IDH2 mutant type small-molecule inhibitor and application thereof

A small molecule inhibitor, IDH2 technology, applied in the direction of medical preparations containing active ingredients, organic active ingredients, drug combinations, etc., can solve the problems of long medication time and high price, and achieve good effect, strong pertinence, and ease high rate effect

Active Publication Date: 2018-06-08
中国医科大学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The price of this drug is very expensive at this stage, and the medication time is long

Method used

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  • IDH2 mutant type small-molecule inhibitor and application thereof
  • IDH2 mutant type small-molecule inhibitor and application thereof
  • IDH2 mutant type small-molecule inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment Construction

[0025] 1. Design of small molecule inhibitors.

[0026] The sequence of wild-type IDH2 is as follows, (SEQ ID No.1):

[0027]

[0028] IDH2 mutant (IDH2R140Q) is different from wild-type IDH2 in that the 140-position R is mutated to Q. Studies have confirmed that acute myeloid leukemia, glioma and osteosarcoma are related to this mutation. The sequence of IDH2R140Q is as follows, (SEQ ID No.2):

[0029]

[0030] Based on the crystal structure of the human IDH2Mutation protein, the applicant docked nearly 1 million small molecules from the Topscience small molecule drug into the above protein by docking proteins and compounds, and screened out those containing at least 3 hydrogen bonds. At least one hydrophobic center, the smaller the docking score, the better. Try to choose a compound with a score above -10, and select this compound after sorting. Figure 5 The MOE software is used to predict the binding model of the small molecule inhibitor to the IDH2 mutant protein,...

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PUM

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Abstract

The invention belongs to the field of molecular therapy and particularly relates to an IDH2 (isocitrate dehydrogenase 2) mutant type small-molecule inhibitor and an application thereof in the inhibition and killing of tumor cells. The IDH2 mutant type small-molecule inhibitor can be used for treating IDH2 mutant type acute myelogenous leukemia, glioma and osteosarcoma and has strong pertinence, the normal physiological activities are not influenced, immature leukocyte can be promoted to be mature, the harm caused to the body of a patient is relatively small, the clinical use effect is relatively good, and the remission rate is relatively high.

Description

technical field [0001] The invention belongs to the field of molecular therapy, and in particular relates to a mutant small molecule inhibitor of isocitrate dehydrogenase 2 (IDH2) and its application in inhibiting and killing tumor cells. Background technique [0002] Malignant tumor is one of the major diseases that threaten human life. Since 2010, malignant tumors have surpassed cardiovascular diseases and become the number one cause of death. The occurrence and development of tumors are closely related to gene mutations. Mutations in normal genes can lead to cancer. At this stage, there are also many marketed drugs targeting small molecule inhibitors at the protein level, for example, inhibitors targeting EGFR site gefitinib, erlotinib and icotinib, which have achieved great clinical success. [0003] Isocitrate dehydrogenase (IDH) is involved in the aerobic metabolism of the tricarboxylic acid cycle in cells, converting isocitrate into ketoglutarate. IDH is closely r...

Claims

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Application Information

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IPC IPC(8): C07D513/04A61K31/519A61P35/00A61P35/02
CPCC07D513/04
Inventor 赵琳魏敏杰张继红宋昕樾
Owner 中国医科大学
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