CN108283635A - Corylin is used as the medical usage of HSP90AB1 inhibitor - Google Patents
Corylin is used as the medical usage of HSP90AB1 inhibitor Download PDFInfo
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- CN108283635A CN108283635A CN201810352212.4A CN201810352212A CN108283635A CN 108283635 A CN108283635 A CN 108283635A CN 201810352212 A CN201810352212 A CN 201810352212A CN 108283635 A CN108283635 A CN 108283635A
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- Prior art keywords
- corylin
- hsp90ab1
- pharmaceutically acceptable
- protein
- inhibitor
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
Abstract
The invention discloses the medical usages that corylin is used as HSP90AB1 inhibitor.It is provided by the invention the experiment proves that corylin be HSP90AB1 effective inhibitor, can be used for prepare inhibit HSP90AB1 pharmaceutical preparation.The pharmaceutical preparation contains corylin or its pharmaceutical salts or its prodrug, also contains pharmaceutically acceptable carrier or excipient, pharmaceutically acceptable dosage form is made；Pharmaceutically acceptable carrier or excipient include one or more solids, semisolid or Auxiliary Liquid Material；Pharmaceutically acceptable dosage form includes tablet, capsule, granule, injection, pill, syrup, powder, paste.
Description
Technical field
The invention belongs to field of medicaments, and in particular to corylin is used as the medical usage of HSP90AB1 inhibitor.
Background technology
Heat shock protein 90 (heat shockprotein, Hsp90) is the highly conserved molecular chaperones that ATP is relied on,
The energy generated using ATP hydrolysis participates in the correct folding of protein, and stable protein structure participates in cell signalling and swashs
The reactions such as plain response and transcriptional control and tumor death, the adjusting for being proliferated related pathways.Hsp90 is various to changing because of environment etc.
The holding of protein stability is most important under stress situation.Other than playing a significant role in normal cell, Hsp90 and bottom
Object albumen is combined the occurrence and development for participating in a variety of diseases, such as malignant tumour, autoimmune disease.He or a variety of carcinogenic eggs
White molecular chaperones, including EGF-R ELISA (epidermal growth factor receptor, EGFR), the mankind
Epidermal growth factor-recepor-2 (human epidermal growth factor receptor-2, HER2), interstitial epidermis turn
Change the factor (mesenchymal-epithelial transition, MET), protein kinase B (protein kinase B, AKT)
Deng.It is now recognized that mankind Hsp90 includes mainly 4 kinds of hypotypes：Hsp90AA1 and Hsp90AB1 are respectively positioned in cytoplasm, and Grp94 is located at
In endoplasmic reticulum, and TRAP1 hypotypes are then positioned in mitochondrial matrix.Hsp90AA1 and Hsp90AB1 have it is 85% homologous, but two
Person acts on difference, and Hsp90AA1 is inducible expression, participates in the adjusting of cytoprotection and cell cycle under stress situation, and
Hsp90AB1 is constructive expression, participates in early embryonic development, signal transduction and cell long-period adaptability.
At present worldwide, lung cancer incidence and the death rate occupy malignant tumour first place, wherein about 85% is non-small
Cell lung cancer.As molecular chaperones, Hsp90 helps to promote folding and the maturation of lung cancer protein, such as EGFR and ALK.It blocks
It is a kind of new strategies in treatment of cancer that these chaperones, which function,.Ramalingam etc. is to Hsp90 new inhibitors
Clinic II phase of ganetespib the study found that in treating advanced pulmonary adenocarcinoma patient procedure, ganetespib with it is mostly western
He matches the treatment of (docetaxel) drug combination compared with docetaxel single therapy, can extend total life of advanced pulmonary adenocarcinoma patient
Deposit the phase (bibliography：A randomized phase II study of ganetespib,a heat shock protein
90inhibitor,in combination with docetaxel in second-line therapy of advanced
non-small cell lung cancer.Ann Oncol,2015,26:1741-1748)。
Invention content
The purpose of the present invention is to provide the medical usages that corylin is used as HSP90AB1 inhibitor.
The above-mentioned purpose of the present invention is achieved by following technical solution：
Corylin is used as the medical usage of HSP90AB1 inhibitor.
It is a kind of inhibit HSP90AB1 pharmaceutical preparation also contain pharmacy containing corylin or its pharmaceutical salts or its prodrug
Upper acceptable carrier or excipient, are made pharmaceutically acceptable dosage form.
Further, pharmaceutically acceptable carrier or excipient include one or more solids, semisolid or liquid
Auxiliary material.
Further, the pharmaceutically acceptable dosage form include tablet, capsule, granule, injection, pill,
Syrup, powder, paste.
