, an intermediate thereof, and a preparation method thereof. The present invention provides a pentaperture heterocyclic compound represented by Formula X, an intermediate thereof, and a preparation method thereof. The preparation method comprises the following steps: reacting a compound represented by Formula IX with citric acid in a solvent to form a salt to obtain a compound represented by Formula X. The compound represented by Formula IX and the compound represented by Formula X are KRAS G12C inhibitors that can be used to prevent and / or treat diseases mediated by KRAS G12C mutations. The preparation method provided by the present invention can achieve 2kg-scale production of the pentaperture heterocyclic compound, demonstrating feasibility for industrial production.

The invention relates to cancer biology, more specifically to the treatment of KRAS mutant cancers. A potent cancer therapy is provided by the combination of a farnesyl transferase inhibitor compound and a KRAS inhibitor compound.