Compound of CDK12 small-molecule inhibitor and application thereof

A technology for small molecule inhibitors and compounds, which can be applied to the active ingredients of heterocyclic compounds, medical preparations containing active ingredients, and drug combinations, etc. To achieve the effect of broad anti-cancer spectrum, good growth inhibition effect and good application prospect

Active Publication Date: 2021-06-18
中国医科大学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the differences of different tumors and the complexity of the tumor environment, the application of existing CDK12 inhibitors on the market is limited, and their types and quantities are still scarce, which cannot meet various clinical needs

Method used

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  • Compound of CDK12 small-molecule inhibitor and application thereof
  • Compound of CDK12 small-molecule inhibitor and application thereof
  • Compound of CDK12 small-molecule inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1 Screening and structure of CDK12 inhibitors.

[0077] CDK12 inhibitors with high affinity and binding stability to the target protein were obtained through multi-layer virtual screening by computer-aided drug design. Molecular simulation drug design software MOE was used to construct pharmacophore screening and molecular docking. From the 1,767,416 small molecular compounds with no known CDK12 inhibitory activity in the ChemDiv, Specs database, 12 advantageous structures were screened layer by layer for experimental verification, and the CDK12 inhibitor of the present invention was obtained.

[0078] 1. Construction of pharmacophore and preliminary screening of small molecule inhibitors of CDK12.

[0079] The CDK12 protein X-ray diffraction model was obtained through the RCSB PDB database, and the pharmacophore was established with the model's own ligand. Use the pharmacophore Query Editor in the MOE software to find and select the key parts of the interacti...

Embodiment 2

[0087] Example 2 Study on antitumor activity of CDK12 small molecule inhibitor compounds.

[0088] 1. Experimental materials.

[0089] 1.1 Cells and Reagents.

[0090] Human colorectal cancer and intestinal epithelial cell lines: HCT116, SW620, HT29, SW480, RKO, LoVo, NCM460, HIEC; human breast cancer and breast epithelial cell lines: MDA-MB-231, BT-549, SKBR3, MCF-7 , T47D, MCF-10A; human ovarian cancer and ovarian epithelial cell lines: SKOV3, A2780, Caov-3, OVCAR-3, HOSEpiC. DMEM medium, L-15 medium, 1640 medium, McCOY's5A medium, DMEM / F12 medium, MEM medium, trypsin, fetal bovine serum (FBS), dimethylsulfoxide (DMSO), MTT (thiazolium blue).

[0091] 2. Experimental methods and conclusions.

[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 superna...

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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 12 (CDK12) inhibitor and application of the compound to treatment of proliferative diseases such as cancers including rectal cancer, breast cancer, ovarian cancer and the like. The CDK12 small-molecule inhibitor is a compound with the following structural general formulas (I)-(XII), a stereoisomer of the compound, or a pharmaceutically acceptable salt, a solvate, a hydrate, a polymorphic substance, a co-crystal substance, a tautomer, an isotope labeled derivative and a prodrug of the compound. The small-molecule inhibitor provided by the invention is relatively wide in anticancer spectrum, has a good growth inhibition effect on various cancer cells such as rectal cancer, breast cancer and ovarian cancer, provides an effective medicine for preventing or treating proliferative diseases, especially cancers in the aspects of structure and action mechanism, and has a relatively good application prospect.

Description

technical field [0001] The invention belongs to the field of pharmacy and tumor diagnosis and treatment, and specifically relates to a class of compounds used as cyclin-dependent kinase 12 (CDK12) inhibitors and used for the treatment of proliferative diseases such as colorectal cancer, breast cancer, ovarian cancer and other tumors aspects of use, etc. Background technique [0002] Cells are the basic structural and functional units of organisms, and the cell cycle is the basic process that ensures the life activities of cells. The cell cycle refers to the whole process that cells go through from the completion of one division to the end of the next division, and is one of the most important life processes in cell life activities. The regulation of the cell cycle is accompanied by the participation of specific cell cycle proteins (cyclins). It is a highly ordered, interlocking, multi-stage, and multi-factor involved precise process, which is very important for the survival...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/12C07D487/04C07D239/69C07D403/12C07D277/82C07D413/12C07D277/56C07D405/14C07D261/14A61K31/4196A61K31/519A61K31/635A61K31/428A61K31/4184A61K31/4245A61K31/496A61K31/454A61K31/42A61P35/00
CPCC07D249/12C07D487/04C07D239/69C07D403/12C07D277/82C07D413/12C07D277/56C07D405/14C07D261/14A61P35/00
Inventor 吴慧哲李阔胡晓云陈秋晨徐东萍孙桐张世林富博识
Owner 中国医科大学
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