It is a discovery of the invention that corylin can be combined with each other with HSP90AB1, (binding ability is positive compound 17-AAG
10 times) and inhibit the expression of the downstreams HSP90AB1 albumen, this shows that corylin is effective inhibitor of HSP90AB1.
Description of the drawings
Fig. 1 is the interaction relationship figure of positive drug 17-AGG and EGFP-HSP90AB1；
Fig. 2 is the interaction relationship figure of corylin and EGFP-HSP90AB1；
Fig. 3 is the interaction relationship figure of CompoundA and EGFP-HSP90AB1；
Fig. 4 is the interaction relationship figure of Neobavaisoflavone and EGFP-HSP90AB1；
Fig. 5 is that various concentration corylin intervenes influences of the 2h to the downstreams HSP90AB1 client protein AKT stability；Phosphoric acid
Change AKT by dephosphorylation, p-AKT is substantially reduced, it was demonstrated that corylin reduces the stability of AKT；
Fig. 6 is that same concentrations (3 μ g/mL) corylin intervention different time is steady to the downstreams HSP90AB1 client protein AKT
Qualitatively influence；Phosphorylation AKT is substantially reduced by dephosphorylation, p-AKT, it was demonstrated that corylin reduces AKT stability.
Specific implementation mode
It is specific with reference to the accompanying drawings and examples to introduce essentiality content of the present invention.
One, experiment material
Corylin purity is more than 95%.The derivative CompoundA and Neobavaisoflavone of corylin are certainly
System, purity are more than 95%.The chemical structural formula of corylin, CompoundA and Neobavaisoflavone is as follows.
Two, experimental method
1, light affinity purification is tested
1) the HCl rinse NHS-Activated Sepharose 4Flow agrose matrix being pre-chilled with 1mM, then
With excessive corylin in coupling buffer (0.2M NaHCO3, 0.5MNaCl, pH 8.3) in 4 DEG C overnight incubation；
2) corylin is fixed on agarose beads.The excessive unreacted benefit of 0.5M ethanol amines (pH 8.3) closing
Bone fat is peaceful.It is spare to be stored in 4 DEG C of refrigerators by Beads after buffered liquid elution；
3) the front and back corylin solution of coupling is analyzed into its coupling efficiency by HPLC respectively；
4) 1%NP-40 lysates (50mM Tris-HCl (pH 7.5), 150mM NaCl, 1%NP-40) elute psoralea corylifolia
Peaceful coupling beads；
5) it after eluting, is mixed with C57BL/6J mouse liver Tissue lysates, 4 DEG C of incubation 2h；
6) it after, is eluted 3 times with 1%NP-40 lysates, then eluted with 5mM corylins；
7) in competitive elution experiments, protein lysate is mixed with 1mM corylins, after 4 DEG C are incubated 2h, then with
Besds mixing is incubated；
8) albumen being bound on beads is identified using mass spectrum.
2, the interaction of molecules of corylin and HSP90AB1
It is prepared by the purifying of 2.1 recombination EGFP-HSP90AB1 albumen
1) pET28a-HSP90AB1-EGFP is expanded and to purify the above plasmid spare；
2) monoclonal：Respective plasmid is converted in BL-21 competent cells, plated overnight, next day picking is each inverting flat
Monoclonal is inoculated in the 4ml LB culture mediums containing 50 μ g/ml Kana on plate, 220rpm, and 37 DEG C of shakings are overnight；
3) it expands：Next day presses 1:100 are inoculated in the 500ml LB culture mediums of 50 μ g/ml Kan, 220rpm, 37 DEG C of shakings
About 2-4h is cultivated, waits for thalline OD600Until value reaches 0.6 or so；
4) it identifies：1ml cultures are taken out, room temperature 12000g centrifuges 2min, abandons supernatant, and bacterium is resuspended in 100 μ l sample-loading buffers
Body precipitates；
5) induced expression：Lactose is added to 0.8g/l, 220rpm, 22 DEG C of shaking overnight incubations of final concentration, inducible protein table
It reaches；
6) it identifies：1ml cultures are taken out, room temperature 12000g centrifuges 2min, abandons supernatant, and bacterium is resuspended in 100 μ l sample-loading buffers
Body precipitates, 4 DEG C of remaining culture, and 4000g centrifuges 12min, abandons supernatant, and precipitation is set -20 DEG C and frozen；
7) lytic cell：With 400 μ l Ni-IDABinding-Buffer (20mM Tris-Hcl, 10mM imidazoles, 0.5M
NaCl, pH 8.0) thalline is resuspended, ultrasonication in ice bath, condition is power 100W, and work 5s, interval 7s, total 25min, breaks
4 DEG C of broken liquid, 12000g centrifuge 20min, take 10 μ l supernatants that the 2x sample-loading buffers of equivalent are added, and precipitate 400 μ l 1x loadings
Buffer solution takes 5 μ l, constant pressure 150V to carry out 12%SDS-PAGE after being resuspended, coomassie brilliant blue R250 dyeing shows band；
8) protein purification：Using Biologic LP tomographic systems, supernatant is crushed with 0.5ml/min flow velocitys loading to Ni-
The Ni-IDA-Sepharose-CL-6B affinity columns that IDA Binding-Buffer are pre-equilibrated.With Ni-IDA Binding-
Buffer is rinsed with 0.5ml/min flow velocitys, until efflux OD280Value reaches baseline.Ni-IDAWashing-Buffer is used respectively
(20mM Tris-HCl, 20mM imidazoles and 50mM imidazoles, 0.5M NaCl, pH 8.0) is rinsed with 1ml/min flow velocitys, until efflux
OD280Value reaches baseline.With Ni-IDAElution-Buffer (20mM Tris-HCl, 250mM imidazoles, 0.5M NaCl, pH
8.0) destination protein is eluted with 1ml/min flow velocitys, collects efflux, finally carry out SDS-PAGE analyses.
(MST) experiment is moved in 2.2 micro thermophoresis
1) labelled protein molecule prepares：Above-mentioned recombination EGFP-HSP90AB1 albumen can be used as MST labelled protein macromoleculars
For testing, high molecular weight protein solution will be marked to be diluted to the concentration range being suitble to the detection of interaction instrument；
2) unmarked small molecule prepares：Select positive HSP90 inhibitor 17-AAG as positive compound, corylin and
Its derivative (CompoundA and Neobavaisoflavone) uses DMSO to be diluted to 10mM as storing solution.Utilize software prediction
Kd values, using MST buffer solutions as solvent, configuration work liquid maximum concentration (this concentration be no more than 20 times of Kd values), backward with this two
Times gradient dilution, is configured to the working solution (10 μ l) of 16 gradient concentrations；
3) macromolecular is combined with small molecule：The macromolecular solution of 10 μ l labels is added into the above working solution, uses liquid-transfering gun
The gently mixing in dof pipes is protected from light and is incubated 5min；
4) loading：After reaching the reaction time, Monolith NT capillaries are directly inserted into reaction tube dof pipes, are drawn
Sample.At this point, not touch the intermediate position of glass tube, capillary is put into sample carrier dish groove successively in sequence；
5) it detects：Parameter in NT control softwares is set, detection is proceeded by, software is carried by instrument after detection
It is analyzed, intends joint account dissociation constant.
3, inhibiting effect of the compound to the downstreams HSP90AB1 protein expression
3.1 total protein of cell extract
1) cell contact plate is stayed overnight, and when cell density reaches 70-80%, insulin (insulin) pre-processes 2h, gives later
After giving various concentration corylin effect 2h or giving the corylin effect different time of 3 μ g/ml, cell culture is discarded
Base, PBS buffer solution clean cell 3 times；
2) after using 0.5ml pancreatin digestion 2min, complete medium 1ml terminates digestion, collects cell in dof pipes,
1000g, centrifuges 5min by 4 DEG C；
3) culture medium is discarded, cell precipitation is obtained, (phosphoric acid has been added in the RIPA lysates that 200 μ l are added in every dof pipes
Change enzyme inhibitor and total protease inhibitor) be fully suspended after, 10-30min is cracked on ice, with 12000g, 4 DEG C of pelleted by centrifugation
5min；
4) collect supernatant to get protein solution, BCA methods measure protein sample concentration, -80 DEG C of remaining sample freeze it is spare,
Or 5 × SDS-PAGE sample-loading buffers are directly added into, and blow and beat uniformly, 10min in 95 DEG C of metal baths makes albumen fully be denaturalized,
Western blot are spare.
3.2BCA methods detect albumen concentration
1) reaction solution prepares：With every hole 0.5ml solution As and 0.0l ml solution B dosages, prepare enough reaction mixtures；
2) point sample：It takes 2 μ l protein solutions in 96 orifice plates, is diluted to 20 μ l with tri-distilled water, each sample is arranged three again
The protein standard substance of various concentration is arranged in hole；
3) it chemically reacts：The reaction mixture of 200 μ l is added per hole, 30min is incubated in 60 DEG C of incubators；
4) it detects：After reaching action time, using microplate reader, absorbance value is detected at 570nm wavelength；
5) albumen concentration is calculated：Standard curve is drawn out according to the concentration of standard items and corresponding absorbance value, then is calculated
The albumen concentration of sample to be tested.
