CN106902112B - Application of the IMB-A6 as androgen receptor antagonists - Google Patents
Application of the IMB-A6 as androgen receptor antagonists Download PDFInfo
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- CN106902112B CN106902112B CN201710132585.6A CN201710132585A CN106902112B CN 106902112 B CN106902112 B CN 106902112B CN 201710132585 A CN201710132585 A CN 201710132585A CN 106902112 B CN106902112 B CN 106902112B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
Abstract
The present invention relates to drug leads fields, specifically disclose IMB-A6 in the application of application and IMB-A6 in preparation treatment androgen disorders and male contraception drug in terms of as androgen receptor antagonists.The present invention is by constructing reliable androgenic activity screening technique, multiple drug leads are tested to the inhibiting effect of estrogen receptor activity, finally discovery IMB-A6 is a kind of novel androgen receptor antagonists, can inhibit the activity of wild type and mutability androgen receptor.Further, the present invention tests the activity of the anti-prostate cancer of IMB-A6, it was found that IMB-A6 has preferable activity for the prostate gland cancer cell such as LNCaP of the AR positive, it is then inactive to the prostate gland cancer cell of AR feminine gender, and its expression activity that can inhibit androgen receptor, it is similar to the miscellaneous Shandong amine of positive drug grace.
Description
Technical field
The present invention relates to new Drug fields, specifically, being related to small molecule compound IMB-A6 as androgen
Application in terms of receptor antagonist.
Background technique
Androgen (Androgen), as androsterone (Testosterone, T), androstanediol (Dihydrotestosterone,
DHT) and adrenosterone etc., be a kind of important steroid sex hormone in human body, by with androgen receptor (Androgen
Receptor, AR) promotion cell differentiation and tissue growth are combined, participate in numerous key physiological functions.In sex body all
There are a certain proportion of androgens.In prostate and skin, androsterone T is converted into DHT by 5α-reductase, and with T-phase ratio, DHT
3-5 times will be higher by the affinity of AR.
AR is a member of nuclear receptor superfamily, and the transcription factor of metal ligand activation is distributed widely in proliferation and non-increasing
Grow tissue.There are three structural domains for AR albumen tool: N-terminal structural domain (N terminal domain, NTD), DNA binding domain (DNA
Binding domain, DBD) and ligand binding domain (Ligand binding domain, LBD).Wherein have in LBD binding domain
One hormone binding pocket (Hormone binding pocket, HBP), when androgen is incorporated into HBP, the Helix12 of AR is sent out
It gives birth to conformation change and becomes exciting conformation (Agonistic conformation), dimerization domain is formed, into nucleus
It combines, plays with the androgen response original part (Androgen response element, ARE) for being located at target gene promoters area
The effect of expression of target gene is activated or inhibited, to regulate and control the physiological function of target tissue.Androgen receptor antagonists as can
It is combined with the active site two (Activity function-2, AF2) on androgen, and Helix-12 is prevented to be in active sites
The molecule set.The generation of many AR related diseases, or since hormonal readiness is not normal, or because of receptor dysfunction, destroy
Normal interaction equilibrium relation.In diseased individuals, drug is controlled by reinforcing or inhibiting receptor activation level can reach
Treat the effect of related disease.Therefore, it is treating in a variety of diseases relevant to androgenic effect and symptom, AR is important target
Mark.Wherein androgen is excited for diseases such as prostate cancer, hyperplasia of prostate, sexual hyperesthesiies；1 levels in female patients with acne, seborrheica skin
An important factor for inflammation, hirsutism, the diseases such as alopecia, thus androgen receptor antagonists are the above-mentioned disease for the treatment of especially prostates
The important drugs of cancer.
Androgen receptor antagonists are the main drugs of current treatment prostate cancer.This kind of drug can be divided into steroid and non-steroid
Two kinds of class.Steroid antiandrogen drug further includes megestrol acetate and tumer hydroxyl for representative with cyproterone acetate (CPA)
Progesterone.Non-steroid antiandrogen object (Nonsteroidal antiandorgens, NSAA) has alpha..alpha..alpha.-Trifluoro-2-methyl-4'-nitro-m-lactotoluidide
The miscellaneous Shandong amine of grace of (hydroxyflutamide, HF), Bicalutamide (bicalutamide, BIC) He Erdai
(enzalutaimide, ENZ), abiraterone (abiraterone).But the drug resistance problems generated in the treatment seriously affect
The curative effect of these drugs, or even can promote the growth of prostate gland cancer cell.Thus, it is short of money to find the novel androgen receptor for the treatment of
Anti-agent is extremely urgent.
Summary of the invention
In order to solve the problems in the existing technology, the object of the present invention is to provide a kind of novel androgen receptor antagonists
Agent --- IMB-A6.
In order to achieve the object of the present invention, technical scheme is as follows:
In a first aspect, the application the present invention provides IMB-A6 as androgen receptor antagonists.
IMB-A6 is a kind of known compound, is purchased from commercial product, such as be purchased from Mcule company, ZINC database
Number is ZINC31534608.
IMB-A6 can inhibit the activity of wild type and saltant type androgen receptor.Saltant type androgen receptor includes
877 threonines (T) → alanine (A), 741 tryptophans (W) → leucine (L) or cysteine (C), 876 phenylpropyl alcohols
Propylhomoserin (F) → leucine (L).It is the mutation that related amino acid is resulted in by the point mutation of AR gene.The production of the mutation
When life is so that drug is in conjunction with AR, the conformation of AR is changed into agonist state by antagonist status, to generate drug resistance to drug
Property, the use of related drugs is constrained, so it is of great significance to the drug resistance problems for overcoming anti-prostate cancer.
The present invention has found that IMB-A6 has good inhibiting effect to F876L mutation receptor through overtesting.Therefore conduct
It is preferred that being mutated androgen receptor antagonists for IMB-A6 as F876L.The drug resistance of F876L mutation receptor and the miscellaneous Shandong amine of grace
Correlation, IMB-A6 can reach the mesh of the treatment miscellaneous drug resistant prostate cancer of Shandong amine of grace by inhibiting F876L to be mutated the activity of receptor
's.
Further, it is found through overtesting, IMB-A6 equally has good inhibiting effect to T877A mutation receptor.Cause
This is preferably, be mutated androgen receptor antagonists for IMB-A6 as T877A.T877A is mutated receptor and alpha..alpha..alpha.-Trifluoro-2-methyl-4'-nitro-m-lactotoluidide
Drug resistance it is related, IMB-A6 can by inhibiting T877A to be mutated the activity of receptor, reach treatment alpha..alpha..alpha.-Trifluoro-2-methyl-4'-nitro-m-lactotoluidide it is drug resistant before
The purpose of column gland cancer.
Second aspect, the present invention provides IMB-A6 and its similar derivatives in the medicine for preparing treatment androgen disorders
Application in object.
The drug for the treatment of androgen disorders of the present invention is prepared by active constituent of IMB-A6, drug
Conventional technical means in the art can be used in specific preparation method.
More specifically, IMB-A6 provided by the invention is mainly for by the excited caused disease of androgen, including male
Hyperplasia of prostate or prostate cancer, sexual hyperesthesia, 1 levels in female patients with acne, seborrhea, hirsutism, alopecia etc..
Optionally, the androgen disorders are hyperplasia of prostate or prostate cancer.It needs to be emphasized that by
It is mainly that androgen receptor signal path is abnormal activation in the pathogenesis of prostate cancer.Its signal path process is male sharp
Element is in conjunction with AR, and AR is activated and dimerization phosphorylation, into nucleus, with the special position DNA (AR Response
Element, ARE) it combines, the transcriptional elements such as RNA polymerase are raised, the transcriptional expression of target gene, such as prostate specific are regulated and controled
The genes such as antigen (PSA), TMPRSS2, FKBP5 (Fig. 1).The signal path can promote prostate epithelial cell under normal circumstances
Differentiation, and cell Proliferation, survival etc. can be then adjusted in the case of sustained activation, to form tumour and deteriorate.The present invention provides
IMB-A6 exactly act on the site AF2 in AR, inhibit the androgen receptor signal path of abnormal activation, to inhibit tumour
Deterioration.Therefore, IMB-A6 of the present invention can have significant curative effect to prostate cancer.
