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Dual inhibitors of AR and BET and use thereof

A technology of use and solvate, applied in the field of polycyclic compound and its double inhibitor of AR and BET

Pending Publication Date: 2020-04-07
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have shown that the gene transcription of BET-resistant CRPC cells does not depend on BRD protein, but is more sensitive to the blockade of AR

Method used

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  • Dual inhibitors of AR and BET and use thereof
  • Dual inhibitors of AR and BET and use thereof
  • Dual inhibitors of AR and BET and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Embodiment 1, the synthesis of compound among the present invention

[0076] The structure of each compound of the present invention in table 1

[0077]

[0078]

[0079]

[0080] (1) Synthesis of compound 001-036:

[0081] The preparation method of compound 001-036 is the same as the compound SKLB-C4558, SKLB-C4570, SKLB-C4561, SKLB-C4582, SKLB-C4567, SKLB-C4583, SKLB-C4579, SKLB-C4590, SKLB-C4596, SKLB-C4604 in CN107814785A , SKLB-C4613, SKLB-C4612, SKLB-C4614, SKLB-C4615, SKLB-C2602, SKLB-C4573, SKLB-C4578, SKLB-C4577, SKLB-C4574, SKLB-C4575, SKLB-C4576, SKLB-C4608, SKLB -C4609, SKLB-C4569, SKLB-C4572, SKLB-C2603, SKLB-C2601, SKLB-C4568, SKLB-C2604, SKLB-C4599, SKLB-C4602, SKLB-C4601, SKLB-C4565, SKLB-C4562, SKLB-C4563 , The preparation method of SKLB-C4560.

[0082] (2) Synthesis of Compound 037:

[0083] a. Deuterated ethanol-d6 (500mg, 10.8mmol) was dissolved in THF (2.7ml) and cooled to 0°C, NaOH (1.3g, 2.4ml) was dissolved in water and added after p...

Embodiment 7

[0176] Example 7 Androgen Receptor Binding Affinity Experiment

[0177] 1. Materials and instruments

[0178]LNCaP cell lysate, 3H-R1881 (PerkinElmer, Cat: NET590250UC, Lot: 2133648), glycerol (Sigma, Cat: G9012, Lot: BCBG6624V), 0.5M EDTA (Invitrogen-15575-038), DTT (Sigma, Cat: 43815, Lot: BCBD7009V), dextran (Sigma, Cat: D1662, Lot: SLBK5258V), activated carbon (Sigma, Cat: 05105, Lot: BCBF9839V), Tris base (Sigma, Cat: T1503-1KG), Protease inhibitor (PerkinElmer, Cat: 6013329, Lot: 77-16371), Scint-tube, 6ml (PerkinElmer, Cat: 6000192), 96-well plate (Agilent, Cat# 5042-1385), TopSeal sealing film (Perkin Elmer , Cat#6050185), Tri-Carb liquid scintillation analyzer (PerkinElmer, 2910TR)

[0179] 2. Method

[0180] The compound to be tested (the compound prepared in Example 1 of the present invention; the positive control Enzalutamide) was diluted with DMSO four times in a four-fold gradient, with a total of 8 concentration points, and 1 μl of each concentration was tran...

Embodiment 8

[0186] Example 8 BET protein binding affinity experiment

[0187] 1. Materials and instruments

[0188] BRD4(1,2)(Cat.No.31044);BRD2(1,2)(Cat.No.31024);BRD3(1,2)(Cat.No.31035);

[0189] BRD9 (Cat.No.B1048); CREBBP (Cat.No.31873); EP300 (Cat.No.31801);

[0190] SMARCA2 (Biogenie); FALZ (Cat.No.31447); TAF1 (D2, Biogenie).(+)-JQ1 (BPS, Cat.No.27402); EnSpire instrument (PerkinElmer, USA).

[0191] 2. Method

[0192] The inhibitory effect of the compound (the compound prepared in Example 1 of the present invention; positive control enzalutamide) on bromodomain-containing proteins BRD4 and BRD9 was evaluated by homogeneous time-resolved fluorescence (HTRF) technique. The test compound was serially diluted to 10 concentrations, with (+)-JQ1 (BPS, Cat. No. 27402) as the reference compound (Ref), and the final concentration of DMSO was 0.1%. Transfer the compound or DMSO to a 384-well assay plate, then add 2x Protein and Peptide Mix and 2x Detection Mix sequentially. After incub...

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Abstract

The present invention provides a polycyclic compound represented by formula (I) and a use in dual inhibitors of AR and BET. Specifically, the present invention provides the use of a compound represented by formula (I) or optical isomers, solvates, pharmaceutically acceptable salts, prodrugs, tautomers, mesomers, racemates, enantiomers, diastereomers, mixture form, metabolites, metabolic precursorsor isotopic substitution form thereof in the preparation of dual inhibitors of AR and BET. Experimental results show that the compounds of the present invention can not only inhibit the transcriptionof PSA and FKBP5 downstream of AR, but also inhibit the transcriptional activity of AR-F876L mutants resistant to anthralin, and also downregulate the expression of BRD4 downstream protein c-Myc, andthe compounds have good binding affinity to AR and BET proteins. The experiment suggests that the compound of the present invention can inhibit the activity of AR and BET protein at the same time, and has a good application prospect in the preparation of medicine for preventing and / or treating diseases related to BET protein.

Description

technical field [0001] The present invention relates to polycyclic compound and its application in AR and BET dual inhibitors. Background technique [0002] 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 domains, namely DNA binding domain (DNA binding domain, DBD), ligand binding domain (ligand binding domain (LBD) and nitrogen-terminal binding domain (N-terminal domain, NTD), DBD and LBD are connected by a hinge region (Hinge). The LBD at the carbon-terminus of AR is the site where AR binds to the ligand, which determines the specificity of the b...

Claims

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Application Information

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IPC IPC(8): A61K31/4439A61K31/4709A61K31/277A61K31/341A61K31/47A61K31/4184A61K31/415A61K31/4155A61K31/42A61K31/422A61K31/4178A61K31/381A61K31/4406A61K31/4409A61K31/505A61K31/44A61K31/4725A61P35/00A61P29/00A61P37/00A61P31/04A61P31/12A61P9/00A61P9/04A61P9/10C07D261/08C07D413/12C07B59/00
CPCA61K31/4439A61K31/4709A61K31/277A61K31/341A61K31/47A61K31/4184A61K31/415A61K31/4155A61K31/42A61K31/422A61K31/4178A61K31/381A61K31/4406A61K31/4409A61K31/505A61K31/44A61K31/4725A61P35/00A61P29/00A61P37/00A61P31/04A61P31/12A61P9/00A61P9/04A61P9/10C07D261/08C07D413/12C07B59/002C07B2200/05C07B59/00C07D401/04A61K31/351
Inventor 余江陈元伟
Owner SICHUAN UNIV
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