4 results about "Kras mutation" patented technology

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 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.

A compound targeting KRAS protein degradation agent and application thereof. The compound is a compound with a structure of F-L-M, or a tautomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof. F is a KRAS protein binding fragment, L is a connecting unit connecting 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 relates to the use of a pyrido[3,4-d]pyrimidin-8-one derivative in preventing, ameliorating or treating lung cancer. Specifically, the present invention is not limited to a specific KRAS mutation (G12C), and exhibited potent cell proliferation inhibitory activity at nM levels in a wide range of RAS / RAF-driven tumor cell lines, such as KRAS G12V, G12S, and Q61H mutations and an NRAS Q61K mutation. Therefore, the pan-RAF inhibitory mechanism of the present invention can effectively block various RAS / RAF downstream signaling pathways, thereby providing excellent anticancer efficacy against a wide range of KRAS / NRAS mutant cancers. In addition, the present invention demonstrated superior efficacy in overcoming complex acquired resistance mechanisms that arise after treatment with a KRAS G12C inhibitor (G12Ci), in the following two aspects. Specifically, the present invention exhibited significantly superior inhibitory efficacy than existing G12C inhibitors (G12Ci) in a KRAS G12C-Y96D model including a secondary mutation at a drug-binding site. In addition, the present invention exhibited superior or similar anticancer activity as compared to G12C inhibitors (G12Ci) in signal bypass models, such as CCDC6-RET fusion. These results indicate that the simultaneous inhibitory activity of DDRs by PHI-501 neutralizes acquired resistance by blocking bypass-activated signaling pathways, thereby overcoming acquired resistance to existing G12C inhibitor (G12Ci) therapeutic agents. In addition, the present invention demonstrated the simultaneous blockade of two pathways critical to the survival of KRAS-driven cancer cells, that is, the MAPK pathway and the PI3K / AKT bypass pathway, at the molecular level. Thus, the phosphorylation of p-ERK (a marker for MAPK activity), p-AKT (a marker for PI3K / AKT activity), and pDDR1 was significantly and simultaneously reduced in both in-vitro and in-vivo models, demonstrating that the dual mechanism of action functions effect