CN107349202A - Applications of the LGK974 in the product for preparing treatment polycystic kidney disease - Google Patents
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Abstract
The invention discloses applications of the LGK974 in the product for preparing treatment polycystic kidney disease.The present invention is with Vil Cre；Pkd2f3/f3Mouse is as ADPKD animal models, the results showed that Wnt signal path inhibitor-LGK974 can weaken Vil Cre；Pkd2f3/f3The renal cyst degree of mouse, can reduce Vil Cre；Pkd2f3/f3The kidney weight ratio of mouse, can reduce Vil Cre；Pkd2f3/f3The renal cystis index of mouse, can reduce Vil Cre；Pkd2f3/f3The content of creatinine and urea nitrogen in the blood of mouse.Analysis of the present invention for ADPKD pathogenesis, significance is respectively provided with for treating the ADPKD research and development of medicine.
Description
Technical field
The invention belongs to biomedicine field, and in particular to LGK974 answering in the product for preparing treatment polycystic kidney disease
With applications of the more particularly to LGK974 in the product for preparing treatment kidney of patients with autosomal dominant polycystic kidney disease disease.
Background technology
Kidney of patients with autosomal dominant polycystic kidney disease (Autosomal Dominant Polycystic Kidney Disease,
ADPKD) disease is one of most common monogenic inheritance nephrosis.Its main clinic symptoms is that bilateral renal is formed greatly
The spherical fluidity tumour to differ in size is measured, and progressive increases, and destroys the 26S Proteasome Structure and Function of kidney, ultimately results in kidney function
Can exhaustion.ADPKD generally falls ill in adult, and its incidence of disease is 1:500-4000, it is last renal failure eventually in the world at present
The fourth-largest main cause exhausted.In addition to nephrosis phenotype, the non-renal tract lesion phenotype of ADPKD patient is also ten clearly demarcated
It is aobvious：There is hepatic cyst in 83% ADPKD patient, and pancreatic cyst, 16% patient occurs in 10% ADPKD patient
There is cerebral aneurysm.Other Pathologies include aortic root, and Thoracic arteries are abnormal, mitral valve prolapse and abdominal hernia
Gas.About 50% patient will appear from last kidney failure eventually after 60 years old.The urea nitrogen (BUN) of normal person refers to model
It is 44-133 μm of ol/L to enclose for 2.14-7.14mmol/L, serum creatinine (Cr) term of reference, as more than 133 μm ol/L of serum creatinine
For the inflammation damnification phase, more than 186 μm ol/L are the renal dysfunction phase, are renal failure stage more than 451umol/L.
Current research result shows that ADPKD Disease-causing genes PKD1 and PKD2 missing can cause classical Wnt signal
The abnormal activation of path, classical Wnt/β-catenin signal paths are likely to close participation the renal cystis forming process
Regulation.
LGK974 is effective specific Porcn inhibitor, IC50 4nM.LGK974 is pressed down by specificity
The acylation of Porcn mediations processed is modified so as to suppress Wnt ligand moleculars such as Wnt-3a secretion.LGKP74 can suppress
Mammal Porcn acyltransferase activities, suppress the activation of Wnts parts and reduce Wnt acceptors LPR6 phosphoric acid
Change so as to promote the reduction of Wnt signal paths expression of target gene, and then suppress the activity of classical Wnt path.LGK974
As effective Porcn specific inhibitors, the current malignant tumour that Wnt parts are relied in treatment.At present, the medicine
Having been used for the clinical I phases tests.Wnt-C59 is also specific Porcn inhibitor, acts on the more of Wnt3A mediations
The activation of the luciferase of poly- TCF binding sites driving.Wnt-C59 can suppress mammal Porcn in nanomolar range
Acyltransferase activity.IC50 is 74pM in HEK293 cells.
The content of the invention
It is an object of the present invention to provide LGK974 new application.
The invention provides applications of the LGK974 in the product for preparing treatment kidney of patients with autosomal dominant polycystic kidney disease.
