CN-117603225-B - Protein degradation targeting chimeric and preparation method thereof

Abstract

The invention provides a protein degradation targeting chimeric body and a preparation method thereof, wherein the targeting chimeric body comprises a target protein ligand, an E3 ligase ligand and a connector, one end of the connector is connected with the target protein ligand, the other end of the connector is connected with the E3 ligase ligand, and the ligase ligand has the structural formula: The preparation method of the protein degradation targeting chimeric adopts a novel E3 ligase ligand, can obtain the protein degradation targeting chimeric compound with high yield and high purity, can effectively degrade various proteins in cells, expands the variety of the protein degradation targeting chimeric, and has wide application prospect.

Inventors

• DONG CHENG
• SHI LEI
• CHEN DONGXING
• SUN JIYUE
• LI YANRAN

Assignees

• 天津医科大学

Dates

Publication Date

20260512

Application Date

20231130

Claims (1)

1. 1. A protein degradation targeting chimeric body is characterized in that the structural formula of the protein degradation targeting chimeric body is selected from one of the following structural formulas: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。

Description

Protein degradation targeting chimeric and preparation method thereof Technical Field The invention belongs to the technical field of medicines, and particularly relates to a protein degradation targeting chimeric and a preparation method thereof. Background Targeting Protein Degradation (TPD) is an emerging therapeutic approach that has been of interest because of its therapeutic potential to modulate proteins that are difficult to target by conventional small molecules. The protein degradation targeting chimeric body (PROTACs) utilizes a natural protein degradation system in cells, namely ubiquitin-proteasome system (UPS), to realize the targeting degradation of target Proteins (POIs). PROTACs is a heterobifunctional molecule consisting of three parts, a target protein ligand, an E3 ligase ligand, and a linking part connecting the two. In the cell, PROTACs molecules bind to the target protein at one end and to the E3 ligase at the other end to form a target protein-PROTACs-E3 ligase ternary complex to bring the target protein and the E3 ligase closer, and promote the E3 ligase to catalyze ubiquitin protein transfer to the target protein. The ubiquitinated target protein is then recognized and degraded by the proteasome, and the physiological functions carried by the target protein will disappear as the target protein dies. The physiological function of the target protein is regulated by degrading the target protein, and an unprecedented new way for researching and preparing biological medicine is opened up. All PROTACs molecules currently use only a few of this type of ligases, mainly VHL, CRBN, MDM, IAPs. The main reasons for this are the difficulty in developing new ligands that bind E3 ligase efficiently and the lack of compounds that can degrade efficiently. Disclosure of Invention In view of the above, the present invention aims to provide a protein degradation targeting chimeric body and a preparation method thereof, so as to provide a novel E3 ligase ligand as a part PROTACs to perform complete PROTACs chemical synthesis, and can effectively degrade a target protein. In order to achieve the above purpose, the technical scheme of the invention is realized as follows: The utility model provides a protein degradation target gomphosis body, includes target protein ligand, E3 ligase ligand and connector, the one end of connector links to each other with target protein ligand, and the other end links to each other with E3 ligase ligand, the structural formula of ligase ligand is: further, the structural formula of the connector is selected from one of the following structural formulas: Wherein n is any integer from 1 to 6, m is any integer from 2 to 5, and x is 1 or 2. Further, the structural formula of the target protein ligand is selected from one of the following structural formulas: further, the structural formula of the protein degradation targeting chimera is selected from one of the following structural formulas: The method for preparing the protein degradation targeting chimera, which comprises the following steps: Slowly dropwise adding (1S, 4S) -4-aminocyclohexane-1-carboxylic acid methyl ester hydrochloride and Et 3 N solution into chloroacetyl chloride solution, stirring overnight at room temperature, then washing with 0.1M HCl solution, naHCO 3 solution and brine in turn, drying the organic phase by anhydrous Na 2SO4, removing the solvent under vacuum to obtain oily residue, dissolving the residue in MeCN, then adding (1H-indol-2-yl) methylamine, naHCO 3 and KI, rectifying back for 12 hours, filtering, removing the solvent under vacuum, purifying the residue by column chromatography to obtain a first intermediate; Dissolving the first intermediate in MeOH and water, adding LiOH-H 2 O, stirring overnight at room temperature, adjusting pH to 7, and removing the solvent under vacuum to obtain a second intermediate; Dissolving the second intermediate in 1, 4-dioxane and water, adding Na 2CO3 and Fmoc-Osu, stirring overnight at room temperature, adjusting pH to 6-7, removing solvent in vacuo, diluting the residue with water, adjusting pH to 4, extracting with ethyl acetate, combining organic layers, drying over anhydrous Na 2SO4, filtering, removing solvent in vacuo, recrystallizing with EtOAc and petroleum ether to give the compound of formula: Compared with the prior art, the protein degradation targeting chimeric and the preparation method thereof have the following advantages: The preparation method of the protein degradation targeting chimeric adopts a novel E3 ligase ligand, can obtain the protein degradation targeting chimeric compound with high yield and high purity, can effectively degrade various proteins in cells, expands the variety of the protein degradation targeting chimeric, and has wide application prospect. Drawings The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification