CN111494384B - Application of IMB-ZNU-G8 in treating androgen receptor activity related diseases - Google Patents
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Abstract
The invention relates to the field of drug development, in particular to application of IMB-ZNU-G8 in treating androgen receptor activity-related diseases. Through early screening and later mechanism research, the invention discovers that IMB-ZNU-G8 can be used as an AR and GR dual-target antagonist, and provides a series of applications according to the AR and GR dual-target antagonist, wherein particularly, the invention proves that the invention tests the anti-prostate cancer activity of IMB-ZNU-G8, and discovers that IMB-ZNU-G8 has better inhibitory activity on GR high-expression Enzalutamide-resistant prostate cancer cells such as 22Rv1, and the invention can be popularized and applied in related treatment and medicament preparation.
Description
Technical Field
The invention relates to the field of drug development, in particular to application of IMB-ZNU-G8 in treating androgen receptor activity-related diseases.
Background
The Androgen Receptor (AR) is a member of the nuclear receptor superfamily, a ligand-activated transcription factor, widely distributed in both proliferative and non-proliferative tissues. The AR protein has three domains: n-terminal domain (NTD), DNA Binding Domain (DBD), and Ligand Binding Domain (LBD). Wherein, the LBD binding domain has a Hormone Binding Pocket (HBP), when Androgen is bound to HBP, Helix12 of AR undergoes conformational change to become an Agonistic conformation, forms a dimerization structure, enters into cell nucleus to be combined with Androgen Response Element (ARE) positioned in a target gene promoter region, and plays a role in activating or inhibiting target gene expression, thereby regulating the physiological function of target tissues. An androgen receptor antagonist, i.e., a molecule that is capable of binding to HBP of AR and blocking Helix-12 in an active position.
Glucocorticoid Receptor (GR) is a member of the nuclear receptor superfamily, belonging to ligand-activated transcription factors, and GR is widely present in various tissue cells of the body, and almost all cells are its target cells. The GR protein has high sequence and structure similarity with AR, and also has three structural domains of NTD, DBD and LBD. When glucocorticoids bind to GR, GR in its activated state forms dimers and transfers into the nucleus where it binds to Glucocorticoid Responsive Element (GRE), acting either as an activator or as a repressor of transcription. Glucocorticoid receptor antagonists are those that bind to GR, thereby inhibiting GR function.
Prostate cancer is a common cancer type in the male population, and in recent years, the incidence rate of prostate cancer in China is on a rapid increase trend. Endocrine therapy is mainly used for hormone-sensitive advanced prostate cancer patients, and the endocrine therapy method comprises castration (surgical castration or drug castration) and antiandrogen therapy. Almost all patients eventually develop hormone-independent prostate cancer or castration-resistant prostate cancer (CRPC).
The androgen receptor antagonist is the AR targeted therapeutic drug for antiandrogen therapy which is the most widely clinically applied at present. Such drugs can be divided into steroids and non-steroids. Steroidal antiandrogen drugs are represented by cyproterone acetate (CPA), and include megestrol acetate and medroxyprogesterone acetate. Examples of Nonsteroidal antiandrogens (NSAA) include Hydroxyflutamide (HF), Bicalutamide (BICA), and the second generation enzalutamide (ENZALUTAIMIDE), abiraterone (ABIRATERANE), ARN-509(Apalutamide), and ODM-201 (Darolutamide). However, the drug resistance problem generated in treatment seriously affects the curative effect of the drugs, and common drug resistance mechanisms of AR targeted treatment drugs comprise AR point mutation, AR amplification, AR variable spliceosome generation, GR expression up-regulation and the like.
Because the AR and the GR belong to the same nuclear receptor superfamily and have high similarity in structure, researches show that when the AR function of a prostate cancer patient receiving enzalutamide treatment is inhibited, the expression of the GR is obviously up-regulated, and about 50 percent of AR regulatory genes are promoted to be re-expressed, so that the drug resistance of the body to the enzalutamide is caused. In vitro studies have shown that GR agonists, such as dexamethasone, can cause resistance of prostate cancer cells to enzalutamide, while the GR antagonist mifepristone can reverse this resistance. Therefore, the development of dual-target antagonists that can simultaneously target AR and GR is of great interest in the treatment of drug-resistant prostate cancer.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention tests the inhibitory action of a plurality of drug leads on the activity of an androgen receptor and a glucocorticoid receptor by constructing a reliable screening method of the androgen receptor and glucocorticoid receptor antagonist, discovers a novel dual-target antagonist of the androgen receptor and the glucocorticoid receptor, namely IMB-ZNU-G8, and provides the following technical scheme based on the discovery:
in a first aspect, the present invention provides the use of IMB-ZNU-G8 as an androgen receptor antagonist and/or glucocorticoid receptor antagonist.