3.3Western blot experiments
1) prepared by gel：Cleaning glass plate dries rear spare.It is different according to destination protein molecular weight by Tables 1 and 2, system
The standby separation gel for being suitble to separation destination protein.Encapsulating immediately is shaken up immediately after TEMED is added in separation gel, fluid-tight separation gel,
The static 30min of room temperature.At this point, concentration glue can be configured according to table 3, after reaching the time, upper water is discarded, the concentration configured is added
Liquid, quick insertion comb, the static 15min of room temperature can be used to subsequent experimental after extracting comb；
2) electrophoresis：Take it is high-temperature denatured after protein sample, it is about that 40 μ g carry out loadings that Tot Prot is added per hole, then plus
Enter electrophoresis liquid rear electrophoresis protein isolate, deposition condition 80V, 30min；120V, 60min；
3) transferring film：After electrophoresis, glass plate, removal concentration glue, after leaving separation gel, with the shape of sandwich are gently pried open
Formula is clamped according to " filter paper-NC films-separation gel-filter paper " sequence, is inserted on wet pivoted frame, is poured into that sufficient amount is wet to turn liquid, you can opens
Begin wet turn.Pay attention to there cannot be bubble generation between separation gel and NC films, plant-grid connection notices that positive and negative anodes are distinguished, and transferring film condition is general
For constant current 320mA, 1-2h, the transferring film time can be adjusted according to destination protein molecular weight difference.
4) it closes：After transferring film, open clip, discard separation gel, take out NC films, put it into 5% newly configure it is de-
In fat milk power solution, it is placed in room temperature on parallel shaking table and closes 1h；
5) primary antibody is incubated：After closing, purpose band is sheared according to destination protein different molecular weight, pays attention to general one
Film only shears a destination protein as possible.It is washed on TBST buffer solution shaking tables 3 times, each 10min.According to antibody specification thinner ratio
Example dilution antibody, purpose band is put in the antibody incubation box of corresponding antibody diluent, 4 DEG C of overnight incubations；
6) secondary antibody is incubated：Next day takes out destination protein band, cleans 3 times with TBST albumen buffer solution shaking tables, every time
10min.Secondary antibody is selected according to primary antibody Species origin.Purpose band is put into corresponding secondary antibody diluent, is slowly shaken on shaking table
It is dynamic to be incubated 1h；
7) develop：After secondary antibody is incubated, destination protein band is washed 3 times with TBST solution, each 10min.Meanwhile matching
ECL chemical luminescence for liquid is set, the destination protein band that washing finishes is put into gel imager, under the conditions of being protected from light, hair is added
Light liquid shows that all luminescent solutions is made to can be uniformly dispersed in band, after being incubated 1min, adjusts visualizer and be exposed imaging.
The optimal separation range of 1 various concentration separation gel of table
2 separation gel preparation method of table
Table 3 5% concentrates glue configuration method
Three, experimental result
1, photoaffinity labeling technology law pull down target proteins
In order to differentiate early period find psoralea corylifolia active constituent corylin action target, illustrate how corylin is
Inhibit the transcriptional activity of SREBPs, and foundation is provided for work such as later stage structure optimizations.This seminar passes through photoaffinity labeling skill
Corylin is connected on magnetic bead (corylin-beads) by art, is incubated with liver homogenate, will be with the method for centrifugation
The Protein Separation that CompoundA-beads is combined comes out, and is identified through protein spectrum after elution.In addition, by the way that Compound is added
A is as competitor, and Compound A-beads competitive binding target proteins, in this way, the albumen that Compound A-beads are combined
It is mostly the background of non-specific binding, by comparison, our successful identifications go out the effect of active constituent corylin in psoralea corylifolia
Target spot is HSP90AB1.
2, the interaction of molecules of compound corylin and HSP90AB1
The interaction between (MST) technology detection macro-molecular protein and micromolecular compound is sprung up using micro heat.
We use positive compounds of the classical inhibitor 17-AAG of HSP90 as this experiment, simultaneously by Molecular Cloning: A Laboratory recombination
Purifying obtains EGFP-HSP90AB1 albumen.EGFP-HSP90AB1 can interact with 17-AGG, and be counted by simulating
It is 266.09 ± 65.76nM (Fig. 1) that it, which is calculated, in conjunction with dissociation constant KD, this data and the numerical value of previous literature report are close.