Optionally, the androgen disorders are male's sexual hyperesthesia.Since male's sexual hyperesthesia is swashed by hero
Disease caused by element is excited, IMB-A6 provided by the invention can reach by the activity of inhibition androgen receptor and treat the disease
Purpose.
Optionally, the androgen disorders are 1 levels in female patients with acne, seborrhea, hirsutism, alopecia etc..When above-mentioned disease
When disease is really caused by androgen access is excited, IMB-A6 of the present invention can effectively be treated above-mentioned disease.
The third aspect, the present invention provides IMB-A6 in the application for preparing male contraceptive pill object space face.
Since IMB-A6 can inhibit the activity of wild type and saltant type androgen receptor, regulation androgen receptor signal is logical
Road, to play inhibiting effect to androgen secretion by feedback regulation.Therefore, IMB-A6 of the present invention can be used as male
The active constituent of contraceptive, effectively realizes contraceptive effect in terms of male contraception.
The beneficial effects of the present invention are:
By screening early period and later period Mechanism Study, present invention discover that the IMB-A6 property of can choose inhibits AR to rely on
The proliferation of LNCaP cell all has the transcription of endogenous AR and AR-F876L mutant, the nuclear location of AR and inhibits to make well
With being novel androgen receptor antagonists.
The present invention tests multiple compounds to estrogen receptor activity by constructing reliable androgenic activity screening technique
Inhibiting effect, finally find that small molecule compound IMB-A6 is a novel androgen receptor antagonists, can inhibit wild
The activity of raw type and mutability androgen receptor.Further, the present invention tests the activity of the anti-prostate cancer of IMB-A6,
It was found that IMB-A6 has preferable activity for the prostate gland cancer cell such as LNCaP of the AR positive.
Detailed description of the invention
Fig. 1 is influence of the IMB-A6 to the wild type AR transcriptional activity being overexpressed in PC-3 in the embodiment of the present invention 1.
Fig. 2 is influence of the IMB-A6 to the AR transcriptional activity of LNCaP endogenous cellular in the embodiment of the present invention 2.
Fig. 3 is that IMB-A6 transcribes the AR of 876 expressed in PC-3, the mutation of 877 amino acids in the embodiment of the present invention 3
Active influence.
Fig. 4 is influence of the IMB-A6 to AR from Chromosome migration to nucleus in the embodiment of the present invention 4.
Fig. 5 is that IMB-A6 is incorporated in the site AF2 in the embodiment of the present invention 5, blocks AR albumen and co-activator PELP-1
Interaction between albumen.
Fig. 6 is the chemical structural drawing of the similar derivatives IMB-B2 and IMB-B3 of IMB-A6 in the embodiment of the present invention 6, ZINC
Number in database is ZINC15669334 and ZINC20991888 respectively, has similar bioactivity with IMB-A6.
Fig. 7 is the activity of the anti-prostate cancer of IMB-A6 in the embodiment of the present invention 7.
Specific embodiment
The preferred embodiment of the present invention is described in detail below in conjunction with embodiment.It will be appreciated that following real
Providing merely to play the purpose of explanation for example is applied, is not used to limit the scope of the present invention.The skill of this field
Art personnel without departing from the spirit and purpose of the present invention, can carry out various modifications and replace to the present invention.
Experimental method used in following embodiments is conventional method unless otherwise specified.
The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.