The IMB-ZNU-G8 is a known compound, is a component compound in a sample library of a national New drug (microorganism) screening center of the institute of medical and Biotechnology of Chinese academy of sciences, and can be purchased from a commercial product, the number of the ZINC database is ZINC32842923, and the structure of the IMB-ZNU-G8 is shown as follows:
the IMB-ZNU-G8 can be combined with a hormone binding pocket of the androgen receptor to antagonize the function of AR, thereby inhibiting the transcription activity of exogenous and endogenous AR and inhibiting the expression of target genes downstream of AR. The inventor finds that IMB-ZNU-G8 can inhibit the function of a wild type AR exogenously transferred by an AR negative PC-3 cell, and the wild type AR can be activated by androgen DHT, so that the proliferation and differentiation of prostate cancer cells are promoted. IMB-ZNU-G8 can treat prostate cancer by antagonizing wild-type AR.
In addition, the inventor finds that IMB-ZNU-G8 has good inhibition effect on T877A mutant AR through experiments. Thus, IMB-ZNU-G8 is preferably used as a T877A mutant androgen receptor antagonist.
In a second aspect, the present invention provides the use of IMB-ZNU-G8 in the manufacture of a medicament for the prevention, alleviation, treatment or regression of disorders associated with androgen receptor and/or glucocorticoid receptor activity.
Preferably, the disease is a disease caused by androgen dysregulation; more preferably, the disease is a disease caused by androgen hyperactivity.
The invention discovers in the research that IMB-ZNU-G8 can be used as androgen receptor antagonist and/or glucocorticoid receptor antagonist, and has further curative effect on the following diseases, wherein the diseases are selected from prostatic cancer, benign prostatic hyperplasia, acne, hirsutism, hyperseborrhea (such as seborrheic dermatitis) and alopecia.
The prostate cancer mentioned in the foregoing of the present invention may be hormone sensitive prostate cancer or hormone tolerant prostate cancer. The pathogenic mechanism of the prostate cancer is mainly the abnormal activation of androgen receptor signaling pathway. The signaling pathway process is that androgen is combined with AR, AR is activated and dimerizes to be phosphorylated, enters cell nucleus, is combined with specific DNA (AR Response Element, ARE), recruits transcription elements such as RNA polymerase and the like, and regulates the transcription expression of target genes, such as genes such as Prostate Specific Antigen (PSA), TMPRSS2, FKBP5 and the like. This signaling pathway normally promotes differentiation of prostate epithelial cells, while continued activation regulates cell proliferation, survival, etc., leading to tumor formation and progression. The IMB-ZNU-G8 provided by the invention acts on HBP sites in AR, and inhibits an abnormally activated androgen receptor signaling pathway, thereby inhibiting the tumor deterioration. Therefore, the IMB-ZNU-G8 has the potential of being used as an effective treatment drug for the prostatic cancer.
Because the T877A mutant AR is related to the drug resistance of the hydroxyflutamide, IMB-ZNU-G8 can achieve the aim of treating the hydroxyflutamide-resistant prostate cancer by inhibiting the activity of the T877A mutant receptor, and therefore, the hormone-resistant prostate cancer is preferably a hydroxyflutamide-resistant prostate.
The glucocorticoid receptor high-expression drug-resistance castration-resistant prostate cancer is drug-resistance prostate cancer generated due to GR high expression after being treated by the existing AR targeted drugs. After the AR targeting therapeutic drug inhibits the AR function, the prostate cancer cells can compensate a part of the AR function by up-regulating the expression of GR, thereby promoting the proliferation of the prostate cancer cells. IMB-ZNU-G8 can inhibit the transcriptional activity of GR by antagonizing the function of GR, thereby inhibiting the expression of target genes downstream of GR. Thus, IMB-ZNU-G8 acts as a glucocorticoid receptor antagonist, and preferably, IMB-ZNU-G8 has a better therapeutic effect against prostate cancer in which glucocorticoid receptor overexpression resistance castration is resistant.
