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Aromatic amine protein degradation chimeric compound targeting AR and BET and application

A compound and solvate technology, applied in the field of drug synthesis, can solve problems such as adverse reactions and drug resistance of small molecule drugs

Active Publication Date: 2020-11-17
HINOVA PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Traditional small-molecule inhibitors inhibit the function of the target protein by binding to the target protein, but long-term use of small-molecule drugs will inevitably lead to drug resistance, and in order to achieve the desired effect, small-molecule compounds need to be in the cell Maintain a certain concentration, and small molecules with a higher concentration will cause adverse reactions due to off-targets. Therefore, finding small molecule compounds that can overcome these defects is of great significance in the development of new drugs

Method used

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  • Aromatic amine protein degradation chimeric compound targeting AR and BET and application
  • Aromatic amine protein degradation chimeric compound targeting AR and BET and application
  • Aromatic amine protein degradation chimeric compound targeting AR and BET and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0192] Embodiment The synthesis of compound 1~194 of the present invention:

[0193] 1: (2S,4R)-1-((S)-2-(2-((5-(4-(3-((3-chloro-4-cyanophenyl)ethyl)amino)-4 -methylphenyl)-3,5-dimethyl-1H-pyrazol-1-yl)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N -((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidinyl-2-carboxamide

[0194]

[0195] 2-((5-(4-(3-((3-chloro-4-cyanophenyl)(ethyl)amino)-4-methylphenyl)-3,5-dimethyl-1H -pyrazol-1-yl)pentyl)oxy)acetic acid (50mg, 0.1mmol), dissolved in 5mL DMF, added N,N-diisopropylethylamine (39mg, 0.3mmol), added HATU (42mg, 0.11mmol), add (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxyl-N-((S)-1-(4-( 4-methylthiazol-5-yl)phenyl)ethyl)-pyrrolidinyl-2-carboxamide (53mg, 0.11mmol), react at room temperature for 2h, wash with 10ml water, extract with 10mL ethyl acetate, and concentrate the organic layer under reduced pressure , separated and purified by thin layer chromatography to obtain 12 mg of white solid, which is the t...

experiment example 1

[0934] Experimental Example 1: Proliferation inhibitory activity of the compound of the present invention on prostate cancer cells

[0935] 1. Biological determination of the inhibitory effect on LNCap / AR cell proliferation

[0936] (1) Experimental materials and instruments:

[0937] LNCaP / AR cell line, 22RV1 cell line (provided by Sichuan Kangcheng Biotechnology Co., Ltd.)

[0938] Fetal bovine serum FBS (Gibco, Cat.No.10099-141)

[0939] 0.01M PBS (Biosharp, Cat. No. 162262)

[0940] RIPM1640 medium (Hyclone, Cat.No.308090.01)

[0941] Penicillin-Streptomycin (Hyclone, Cat.No.SV30010)

[0942] Cell counting kit-8 kit (Signalway Antibody, Cat.No.CP002)

[0943] Dimethylsulfoxide DMSO (Sigma, Cat.No.D5879)

[0944] Centrifuge Tube, 15ml (Excell Bio, Cat.No.CS015-0001)

[0945] Cell Culture Dish, (Excell Bio, Cat.No.CS016-0128)

[0946] Cell culture plate 96-well cell culture cluster (Corning, Cat.No.3599)

[0947] Microplate reader (Thermo Multiskan MK3 type)

[094...

experiment example 2

[0969] Experimental Example 2: Western Blot Determination of Down-regulation of Compounds on Androgen Receptor AR and BRD4 Protein Expression

[0970] 1. Experimental materials:

[0971] CWR22RV1 cells (Cell Bank of Chinese Academy of Sciences, TCHu100)

[0972] FBS (Gibco, Cat. No. 10099-141)

[0973] 0.01M PBS (Biosharp, Cat. No. 162262)

[0974] RIPM1640 (Hyclone, Cat. No. 308090.01)

[0975]Penicillin-Streptomycin (Hyclone, Cat. No. SV30010)

[0976] Dimethylsulfoxide DMSO (Sigma, Cat.No.D5879)

[0977] Centrifuge tube 15ml (Excell Bio, Cat.No.CS015-0001)

[0978] Cell culture plate (Excell Bio, Cat.No.CS016-0128)

[0979] 6-well cell culture cluster (Corning, Cat. No. 3516)

[0980] RIPA lysate buffer (Beyotime, Cat.No.P0013B)

[0981] Protein loading buffer (Beyotime, Cat.No.P0015L)

[0982] CA protein detection kit (Beyotime, Cat.No.P0012)

[0983] SDS-PAGE gel preparation kit (Chengdu Baihe Technology Co., Ltd., Cat.No.PG112)

[0984] Anti-β-tubulin mouse mA...

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Abstract

The invention relates to an aromatic amine protein degradation chimeric compound targeting AR and BET and an application thereof, and particularly provides a compound as shown in a formula I in the description. Experimental results show that the compound can degrade AR and BRD4 in a targeted manner and reduce protein expression of the AR and the BRD4 at the same time. The compound can inhibit proliferation of various prostate cancer cells, can inhibit proliferation of a prostate cancer cell line LNCaP / AR with multiple expression of an androgen receptor AR, and also shows a good inhibition effect on prostate cancer cell lines 22RV1 resistant to prostate cancer drugs (enzalutamide) on the market. The compound also shows good metabolic stability, and has good application prospects in preparation of androgen receptor and / or BET protein degradation targeting chimeras and drugs for treating androgen receptor and BET regulated related diseases.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a protein degradation chimera compound targeting AR and BET of aromatic amines and its application. Background technique [0002] In the context of a growing and aging global population, the incidence of prostate cancer continues to increase, and the main treatment for prostate cancer is androgen deprivation therapy. Androgen receptor (AR) belongs to the nuclear receptor family and is a ligand-dependent transcription factor. Abnormal regulation of AR signaling pathway plays an important role in the occurrence and development of prostate cancer. Studies have shown that castration-resistant prostate cancer (CRPC) still depends on the role of AR. The androgen receptor consists of 918 amino acids and has similar structure and function to other nuclear receptors. It consists of three important structural domains, namely DNA binding domain (DNA binding domain, DBD), ligand binding domain...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062C07D413/14C07D417/14A61P35/00A61P13/08A61P21/00A61K31/454A61K31/4545A61K38/05
CPCC07K5/06034C07D413/14C07D417/14A61P35/00A61P13/08A61P21/00A61K38/00Y02P20/55A61K47/545A61K47/55A61K47/54
Inventor 杜武吕海斌李海波秦德锟艾朝武李宇段京义涂志林张承智陈元伟李兴海
Owner HINOVA PHARM INC
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