It is therefore believed that this evaluation system is reliable.Then, we utilize this system thinking recombinant protein EGFP-HSP90AB1 and benefit
It interacts between bone fat is peaceful, as a result similar with 17-AAG, equally with EGFP-HSP90AB1 albumen phase can occur for corylin
Interaction, and it is 24.65 ± 10.16nM (Fig. 2) that it, which combines dissociation constant, the dissociation constant of this numeric ratio 17-AAG low 10
Times or more.Illustrate that corylin can be combined with each other with HSP90AB1 and binding ability is 10 times stronger than positive compound 17-AAG.
After the binding site that clear corylin is combined with HSP90AB1, we, which further analyze corylin structure effect, closes
System.First, the chemical constitution based on corylin carries out modification to its phenolic hydroxyl group and is transformed into methoxyl group, and by this compound
It is named as Compound A.It is tested by MST and finds that Compound A can hardly be combined (Fig. 3) with HSP90AB1, show to mend
The importance of the peaceful phenolic hydroxyl group of bone fat.And another compound N eobavaisoflavone after modifying can still be tied with HSP90AB1
It closes, dissociation constant is 37.24 ± 47.84nM (Fig. 4).
3, inhibiting effect of the compound corylin to the downstreams HSP90AB1 protein expression
Above-mentioned experiment proves that corylin can effectively be combined with HSP90AB1.In order to determine corylin and HSP90AB1
In conjunction with it is rear whether be inhibiting effect to HSP90AB1, seminar determines corylin intervention to the downstreams HSP90AB1 client protein
The influence of AKT.If corylin is inhibiting effect to HSP90AB1 after being combined with HSP90AB1, inevitably result in downstream
Client protein AKT is unstable, and phosphorylation AKT can be by dephosphorylation, and then p-AKT is reduced.Western blot results are as schemed
5, shown in 6, corylin intervene after in cell p-AKT significantly reduce, and in when m- dose dependent.
To sum up, corylin is effective inhibitor of HSP90AB1, can be used for preparing the medicine for inhibiting HSP90AB1
Object preparation.The pharmaceutical preparation contains corylin or its pharmaceutical salts or its prodrug, also contain pharmaceutically acceptable carrier or
Pharmaceutically acceptable dosage form is made in excipient；Pharmaceutically acceptable carrier or excipient include one or more solid
Body, semisolid or Auxiliary Liquid Material；Pharmaceutically acceptable dosage form includes tablet, capsule, granule, injection, pill, sugar
Starch agent, powder, paste.
Claims (4)
1. corylin is used as the purposes of HSP90AB1 inhibitor.
2. a kind of pharmaceutical preparation inhibiting HSP90AB1, it is characterised in that：Containing corylin or its pharmaceutical salts or its prodrug, also
Containing pharmaceutically acceptable carrier or excipient, pharmaceutically acceptable dosage form is made.
3. pharmaceutical preparation according to claim 2, it is characterised in that：The pharmaceutically acceptable carrier or excipient
Including one or more solids, semisolid or Auxiliary Liquid Material.
4. pharmaceutical preparation according to claim 2, it is characterised in that：The pharmaceutically acceptable dosage form includes piece
Agent, capsule, granule, injection, pill, syrup, powder, paste.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110090208A (en) * | 2019-04-24 | 2019-08-06 | 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） | Corylin is preparing Nrf2 inhibitor, is inhibiting the application of the drug of related disease, anticancer drug with Nrf2 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106619605A (en) * | 2017-01-22 | 2017-05-10 | 中国药科大学 | Medicinal application of corylin |
-
2018
- 2018-04-19 CN CN201810352212.4A patent/CN108283635A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106619605A (en) * | 2017-01-22 | 2017-05-10 | 中国药科大学 | Medicinal application of corylin |
Non-Patent Citations (1)
| Title |
|---|
| 聂丽娟等: "补骨脂抗氧化及抗肿瘤活性成分的研究", 《蚌埠医学院学报》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110090208A (en) * | 2019-04-24 | 2019-08-06 | 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） | Corylin is preparing Nrf2 inhibitor, is inhibiting the application of the drug of related disease, anticancer drug with Nrf2 |
| WO2020215481A1 (en) * | 2019-04-24 | 2020-10-29 | 广东省中医院 | Applications of psoralen in preparing nrf2 inhibitor, medicament for nrf2 inhibition-related diseases, and anticancer medicament |
| CN110090208B (en) * | 2019-04-24 | 2021-11-23 | 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） | Application of psoralen in preparation of Nrf2 inhibitor, medicine for treating diseases related to Nrf2 inhibition and anticancer medicine |
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Application publication date: 20180717 |