In addition, because GR overexpression is one of the important causes of drug resistance of anti-androgen drugs such as enzalutamide and abiraterone, among the hormone-resistant prostate cancers, IMB-ZNU-G8 has a better therapeutic effect on enzalutamide-resistant prostate cancer or abiraterone-resistant prostate cancer.
In a third aspect, based on the fact that IMB-ZNU-G8 can be used as an antagonist of androgen receptor and glucocorticoid receptor, the invention further provides the use of IMB-ZNU-G8 in the preparation of a medicament for male contraception.
In a fourth aspect, based on the fact that IMB-ZNU-G8 can be used as an antagonist of androgen receptor and glucocorticoid receptor, the invention further provides the use of IMB-ZNU-G8 in the preparation of a medicament for treating hypersensitive, sexual deviation, benign prostatic hyperplasia, acne vulgaris, androgenic alopecia or hirsutism.
In a fifth aspect, based on the availability of IMB-ZNU-G8 as antagonists of androgen and glucocorticoid receptors, the present invention further provides the use of IMB-ZNU-G8 in the manufacture of a medicament for the purposeful prevention or resistance to virilization in the context of degenerating females undergoing sex-resetting therapy.
The "medicine" mentioned in the invention refers to a medicine prepared by taking IMB-ZNU-G8 as an active ingredient, and other components and preparation methods in the medicine can be adjusted according to the prior art and actual needs in the field.
The invention has the beneficial effects that:
through early screening and later mechanism research, the invention discovers that the IMB-ZNU-G8 can selectively antagonize the functions of exogenous and endogenous AR and can be used as a novel androgen receptor antagonist. Meanwhile, IMB-ZNU-G8 can also selectively antagonize GR function, inhibit the expression of downstream target genes of GR, and can be used as a novel glucocorticoid receptor antagonist. In conclusion, the invention finds that IMB-ZNU-G8 can be used as an AR and GR dual-target antagonist.
According to the invention, the inhibition effect of a plurality of compounds on the activities of AR and GR is tested by constructing a reliable screening method of the AR and GR double-target antagonist, and finally, the small molecular compound IMB-ZNU-G8 is found to be an AR and GR double-target antagonist with a novel structure and good activity, and can inhibit the functions of AR and GR, thereby inhibiting the expression of the downstream target genes of AR and GR. Furthermore, the invention tests the anti-prostate cancer activity of IMB-ZNU-G8, and finds that IMB-ZNU-G8 has better inhibitory activity on GR highly-expressed Enzalutamide-resistant prostate cancer cells such as 22Rv1, and can be popularized and applied in related treatment and medicament preparation.
Drawings
FIG. 1 is a graph showing the measurement of the expression level of glucocorticoid receptor GR protein in different types of prostate cancer cell lines for guiding the selection of drug screening cell models, according to example 1 of the present invention;
FIG. 2 is a diagram of the test system constructed in example 2 of the present invention that can be used to evaluate the effect of compounds on the transcriptional activity of endogenous AR, exogenous AR and endogenous GR; in FIG. 2, panel A is the effect of enzalutamide on the transcriptional activity of exogenously expressed wild-type AR in example 2 of the present invention; panel B is the effect of enzalutamide on the transcriptional activity of endogenously expressed AR in example 2 of the invention; panel C is the effect of mifepristone on the transcriptional activity of endogenously expressed GR in example 2 of the invention;
FIG. 3 is a graph showing the effect of IMB-ZNU-G8 on the transcriptional function of exogenous AR in example 3 of the present invention;
FIG. 4 is a graph showing the effect of IMB-ZNU-G8 on the transcriptional function of endogenous AR in example 4 of the present invention;
FIG. 5 is a graph showing the effect of IMB-ZNU-G8 on the transcriptional function of endogenous GR in accordance with example 5 of the present invention;
FIG. 6 shows the effect of IMB-ZNU-G8 on the proliferation of GR-expressing Enzalutamide-resistant AR positive prostate cancer cells 22Rv1 in example 6 of the present invention.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products available from regular distributors, not indicated by the manufacturer.