Embodiment 1IMB-A6 can inhibit the activity of wild-type androgen receptor
By 1.4 × 105The PC-3 cell suspension of a/mL is inoculated in 24 orifice plates according to every 500 μ L of hole.It is long extremely to cell
When 80%, every hole cotransfection 100ng PSA-luc, 20ngAR-WT and 1ng pCMV-Renilla plasmid.6h will be cultivated after transfection
Base changes 1640 culture medium of phenol red-free RPMI of the FBS containing 10%charcoal-stripped into；After transfection for 24 hours,
Wherein 1 μ L is added in the IMB-A6 of one group of DHT+ respective concentration according to every hole 1nM or the miscellaneous Shandong amine of grace, and another group according to every hole
1 μ L is added in the miscellaneous Shandong amine of the IMB-A6 or grace of DMSO or respective concentration, continues culture for 24 hours.Finally culture medium is sopped up, every hole is added
1 × PLB of 100 μ L cracks 20min, collects cell lysate into clean EP pipe, and centrifugation takes 20 μ L of supernatant to completely white
In 96 orifice plate of color, according to Promega companyThe specification of Luciferase Assay System kit,
Fluorescent value is measured with 960 microplate reader of Centro XS3LB.Three groups of experimental setup are parallel, and have carried out statistical analysis,
P < 0.01 middle * * is using DHT group as reference.Experimental data withIt indicates, and is mapped with GraphPad Prism 5.0
(see Fig. 1) and statistical analysis.
The experimental principle be by the target gene prostate-specific antigen of AR (prostate specific antigen,
PSA promoter) and firefly luciferase gene coupling, with after calibrating firefly luciferase activity (relative fluorescence,
RLU) the transcriptional activity of Lai Fanying AR.Experimental result shows that IMB-A6 has the AR transcriptional activity of wild type to be inhibited well
Effect, is presented dose-dependence under 0.25 μM -5 μM five concentration.At 0.25 μM, function and effect are with the miscellaneous Shandong amine of 5 μM of grace
Function and effect it is close.This group of experimental result illustrates that IMB-A6 can inhibit the transcriptional activity of wild type AR to act on, and inhibits strong
It spends similar to the miscellaneous Shandong amine of grace.
Embodiment 2IMB-A6 can inhibit the activity of endogenous androgens receptor
Since heterogenous expression androgen receptor is there may be phenomenon is overexpressed, simultaneously because plasmid transfection process may lead
Play false positive results.Thus, We conducted the active experiments that IMB-A6 inhibits endogenous androgens receptor.Specific experiment step
Rapid reference embodiment 1, the difference is that: it is done using LNCaP cell and is this time tested, cotransfection is every hole 100ng PSA-
Luc and 1ng pCMV-Renilla plasmid, other operations are identical.Three groups of experimental setup are parallel, and have carried out statistical analysis,
P < 0.01 wherein * P < 0.05, * * is using DHT group as reference.Experimental data withIt indicates, and with GraphPad Prism 5.0
It is mapped (see Fig. 2) and statistical analysis.
IMB-A6 has dose-dependent inhibition effect, and this inhibition to the transcriptional activity of the endogenous AR of LNCaP
It acts on more significant in LNCaP cell.Compare the result of LNCaP it is found that IMB-A6 is to endogenous androgens in this group experiment
Receptor is inhibited, further demonstrates that the activity of androgen receptor can be effectively suppressed in it.
Androgen receptor access is extremely important in prostate cancer patient, by IMB-A6 in embodiment 1 to androgen receptor
The inhibiting effect of body, can absolutely prove IMB-A6 can pair prostate cancer treatment have potential application.
Meanwhile IMB-A6 can also be applied to the other and excited relevant disease of androgen as androgen receptor antagonists
Such as: male's sexual hyperesthesia；Male contraception drug；1 levels in female patients with acne, seborrhea, hirsutism, alopecia etc..
Embodiment 3IMB-A6 can inhibit the activity of saltant type androgen receptor
Currently, having studied the mutation for having found some series A R critical sites, including 741 tryptophan (W) → bright ammonia
Sour (L) or cysteine (C), 877 threonines (T) → alanine (A), 876 phenylalanines (F) → leucine (L).Its
Middle W741C mutation is the main reason for Bicalutamide generates drug resistance, and T877A mutation is that alpha..alpha..alpha.-Trifluoro-2-methyl-4'-nitro-m-lactotoluidide generates the main of drug resistance
Reason.Specific experiment step is a difference in that when cotransfection referring to embodiment 1 and changes AR-WT into AR-F876L or AR-T877A
The plasmid of mutation, other operations are identical.Three groups of experimental setup parallel, and has carried out statistical analysis, wherein * P < 0.05, * * P
< 0.01, using DHT group as reference.Experimental data withIt indicates, and is mapped with GraphPad Prism 5.0 (see Fig. 3)
And statistical analysis.
