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DCAF15-based protein degradation targeting chimeric body as well as preparation method and application thereof

A group and alkyl technology, applied in the field of bifunctional compounds, can solve problems such as large molecular weight, poor selectivity of PROTAC molecules, and high specific surface area

Inactive Publication Date: 2021-02-26
EAST CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, only PROTAC molecules based on two E3 ligases, VHL and CRBN, have been widely used, but the PROTAC molecules based on the structure of the CRBN ligand Thalidomide series have poor selectivity, and these PROTAC molecules can simultaneously degrade the natural substrate of CRBN, IKAF1. / IKZF3 (mostly considered an off-target effect)
The molecular weight of the VHL ligand is too large, the specific surface area is too high
This is not conducive to the druggability of PROTAC molecules

Method used

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  • DCAF15-based protein degradation targeting chimeric body as well as preparation method and application thereof
  • DCAF15-based protein degradation targeting chimeric body as well as preparation method and application thereof
  • DCAF15-based protein degradation targeting chimeric body as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0150] Embodiment one: the preparation of each compound

Embodiment 1-1

[0151] Example 1-1, (S)-N-(3-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f] [1,2,4]Triazolo[4,3-a][1,4]diazepine-6-yl)acetamido)propyl)-4-(N-(3-cyano-4 Synthesis of -methyl-1H-indol-7-yl)sulfamoyl)benzamide (DP001)

[0152]

[0153] Take 7-amino-4-methyl-1H-indole-3-carbonitrile (200mg, 1.17mmol), pyridine (232mg, 2.93mmol) dissolved in 5mL THF solution, stirred for 10min under ice bath, 4-(chlorosulfonyl ) Benzoic acid (388mg, 1.76mmol) was dissolved in 5mL THF solution and added to the reaction system. R.T. reacted overnight. After the reaction was complete, it was extracted with ethyl acetate, washed twice with water, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 4-(N-(3-cyano-4-methyl-1H-indol-7-yl)ammonia Sulfonyl)benzoic acid (304 mg, 73% yield).

[0154] Dissolve 4-(N-(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl)benzoic acid (25mg, 0.07mmol) in 2mL DMF, add N-tert-butoxy Carbonyl-1,3-propanediamine (14mg, 0.08mmol), D...

Embodiment 1-2

[0156] Example 1-2, (S)-N-(2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2 -f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamido)ethoxy)ethyl)-3-(N- Synthesis of (3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl)benzamide (DP002)

[0157]

[0158] Take 7-amino-4-methyl-1H-indole-3-carbonitrile (81mg, 0.48mmol), pyridine (94mg, 1.19mmol) dissolved in 3mL THF solution, stirred for 10min under ice bath, 3-(chlorosulfonyl ) Benzoic acid (157mg, 0.71mmol) was dissolved in 3mL THF solution, and added to the reaction solution. R.T. reacted overnight. After the reaction was complete, it was extracted with ethyl acetate, washed twice with water, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 3-(N-(3-cyano-4-methyl-1H-indol-7-yl)ammonia Sulfonyl)benzoic acid (126mg, yield 75%); 3-(N-(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl)benzoic acid (25mg, 0.07 mmol) was dissolved in 2 mL of DMF, [2-(2-aminoethoxy) ethyl] tert-butyl carbamate (14 mg, 0...

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Abstract

The invention relates to an E3 ligase DCAF15 small molecule ligand compound and a bifunctional compound containing the same. According to the description of the invention, the bifunctional compound isused as a degradation agent of target proteins based on a protein degradation targeting chimeric body (PROTAC) technology. The invention describes the bifunctional compound, one end of the bifunctional compound contains a ligand combined with E3 ligase DCAF15, the other end of the bifunctional compound contains a ligand combined with a target protein, and the target protein is placed near the E3ligase DCAF15 through proper connecting group connection to realize ubiquitination degradation of the target protein. The synthetizable compound has good pharmacological activity of degrading target protein in vitro and vivo, so that the synthetizable compound has a wide application prospect in the aspect of degrading various pathogenic proteins.

Description

technical field [0001] The present invention relates to a class of bifunctional compounds that were found to be able to ubiquitinate and degrade target proteins. In particular, the present invention relates to compounds comprising at one end a ligand that binds the E3 ubiquitin ligase DCAF15 (defined as group), and the other end contains a ligand that binds the target protein (definition group), through the appropriate The linker allows the target protein to be placed in the vicinity of the E3 ubiquitin ligase DCAF15, causing the target protein to be ubiquitinated and eventually degraded. Background technique [0002] As one of the post-translational modifications of proteins, ubiquitination plays a vital role in protein localization, metabolism, function regulation and degradation. Ubiquitin is one of the key factors to maintain protein homeostasis in cells. The targeted degradation of proteins based on the ubiquitin-proteasome system is currently a hot direction in t...

Claims

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Application Information

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IPC IPC(8): C07D495/14C07D209/42C07D401/12A61K31/5517A61K31/4439A61P35/00
CPCC07D495/14C07D209/42C07D401/12A61P35/00
Inventor 陈益华米大钊李亮裴海翔李大力刘明耀
Owner EAST CHINA NORMAL UNIVERSITY
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