Example 1 measurement of the expression level of glucocorticoid receptor GR protein in different types of prostate cancer cell lines for guidance in selection of drug screening cell models
In order to detect the expression level of GR protein in the three common prostate cancer cell lines and further guide researchers to select drug screening cell models, the invention designs the following experiments:
2.0X 105A/mL suspension of LNCaP or 22Rv1 or PC-3 cells was seeded at 2mL per well in 6-well plates. The culture medium used by the LNCaP and 22Rv1 cells is RPMI 1640 culture medium containing 10% of activated carbon-treated Fetal Bovine Serum (FBS), and the culture medium used by the PC-3 cells is F-12K culture medium containing 10% of activated carbon-treated Fetal Bovine Serum (FBS); cells were cultured in a carbon dioxide incubator at 37 ℃. After 72 hours of cell culture, 80. mu.L of RIPA lysate was added to each well, the lysate was transferred to 1.5ml EP tubes for 30 minutes on ice, 20. mu.L of 5 Xprotein loading buffer (loading buffer) was added to each tube, and the tubes were cooked for 30 minutes in a metal bath at 100 ℃. SDS-PAGE gel electrophoresis separation, and Western Blot to detect the expression quantity of GR protein and reference protein beta-actin. FIG. 1 is a graph showing the expression levels of GR protein in different types of prostate cancer cell lines in example 1 of the present invention.
The test result shows that the expression of GR protein is not detected in AR positive prostate cancer cell LNCaP cells, the expression of GR protein is moderate in AR positive prostate cancer cell 22Rv1 cells, and the expression of GR protein is high in AR negative prostate cancer cell PC-3 cells. This experiment demonstrates that LNCaP cells can be used as a cell model for evaluating the effect of compounds on endogenous AR transcriptional activity, PC-3 cells exogenously transfected with AR plasmids can be used as a cell model for evaluating the effect of compounds on exogenous AR transcriptional activity, and PC-3 cells can also be used as a cell model for evaluating the effect of compounds on endogenous GR transcriptional activity.
Example 2 construction of an assay System that can be used to evaluate the Effect of Compounds on the transcriptional Activity of endogenous AR, exogenous AR, and endogenous GR
According to the conclusions drawn in example 1, the present invention uses LNCaP cells to test the effect of compounds on endogenous AR transcriptional activity, PC-3 cells transfected with AR plasmid to test the effect of compounds on exogenous AR transcriptional activity, and PC-3 cells to test the effect of compounds on endogenous GR transcriptional activity. The specific operation method comprises the following steps:
mixing 1.0X 105PC-3 or LNCaP cell suspension at a concentration of 500. mu.L/well was seeded into 24-well plates. When the cells were grown to 60%, the PC-3 cell group was co-transfected with 100ng of PSA-luc, 20ng of AR-WT, and 1ng of pCMV-Renilla plasmid per well (System 1, evaluation System for exogenous AR transcriptional repression Activity), with 100ng of PSA-luc and 1ng of pCMV-Renilla plasmid per well (System 2, evaluation System for endogenous AR transcriptional repression Activity), and with 100ng of MMTV-luc and 1ng of pCMV-Renilla plasmid per well (System 3, evaluation System for endogenous GR transcriptional repression Activity), per PC-3 cell group. The medium was changed to phenol red-free RPMI 1640 medium containing 10% charcoal-treated Fetal Bovine Serum (FBS) 6 hours after transfection; after 24 hours of transfection, 2 mu L of dimethyl sulfoxide is added into each hole of the solvent group of the system 1 and the system 2, 1 mu L of dihydrotestosterone and 1 mu L of dimethyl sulfoxide with specified concentration are respectively added into each hole of the dihydrotestosterone group, and 1 mu L of dihydrotestosterone and 1 mu L of enzalutamide with specified concentration are respectively added into the enzalutamide group; 2 μ L of dimethyl sulfoxide was added to each well of the solvent set of System 3, and a dexamethasone set was added to each wellDexamethasone with the specified concentration 1 mu L and dimethyl sulfoxide with the specified concentration 1 mu L are respectively added, and dexamethasone with the specified concentration 1 mu L and mifepristone with the specified concentration 1 mu L are respectively added in the mifepristone group. The culture was continued for 24 hours. Finally, the medium was aspirated off, 100. mu.L of 1 XPLB was added to each well for lysis for 20 minutes, the cell lysate was collected in a clean EP tube, centrifuged, and 20. mu.L of the supernatant was applied to a clean white 96-well plate according to Promega corporation
Instructions for the Luciferase Assay System kit fluorescence was measured using a Centro XS3 LB 960 microplate reader. Three sets of replicates were set up and statistically analyzed, of which<0.05,**P<0.01，***P<0.001 is the dihydrotestosterone group or the dexamethasone group as reference. Experimental data on
Expressed and plotted using GraphPad Prism 5.0 (see figure 2) and statistically analyzed. In FIG. 2, panel A is the effect of enzalutamide on the transcriptional activity of exogenously expressed wild-type AR in example 2 of the present invention; panel B is the effect of enzalutamide on the transcriptional activity of endogenously expressed AR in example 2 of the invention; panel C is the effect of mifepristone on the transcriptional activity of endogenously expressed GR in example 2 of the invention.