Experimental result shows that IMB-A6 is mutated F876L and the transcriptional activity of T877A mutation AR also has inhibition well to make
With.
Experimental result is as shown in Figure 3A, and IMB-A6 is under 10.00 μM, 1.00 μM, 0.10 μM of three concentration, to AR-F876L
Transcriptional activity all have good inhibiting effect, and dose-dependence is presented.And IMB-A6 is at 10.00 μM to AR-
The inhibiting effect of the transcriptional activity of F876L is very significant, compared with the exercising result of the miscellaneous Shandong amine of grace, shows that IMB-A6 can overcome
The miscellaneous Shandong amine of grace resistance problems due to caused by the 876 amino acids mutation of AR.
When experimental result 10.00 μM of concentration as shown in Figure 3B, it is aobvious that IMB-A6 inhibits the transcriptional activity of T877A mutation AR to have
Work property, and the comparison medicine alpha..alpha..alpha.-Trifluoro-2-methyl-4'-nitro-m-lactotoluidide as the experimental system can activate the transcriptional activity of T877A mutation AR, and
The result of report is consistent, thus the experimental result is effective and feasible.T877A saltant type androgen receptor be used for a long time hydroxyl fluorine he
It is common in the patient of amine, it, can be abundant by IMB-A6 in embodiment 3 to the inhibiting effect of T877A saltant type androgen receptor
Illustrate that IMB-A6 can overcome the alpha..alpha..alpha.-Trifluoro-2-methyl-4'-nitro-m-lactotoluidide drug resistance problems generated by T877A mutation.
Influence of the embodiment 4IMB-A6 to AR from Chromosome migration to nucleus
The cell being copolymerized on burnt ware will be inoculated in be washed 2 times with 1mL PBS, each 5min.Use 4% paraformaldehyde of 0.5mL
Stand fixed 15min.It is washed 3 times with PBS, each 5min.15min is penetrated with 0.5mL 0.2%TritionX-100.Use 2%
BSA closes 1h.The primary antibody dilution (1:100) of AR, 4 DEG C of overnight incubations are added.It is washed 4 times using PBS, each 5min.It is added
The secondary antibody diluent (1:100) of the upper goat-anti rabbit of FITC label is incubated for 1-2h.Washing 3 times, each 5min.It is added anti-with DAPI
Fluorescent quenching mounting liquid, every ware 2 drip.Image collection is carried out with ZEISS LSM710 microscope.
Test result such as Fig. 4 shows that for the green fluorescence that AR albumen is issued under the DHT effect of 1nM, AR's appraises and decides bit rate
Nucleus is gathered in for more than 90% or so, and the bit rate of appraising and deciding of the miscellaneous Shandong amine of IMB-A6, grace treated AR is about 20%, nucleus
There is AR albumen with cytoplasm.This illustrates that A6 can reduce the nuclear location effect of AR, thus the transcriptional activity to inhibit AR.
Embodiment 5IMB-A6 is incorporated in the site AF2, blocks AR albumen and the phase interaction between co-activator PELP-1 albumen
With
Specific experiment step is: 48h harvests cell after transfection, and appropriate cell lysis buffer solution is added and (inhibits containing protease
Agent), 30min is cracked on ice, and cell pyrolysis liquid takes supernatant after 4 DEG C, maximum (top) speed centrifugation 30min；Take a small amount of lysate in case
Western blot analysis, remaining lysate add the corresponding AR antibody of 1 μ g to be added to cell pyrolysis liquid, and 4 DEG C are slowly rocked incubation
Overnight；10 μ L protein A sepharose 4Bs are taken, are washed 3 times with appropriate lysis buffer, 3,000rpm is centrifuged 3min every time；It will be pre-
Processed 10 μ L protein A sepharose 4B is added to 4 DEG C of slow rock in the cell pyrolysis liquid overnight with antibody incubation and incubates
2-4h is educated, couples AR antibody with protein A sepharose 4B；After immune precipitation, at 4 DEG C with the centrifugation of 3,000rpm speed
Sepharose 4B is centrifuged to tube bottom by 3min；Supernatant is carefully sucked, sepharose 4B is washed 3~4 times with 1ml lysis buffer；Finally
It is added 2 × SDS sample-loading buffer of 15 μ L, boiling water boiling 5 minutes；SDS-PAGE,Western blotting.
