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Application of IMB-A6 serving as androgen receptor antagonist

A technology of androgen receptor and IMB-A6, which is applied in the field of new drug leads, can solve the problems of promoting the growth of prostate cancer cells and affecting the curative effect, and achieving the effect of contraceptive effect

Active Publication Date: 2017-06-30
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the problem of drug resistance developed during treatment seriously affects the efficacy of these drugs and even promotes the growth of prostate cancer cells

Method used

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  • Application of IMB-A6 serving as androgen receptor antagonist
  • Application of IMB-A6 serving as androgen receptor antagonist
  • Application of IMB-A6 serving as androgen receptor antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1I

[0033] Embodiment 1IMB-A6 can suppress the activity of wild-type androgen receptor

[0034] will be 1.4×10 5PC-3 cell suspension per mL was inoculated in a 24-well plate at 500 μL per well. When the cells grew to 80%, each well was co-transfected with 100ng PSA-luc, 20ngAR-WT and 1ng pCMV-Renilla plasmids. 6 hours after transfection, the medium was replaced with phenol red-free RPMI 1640 medium containing 10% charcoal-stripped FBS; after 24 hours of transfection, one group was treated with 1 nM DHT + corresponding concentration of IMB-A6 or Enzalu in each well Add 1 μL of amines to each well, and add 1 μL of DMSO or corresponding concentration of IMB-A6 or enzalutamide to each well of the other group, and continue to culture for 24 hours. Finally, suck off the medium, add 100 μL of 1×PLB to each well to lyse for 20 minutes, collect the cell lysate into a clean EP tube, centrifuge, take 20 μL of the supernatant into a clean white 96-well plate, and follow the instructions of ...

Embodiment 2I

[0036] Example 2IMB-A6 can inhibit the activity of endogenous androgen receptor

[0037] There may be overexpression of androgen receptor due to exogenous expression, and false positive results may be caused by the plasmid transfection process. Therefore, we performed an experiment that IMB-A6 inhibits the activity of endogenous androgen receptor. The specific experimental steps refer to Example 1, the difference is that: LNCaP cells are used for this experiment, co-transfection is 100ng PSA-luc and 1ng pCMV-Renilla plasmid per well, and other operations are the same. Three parallel groups were set up in the experiment, and the statistical analysis was carried out, among which *P , and use GraphPad Prism 5.0 for graphing (see figure 2 ) and statistical analysis.

[0038] IMB-A6 had a dose-dependent inhibitory effect on the transcriptional activity of the endogenous AR of LNCaP, and this inhibitory effect was more pronounced in LNCaP cells. Comparing the results of LNCaP, i...

Embodiment 3I

[0041] Example 3 IMB-A6 can inhibit the activity of the mutant androgen receptor

[0042] At present, some series of AR mutations have been discovered, including tryptophan (W) → leucine (L) or cysteine ​​(C) at position 741, threonine (T) → alanine at position 877 amino acid (A), 876 phenylalanine (F) → leucine (L). Among them, the W741C mutation is the main cause of bicalutamide resistance, and the T877A mutation is the main cause of hydroxyflutamide resistance. The specific experimental steps refer to Example 1, the difference is that AR-WT is replaced with AR-F876L or AR-T877A mutant plasmids during co-transfection, and other operations are the same. Three parallel groups were set up in the experiment, and statistical analysis was carried out, among which *P , and use GraphPad Prism 5.0 for graphing (see image 3 ) and statistical analysis.

[0043] The experimental results showed that IMB-A6 also had a good inhibitory effect on the transcriptional activity of F876L mut...

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Abstract

The invention relates to the field of medicine primers, and particularly discloses an application of IMB-A6 serving as an androgen receptor antagonist and an application of the IMB-A6 to preparation of androgen imbalance disease treating medicines and male contraception pills. By building a reliable androgen activity screening method, the inhibiting effect of a plurality of medicine primers on androgen receptor activity is tested to finally find that the IMB-A6 is a novel androgen receptor antagonist, and activity of wild and mutagenic androgen receptors can be inhibited. Further, activity of the prostate cancer resistance of the IMB-A6 is tested to find that the IMB-A6 has good activity for AR positive prostate cancer cells such as LNCaP and has no activity for AR negative prostate cancer cells, the expression activity of the androgen receptors can be inhibited, and the IMB-A6 is similar to positive medicines such as enzalutamide.

Description

technical field [0001] The invention relates to the field of new drug leads, in particular to the application of the small molecular compound IMB-A6 as an androgen receptor antagonist. Background technique [0002] Androgen, such as androsterone (Testosterone, T), dihydrotestosterone (Dihydrotestosterone, DHT) and adrenal androsterone, is an important class of steroidal sex hormones in the human body. , AR) combine to promote cell differentiation and tissue growth, and participate in many key physiological functions. A certain percentage of androgens are present in both men and women. In the prostate and skin, androsterone T is converted to DHT by 5α-reductase, and compared with T, the affinity of DHT for AR is 3-5 times higher. [0003] AR, a member of the nuclear receptor superfamily, is a ligand-activated transcription factor widely distributed in proliferating and non-proliferating tissues. AR protein has three structural domains: N terminal domain (N terminal domain,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/415A61K31/50A61P13/08A61P35/00A61P15/00A61P17/10A61P17/08A61P17/14A61P17/00A61P15/16A61P5/28
CPCA61K31/415
Inventor 周金明刘阳光何阳吴萌李晓宇岑山
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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