The experimental principle of FIGS. 2A and 2B is that the promoter of Prostate Specific Antigen (PSA) as the target gene of AR is coupled to the firefly luciferase gene, and the transcription activity of AR is reflected by the calibrated firefly luciferase activity (relative fluorescence value, RLU). The experimental principle of FIG. 2C is to couple the downstream target Mouse Mammary Tumor Virus (MMTV) gene sequence of GR to the firefly luciferase gene, reflecting the transcriptional activity of GR with the calibrated firefly luciferase activity (relative fluorescence value, RLU).
The experimental results show that the inhibition efficiency of enzalutamide on AR transcriptional activity is consistent with the results reported in the literature, and the inhibition efficiency of mifepristone on GR transcriptional activity is consistent with the results reported in the literature. The bifluorin plum reporter system constructed by the invention can be used for evaluating the influence of a compound on the transcriptional activity of AR and the transcriptional activity of GR.
Example 3 IMB-ZNU-G8 inhibits the transcriptional function of exogenous AR
The system for evaluating the transcription repression activity of exogenous AR constructed in example 2 was used except that 2. mu.L of dimethyl sulfoxide was added to each well of the solvent group, 1. mu.L of dihydrotestosterone and 1. mu.L of dimethyl sulfoxide were added to each well of the dihydrotestosterone group, and 1. mu.L of dihydrotestosterone and 1. mu.L of IMB-ZNU-G81 were added to each well of the administration group. Three sets of replicates were set up and statistically analyzed, of which<0.05,**P<0.01，***P<0.001 is the dihydrotestosterone group. Experimental data on
Expressed and plotted using GraphPad Prism 5.0 (see figure 3) and statistically analyzed.
Experimental results show that IMB-ZNU-G8 has a good inhibition effect on exogenous AR transcription activity, the inhibition rate on AR transcription is 70.1% at a concentration of 20 mu M, and the inhibition effect shows a dose-dependent relationship at a concentration of 5.00 mu M-20.00 mu M. The results of this set of experiments demonstrate that IMB-ZNU-G8 has the effect of inhibiting the transcriptional activity of exogenous AR.
Example 4 IMB-ZNU-G8 inhibits the transcriptional function of endogenous AR
The system for evaluating the endogenous AR transcription repression activity constructed in example 2 was used except that 2. mu.L of dimethyl sulfoxide was added to each well of the solvent group, 1. mu.L of dihydrotestosterone and 1. mu.L of dimethyl sulfoxide were added to each well of the dihydrotestosterone group, and 1. mu.L of dihydrotestosterone and 1. mu.L of IMB-ZNU-G81 were added to each well of the administration group. Three sets of replicates were set up and statistically analyzed, of which<0.05,**P<0.01，***P<0.001 is the dihydrotestosterone group. Experimental data on
Expressed and plotted using GraphPad Prism 5.0 (see figure 4) and statistically analyzed.
Experimental results show that IMB-ZNU-G8 has a good inhibition effect on endogenous AR transcription activity, the inhibition rate on AR transcription is 74.1% at a concentration of 20 mu M, and the inhibition effect presents a dose-dependent relationship at a concentration of 5.00 mu M-20.00 mu M. The results of this set of experiments demonstrate that IMB-ZNU-G8 has the effect of inhibiting the transcriptional activity of endogenous AR. According to the experimental result in the embodiment 3 of the invention, IMB-ZNU-G8 can inhibit the transcription activities of exogenous and endogenous ARs and can antagonize the AR function.