The principle of the experiment is that AR needs to raise a series of co-activators during transcriptional expression, wherein PELP1
The bridge bone of (Proline-glutamic acid-and leucine-rich protein 1) as AR and co-activator
Frame can have been reported small peptide compounds by being incorporated in AF2, block the effect between AR and PELP1 in conjunction with the site AF2 of AR,
To inhibit the transcription of AR.For experimental result as shown in figure 5, in protein precipitation group, 10 μM of IMB-A6 significantly reduces PELP-1
The content of albumen, and 1 μM of when, is not obvious, and there is concentration dose to rely on effect.Prove that IMB-A6 can be combined in the site AF2,
To block the interaction between AR albumen and co-activator PELP-1 albumen.
The homologue of embodiment 6IMB-A6 equally has similar bioactivity
Similarity searching is carried out to IMB-A6 in ZINC database, it is found that the similar derivatives of IMB-A6 and IMB-A6 have
There is similar bioactivity, the number in ZINC database is ZINC15669334 and ZINC20991888 respectively, and Fig. 6 is
The chemical structural drawing and inhibition expression of androgen receptor activity of IMB-B2 and IMB-B3, is purchased from Mcule company.
The activity of the anti-prostate cancer of embodiment 7IMB-A6
The present embodiment tests the activity of the anti-prostate cancer of IMB-A6, prostate cancer of the discovery IMB-A6 for the AR positive
Cell such as LNCaP has preferable active (Fig. 7 A), then inactive to the prostate gland cancer cell of AR feminine gender (Fig. 7 B), and inhibits
The expression activity (Fig. 7 C) of androgen receptor, it is similar to the miscellaneous Shandong amine of positive drug grace.
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, fall within the scope of the claimed invention without departing from theon the basis of the spirit of the present invention.
Claims (2)
- Application of the 1.IMB-A6 in the drug of preparation treatment androgen disorders, the androgen disorders are to be swashed by hero Disease caused by element is excited；Wherein, the structural formula of the IMB-A6 is as follows:
- 2. application according to claim 1, which is characterized in that the androgen disorders are prostate cancer.
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| CN109432097A (en) * | 2018-11-27 | 2019-03-08 | 浙江师范大学 | The application in column gland cancer drug before the treatment of ZJU-IMB-Z19 compound |
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| WO2020178441A1 (en) * | 2019-03-06 | 2020-09-10 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Inhibitors of ngal protein |
| CN111943889B (en) * | 2020-07-24 | 2022-07-22 | 中国医学科学院医药生物技术研究所 | Bis-aryl amine compound and preparation method and application thereof |
| CN113943738B (en) * | 2021-09-29 | 2023-06-13 | 西南医科大学 | Androgen receptor mutant ARv33 and application thereof in prostate cancer drug development |
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| US9233946B2 (en) * | 2010-09-17 | 2016-01-12 | Kancera Ab | Sulfonamide compounds |
| EP2991644B1 (en) * | 2013-04-04 | 2020-03-25 | University of Maryland, Baltimore | Nonsteroidal and steroidal compounds with potent androgen receptor down-regulation and anti prostate cancer activity |
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| CN109432097A (en) * | 2018-11-27 | 2019-03-08 | 浙江师范大学 | The application in column gland cancer drug before the treatment of ZJU-IMB-Z19 compound |
| CN109432097B (en) * | 2018-11-27 | 2021-04-23 | 浙江师范大学 | Application of ZJU-IMB-Z19 compound in medicine for treating prostatic cancer |
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