Compound of CDK7 small-molecule inhibitor, and application thereof

A technology of small molecule inhibitors and compounds, applied in the fields of pharmacy and tumor diagnosis and treatment

Active Publication Date: 2020-12-01
中国医科大学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still no small molecule inhibitors of CDK7 used in clinical practice. Theref

Method used

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  • Compound of CDK7 small-molecule inhibitor, and application thereof
  • Compound of CDK7 small-molecule inhibitor, and application thereof
  • Compound of CDK7 small-molecule inhibitor, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Example 1 Screening and structural identification of CDK7 inhibitors.

[0079] The inventors applied the method of computer-aided drug design to obtain CDK7 inhibitors with high affinity and binding stability with the target protein through multi-layer virtual screening. Molecular simulation drug design software MOE was used to construct pharmacophore screening and molecular docking. The CDK7 inhibitor of the present invention was obtained from the 150w small molecular compounds with no known reports of CDK7 inhibitory activity in the ChemDiv, Specs database, which were screened layer by layer to 10 advantageous structures for experimental verification.

[0080] 1. Construction of pharmacophore and preliminary screening of small molecule inhibitors of CDK7.

[0081] The reported 184 CDK7 inhibitors were obtained as positive compounds through the BindingDB database, and 14 compounds with Ki A volume sphere covering all atoms was constructed, and finally a pharmacophore ...

Embodiment 2

[0087] Example 2 Antitumor activity of potential small molecule inhibitors of CDK7.

[0088] 1. Experimental materials.

[0089] 1) Cells and reagents.

[0090] Human breast cancer cell lines SKBR3, MCF-7, T47D; human colorectal cancer cell lines HCT116, SW620, HT29, SW480, RKO; human ovarian cancer cell lines SKOV3; human glioma cell lines U87, U251; human liver cancer cells Lines HuH-7, BEL-7402; human lung cancer cell lines A549, H460. DMEM medium, L-15 medium, 1640 medium, McCOY's5A medium, DMEM / F12 medium, trypsin, fetal bovine serum (FBS), dimethylsulfoxide (DMSO), MTT (thiazolium blue) .

[0091] 2. Experimental method.

[0092] 2.1 Cell culture.

[0093] Take the cells out of the -80°C deep freezer or liquid nitrogen storage tank, quickly place them in a 37°C water bath to thaw, then transfer the cells to a 2mL centrifuge tube, centrifuge at 1200rmp for 5min, discard the containing Liquid supernatant, add 1mL of the corresponding medium containing 10% fetal bovin...

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Abstract

The invention belongs to the field of pharmacy and tumor diagnosis and treatment, and particularly relates to a compound serving as a cyclin-dependent kinase 7 (CDK7) inhibitor, and application of thecompound in treatment of proliferative diseases such as cancers including breast cancer, ovarian cancer, colon cancer, liver cancer, lung cancer and glioma. The CDK7 small-molecule inhibitor is a compound with the structural general formulas (I)-(X), or a stereoisomer, a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, isotope labeled derivative or prodrug thereof. The small-molecule inhibitor provided by the invention is wide in anticancer spectrum; the compound has a good growth inhibition effect on various cancer cells such as liver cancer, stomach cancer, colorectal cancer, ovarian cancer, glioma, lung cancer and the like, provides an effective drug for preventing or treating proliferative diseases, especially cancers, in the aspects of structure and action mechanism, and has a good application prospect.

Description

technical field [0001] The invention belongs to the field of pharmacy and tumor diagnosis and treatment, and in particular relates to a class of compounds used as cyclin-dependent kinase 7 (CDK7) inhibitors and used for the treatment of proliferative diseases such as cancers including breast cancer, ovarian cancer, colon cancer, liver cancer, Uses for lung cancer and glioma, etc. Background technique [0002] Malignant tumors are one of the major diseases that threaten human health. It is estimated that by 2020, there will be 15 million new cancer patients in the world, and the number of cancer deaths is also rising rapidly around the world, which may increase to 13.2 million. The prevention and treatment of tumors has become an important research topic in the medical circles of various countries. [0003] Cell cycle is one of the most important processes in cell life activities, and is the core of cell life operation. The regulation of the cell cycle is a highly ordered,...

Claims

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Application Information

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IPC IPC(8): C07D309/08C07D249/12C07D403/04C07D405/04C07D271/06C07D495/04C07D417/04C07D405/12C07C311/19A61K31/351A61K31/4196A61K31/433A61K31/422A61K31/4245A61K31/519A61K31/427A61K31/407A61K31/496A61K31/18A61P35/00
CPCC07D309/08C07D249/12C07D403/04C07D405/04C07D271/06C07D495/04C07D417/04C07D405/12C07C311/19A61P35/00
Inventor 吴慧哲吴雨桐徐东萍孙桐胡晓云富博识陈秋晨
Owner 中国医科大学
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