Example 5 IMB-ZNU-G8 inhibits the transcriptional function of GR
The PC-3 cells have high GR expression level, but the cells hardly express AR, so the effect of IMB-ZNU-G8 on GR transcription activity is researched by using the PC-3 cells. The specific experimental procedures were carried out according to the method of operating the endogenous GR transcriptional repression activity evaluation system of example 2, except that: 2 mu L of dimethyl sulfoxide is added into each hole of the solvent group, 1 mu L of dexamethasone and 1 mu L of dimethyl sulfoxide with specified concentrations are added into each hole of the dexamethasone group, and 1 mu L of dexamethasone and 1 mu L of IMB-ZNU-G81 with specified concentrations are added into the administration group. The other operations are the same. Three sets of replicates were set up and statistically analyzed, where P<0.05，**P<0.01 is referred to the dexamethasone group. Experimental data on
Expressed and plotted using GraphPad Prism 5.0 (see figure 5) and statistically analyzed. FIG. 5 is a graph showing the effect of IMB-ZNU-G8 on the transcriptional activity of GR endogenously expressed in PC-3 in example 5 of the present invention.
The experimental result shows that mouse breast cancer virus (MMTV) can be selectively activated by GR, and the transcriptional function of GR is preliminarily tested by detecting the fluorescence value of MMTV-luc plasmid. Experimental results show that dexamethasone can activate the GR function, and IMB-ZNU-G8 can antagonize the activation of dexamethasone on GR, so that the transcriptional function of GR is inhibited.
Example 6 IMB-ZNU-G8 inhibits the proliferation of Nzalutamide-resistant prostate cancer 22Rv1 cells with high GR expression
22Rv1 is an enzalutamide-resistant prostate cancer cell in which GR is expressed in significantly higher amounts than non-enzalutamide-resistant LNCaP cells. Mixing 1.0X 104Each mL of 22Rv1 cell suspension, according toThe cells were plated in 96-well plates at 200. mu.L per well. After plating for 24 hours, 1. mu.L of DMSO or IMB-ZNU-G8 at various concentrations or enzalutamide at various concentrations was added to each well and incubation was continued for 72 hours. Adding 20 mu L of MTT reagent into each hole, continuously incubating for 4h in a carbon dioxide constant-temperature incubator, finally sucking out the culture medium, adding 100 mu L of isopropanol into each hole, shaking and uniformly mixing for 10 min on a 96-hole plate oscillator, and measuring the absorbance value of the mixture by using an Enspire 2300 multifunctional microplate reader at the wavelength of 570 nM. Three groups of parallels are set in the experiment and are subjected to statistical analysis, and the data are subjected to percentage treatment by taking the value of the dimethyl sulfoxide group as a reference. Experimental data on
Expressed and plotted with GraphPad Prism 5.0 (see figure 6). FIG. 6 shows the effect of IMB-ZNU-G8 on the proliferation of GR-expressing Enzalutamide-resistant AR positive prostate cancer cells 22Rv1 in example 6 of the present invention.
The experimental results show that IMB-ZNU-G8 has an IC50 value of 10.2. mu.M for inhibiting 22Rv1 cell proliferation and that ENZALULAMIN has an IC50 value of more than 50. mu.M for inhibiting 22Rv1 cell proliferation, and therefore, the experiment shows that IMB-ZNU-G8 still has activity for prostate cancer species that are ineffective in the treatment of ENZALUMIN. Through the antagonism on double targets of AR and GR, IMB-ZNU-G8 can be used as a novel Enzalutamide drug-resistant prostate cancer treatment drug caused by GR high expression.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (9)
- Use of IMB-ZNU-G8 for the manufacture of a medicament for the prevention, alleviation, treatment or regression of prostate cancer associated with androgen receptor and/or glucocorticoid receptor activity, said IMB-ZNU-G8 having the structure:
- 2. the use according to claim 1, wherein said IMB-ZNU-G8 is as androgen receptor antagonist and/or glucocorticoid receptor antagonist.
- 3. The use of claim 1, wherein said IMB-ZNU-G8 is a T877A mutant androgen receptor antagonist.
- 4. The use of claim 2 or 3, wherein said IMB-ZNU-G8 binds to the hormone binding pocket of the androgen receptor.
- 5. The use according to claim 1, wherein the prostate cancer is caused by androgen dysregulation.
- 6. The use of claim 5, wherein said prostate cancer is caused by androgen hyperactivity.
- 7. The use of claim 1, wherein the prostate cancer is hormone sensitive prostate cancer or hormone resistant prostate cancer.
- 8. The use of claim 7, wherein the hormone-resistant prostate cancer is hydroxyflutamide-resistant prostate or glucocorticoid receptor overexpression resistance castration-resistant prostate cancer.
- 9. The use of claim 8, wherein the glucocorticoid receptor-overexpressing drug-resistant castration-resistant prostate cancer is an enzalutamide-resistant prostate cancer or an abiraterone-resistant prostate cancer.
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