Dual-target PROTAC construction method and application thereof

A dual-target, target protein technology, applied in chemical instruments and methods, medical preparations containing active ingredients, pharmaceutical formulations, etc., can solve the accumulation of natural substrate proteins, ubiquitination and degradation of natural substrate proteins. problem, to achieve the effect of renal anemia and renal protection

Inactive Publication Date: 2019-05-17
THE FIRST AFFILIATED HOSPITAL OF SUN YAT SEN UNIV
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AI Technical Summary

Problems solved by technology

[0006] Using small molecules as the E3 recognition ligands of PROTACs greatly improves the membrane permeability of PROTACs, but due to the high affinity between small molecules and E3, it may Causes the ubiquitination and degradation of E3 natural substrate protein to be hindered, so that the natural substrate protein of E3 accumulates and produces off-target effects

Method used

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  • Dual-target PROTAC construction method and application thereof
  • Dual-target PROTAC construction method and application thereof
  • Dual-target PROTAC construction method and application thereof

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Embodiment 1

[0040] 1. Combining computer virtual screening and SPR technology to find small molecules that specifically bind to the target protein Smad3

[0041] Based on our previous research results, we have successfully screened out a small molecule that can specifically bind to the target protein Smad3, the structural formula is shown in formula (I), and confirmed that the PROTAC constructed with this small molecule as the target protein ligand can target Ubiquitination degrades the Smad3 protein, so we still use this small molecule as the target protein ligand for the construction of a new dual-target PROTAC.

[0042]

[0043] 2. Determination of the linking site between the small molecule ligand of the target protein and the Linker

[0044] Molecular docking of the above small molecules screened in the previous stage with Smad3, see Figure 4 . It can be seen that the amine group (-NH3+) on the upper part of the small molecule No. 8 forms a hydrogen bond with the carboxyl group a...

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Abstract

The invention provides a dual-target PROTAC construction method and a specific dual-target PROTAC construction method and application, and provides the concept of dual-target PROTAC design for the first time, that is, PROTAC degrades the target protein I by selecting a specific E3 while the degradation of the E3 natural substrate protein is blocked due to the competition of PROTAC to E3, that is,a target protein II rises. By adopting the method, Smad3 can not only be degraded by targeting ubiquitination for the first time, but also the HIF-alpha protein level of dual-target PROTAC can be upregulated meanwhile, and the PROTAC theoretically has multiple anti-fibrosis and renal protective effects on renal anemia.

Description

technical field [0001] The invention relates to a method for constructing PROTAC with dual targets and its application. Background technique [0002] With the change of people's lifestyle, the incidence of chronic kidney disease (CKD) such as diabetes and hypertension is increasing day by day, and CKD has become a worldwide public health problem. At present, there are very limited effective means of clinical treatment for CKD patients. A considerable number of CKD patients eventually develop end-stage renal disease (ESRD), requiring expensive renal replacement therapy, which brings a great burden to families and society. How to prevent CKD from progressing to ESRD is a priority research topic in my country's "National Medical Development Strategy". [0003] Although glomerulosclerosis and renal interstitial fibrosis are clearly the pathological basis of CKD progression, and the application of Smad3 inhibitors, miR-21 antagonists and other methods have successfully blocked t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062A61K38/05A61P13/12A61P7/06
CPCC07K5/06034C07K19/00A61P13/12A61P7/06A61K38/00
Inventor 王欣杨嘉怡范瑾瑾冯少珍骆宁
Owner THE FIRST AFFILIATED HOSPITAL OF SUN YAT SEN UNIV
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