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PARP7 small-molecule inhibitor compound and application thereof

A technology of small molecule inhibitors and compounds, applied in the direction of active ingredients of heterocyclic compounds, medical preparations containing active ingredients, drug combinations, etc., can solve the problems of no PARP7 inhibitors, etc., achieve good growth inhibition and good application prospects , Broad spectrum anti-cancer effect

Active Publication Date: 2021-06-11
中国医科大学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This shows that PARP7 inhibitors may be excellent tumor therapy drugs, but there are still no PARP7 inhibitors widely used clinically, and there are still many places to be elucidated about the function of PARP7

Method used

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  • PARP7 small-molecule inhibitor compound and application thereof
  • PARP7 small-molecule inhibitor compound and application thereof
  • PARP7 small-molecule inhibitor compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1 Screening and structure of PARP7 inhibitors.

[0073] 1. Construction of pharmacophore and preliminary screening of PARP7 small molecule inhibitors.

[0074] PARP7 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 that have no known reports of PARP7 inhibitory activity derived from the ChemDiv and Specs databases, 11 dominant structures were screened layer by layer for experimental verification, and the PARP7 inhibitor of the present invention was obtained.

[0075] The 3D structure of PARP7 protein was obtained by modeling in the SWISS-MODEL database, and molecular docking was carried out with the active site of PARP7 kinase in the MOE software, and the natural substrate NAD molecule of the prote...

Embodiment 2

[0083] Example 2 Study on antitumor activity of PARP7 small molecule inhibitor compounds.

[0084] 1. Experimental materials.

[0085] 1.1 Cells and Reagents.

[0086] 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).

[0087] 2. Experimental methods and conclusions.

[0088] 2.1 Cell culture.

[0089] 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 potential inhibitor of poly adenosine diphosphate ribose polymerase 7 (PARP7) and application of the potential inhibitor to treatment of colorectal cancer, breast cancer, ovarian cancer and other tumors. The PARP7 small-molecule inhibitor is a compound with the following structural general formulas (I)-(XI), 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 and has a good growth inhibition effect on various cancer cells such as rectal cancer, breast cancer and ovarian cancer. The invention 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 potential inhibitors of polyadenosine diphosphate-ribose polymerase 7 (PARP7) and its use in treating various tumors such as colorectal cancer, breast cancer, and ovarian cancer . Background technique [0002] DNA damage is a permanent change in the DNA nucleotide sequence that occurs during replication and leads to changes in genetic characteristics. If DNA damage or changes in genetic information cannot be corrected, it will affect the function or survival of cells. The repair of DNA damage is a highly ordered, interlocking, multi-stage, precise process involving multiple factors. PARP is a key player in DNA repair. The full name of PARP is poly-ADP-ribose polymerase, that is, poly-ADP-ribose polymerase, which is involved in a series of cellular processes including DNA repair and genome stability maintenance. The protein family c...

Claims

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Application Information

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IPC IPC(8): C07D403/06C07D333/38C07D239/36C07D309/36C07D491/147C07D217/26C07D491/052C07D519/00C07D251/52C07D413/14A61K31/4178A61K31/381A61K31/351A61K31/519A61K31/472A61K31/436A61K31/53A61K31/506A61K31/513A61P35/00
CPCC07D403/06C07D333/38C07D239/36C07D309/36C07D491/147C07D217/26C07D491/052C07D519/00C07D251/52C07D413/14A61P35/00
Inventor 吴慧哲胡晓云李阔陈秋晨徐东萍孙桐张明荣赵英棋
Owner 中国医科大学
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