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idh2 mutant inhibitors and uses thereof

A mutant and inhibitor technology, applied in the field of medicine, can solve problems such as cell metabolism disorders

Active Publication Date: 2019-09-10
JIANGSU PROVINCE INST OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Another view is that the structure of 2-HG is similar to that of α-KG, and it can competitively inhibit the targets of α-KG, such as histone demethylase, TET1 / 2 hydroxymethyl The methylation of DNA and histone directly affects the expression and differentiation of mRNA, leading to the disorder of cell metabolism

Method used

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  • idh2 mutant inhibitors and uses thereof
  • idh2 mutant inhibitors and uses thereof
  • idh2 mutant inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1: Compounds against IDH 2 Determination of inhibitory activity of / R140Q

[0071] IDH 2 The / R140Q mutant can catalyze the conversion of α-KG to 2-HG while simultaneously oxidizing NADPH to NADP+ . Therefore, the inhibitory activity of a compound against the IDH2 / R140Q mutant can be determined by measuring the depletion value of NADPH.

[0072] The detailed method is: add a reaction solution containing 25mM Tris (pH7.4), 150mM NaCl, 10mM MgCl2, 0.03%BSA to a 96-well plate, add 100ng / mL IDH 2 / R140Q and different concentrations of compounds were incubated at 30°C for 1 hour, and then 1mM α-KG and 10μM NADPH were added, the total system was 200μL, and the change in the absorbance of NADPH within 16 hours was continuously detected using a Thermo microplate reader at 30°C and 340nM wavelength. The final concentration gradient of the compound was set to (10000, 5000, 1000, 500, 100, 50, 10, 5, 1, 0.5, 0.1, 0.01) nM, and the inhibitory activity IC of the compound ...

Embodiment 2

[0073] Example 2: Compounds against IDH 2 Inhibitory activity assay of / R172K

[0074] The IDH2 / R172K mutant can catalyze the conversion of α-KG to 2-HG while simultaneously oxidizing NADPH to NADP + . Therefore, the inhibitory activity of the compound against IDH2 / R172K mutant can be determined by measuring the consumption value of NADPH.

[0075] Refer to Example 1 for the detailed measurement method.

Embodiment 3

[0076] Example 3: Compound versus wild-type IDH 2 Inhibitory activity assay of

[0077] Wild-type IDH2 in NADP + Under the auxiliary action, isocitrate ICT is catalyzed to α-KG, accompanied by the generation of NADPH. Therefore, the inhibitory activity of a compound against IDH2 can be determined by detecting the increase in NADPH.

[0078] The detailed method is as follows: add a reaction solution containing 50mM Tris (pH7.4), 5mM MgCl2, 0.03% BSA to a 96-well plate, add 100ng / mL IDH2 and compounds of different concentrations, incubate at 30°C for 1 hour, and then add 200μM ICT and 200 μM NADP + , the total system was 200 μL, and the absorbance value change of NADPH was continuously detected within 16 hours using a Thermo microplate reader at 30°C and 340nM wavelength. The final concentration gradient of the compound was set to (10000, 5000, 1000, 500, 100, 50, 10, 5, 1, 0.5, 0.1, 0.01) nM, and the inhibitory activity IC of the compound on IDH2 after 16 hours was calculat...

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Abstract

The invention relates to a compound of formula I shown in the description and its pharmaceutically salts, solvents and hydrates, as well as a pharmaceutical composition comprising the compound of formula I and application thereof as an IDH (isocitrate dehydrogenase 2) mutant inhibitor in the preparation of drugs for treating IDH mutation related diseases.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to an IDH mutant inhibitor and its use in preparing a medicine. Background technique [0002] One of the important features of cancer is the alteration of cell intrinsic metabolism, and the tricarboxylic acid cycle is an important way to affect metabolism. It has been found that the mutations of three enzymes in the tricarboxylic acid cycle are closely related to cancer, which are succinate dehydrogenase, fumarate hydratase and isocitrate dehydrogenase (IDH) discovered in recent years. The IDHs expressed in human cells are divided into three categories: IDH1 in the cytoplasm and IDH2 and IDH3 in the mitochondria, and cancer-related mutations mainly occur in IDH1 and IDH2. Acute myeloid leukemia (AML) is a malignant tumor disease characterized by abnormal proliferation of myeloid leukocytes. . Cancer genomics studies have found that about 13% of AML patients carry IDH2 mutated ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/135C07D307/52C07C319/20C07C323/44C07C315/04C07C317/42C07C273/18C07C275/40C07C275/42C07D317/66C07D213/71C07D213/75C07D409/12C07D335/02C07D309/04C07D295/155C07D209/08C07D333/24C07D333/32C07D333/20C07D307/14C07D239/42C07D307/16A61K31/402A61K31/4025A61K31/381A61K31/505A61K31/341A61K31/5375A61K31/277A61K31/404A61K31/4155A61K31/495A61K31/36A61K31/17A61K31/351A61K31/382A61K31/44A61K31/4436A61P35/00A61P35/02
Inventor 曹鹏陈姣杨杰
Owner JIANGSU PROVINCE INST OF TRADITIONAL CHINESE MEDICINE
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