Present invention also offers applications of the LGK974 at least one of following (1)-(4) product is prepared：
(1) product of sickened body renal cyst degree is weakened；
(2) product of sickened body kidney weight ratio is reduced；
(3) product of the renal cystis index of sickened body is reduced；
(4) product of creatinine and/or urea nitrogen content in sickened body blood is reduced.
It is a further object to provide a kind of product.
The active component of product provided by the invention is LGK974；The purposes of the product is in following (a)-(e)
At least one：
(a) kidney of patients with autosomal dominant polycystic kidney disease is treated；
(b) sickened body renal cyst degree is weakened；
(c) sickened body kidney weight ratio is reduced；
(d) the renal cystis index of sickened body is reduced；
(e) creatinine and/or urea nitrogen content in sickened body blood are reduced.
In above-mentioned application or the said goods, the sickened body is with kidney of patients with autosomal dominant polycystic kidney disease clinical condition
The body of shape.
In above-mentioned application or the said goods, the product is medicine.
The present invention is with Vil-Cre；Pkd2f3/f3Mouse has carried out the suppression of Wnt signal paths as ADPKD animal models
The effect disquisition that agent-LGK974 and Wnt-C59 treats to kidney of patients with autosomal dominant polycystic kidney disease (ADPKD),
As a result show, Wnt signal path inhibitor-LGK974 has for treatment kidney of patients with autosomal dominant polycystic kidney disease
Certain effect, is embodied in：(1) Vil-Cre can be weakened；Pkd2f3/f3The renal cyst degree of mouse；(2) can drop
Low Vil-Cre；Pkd2f3/f3The kidney weight ratio of mouse；(3) Vil-Cre can be reduced；Pkd2f3/f3Creatinine in the blood of mouse
And/or the content of urea nitrogen.The present invention is for kidney of patients with autosomal dominant polycystic kidney disease (ADPKD) pathogenesis
Analysis, the research and development for the medicine for the treatment of kidney of patients with autosomal dominant polycystic kidney disease (ADPKD) are respectively provided with significance.
Brief description of the drawings
Fig. 1 is the PCR testing results of backcross progeny murine genes type.Wherein, Figure 1A is for Pkd2 gene PCRs
Testing result, Pkd2f3/f3For Pkd2 gene pures, Pkd2+/f3For Pkd2 genetic heterozygosis；Figure 1B is for Cre
The PCR testing results of gene, Vil-Cre are expression Vil-Cre；WT is not express Vil-Cre.
Fig. 2 is Vil-Cre；Pkd2f3/f3Mouse simulation mankind ADPKD disease phenotype.Wherein, Tu2AWei
Vil-Cre；Pkd2f3/f3Mouse kidney form；Fig. 2 B are Vil-Cre；Pkd2f3/f3Mouse liver form；Fig. 2 C are
Vil-Cre；Pkd2f3/f3Mice pancreatic form；Fig. 2 D are Vil-Cre；Pkd2f3/f3The kidney cross section of mouse；Fig. 2 E are
Pkd2f3/f3The kidney cross section of mouse.
Fig. 3 is that the kidney of two groups of mouse visually observes and HE coloration results.Wherein, Fig. 3 a visually observe for control group
As a result；Fig. 3 b are treatment group's visual results；Fig. 3 c are control group HE coloration results；Fig. 3 d are treatment group
HE coloration results.
Fig. 4 is the kidney weight ratio measurement result of two groups of mouse.
Fig. 5 is the renal cystis assessment of indices result of two groups of mouse.
Fig. 6 is the assay result of urea nitrogen (BUN) and creatinine (Cr) in the blood of two groups of mouse.Wherein,
Fig. 6 A are creatinine content；Fig. 6 B are urea nitrogen content.
Embodiment
Experimental method used in following embodiments is conventional method unless otherwise specified.
Material used, reagent etc., unless otherwise specified, are commercially obtained in following embodiments.
Pkd2 in following embodimentsf3/f3Mouse is recorded in document " lngyu Kim, Tianbing Ding, Yulong Fu, et
al.Conditional Mutation of Pkd2Causes Cystogenesis and Upregulatesβ-Catenin.J Am
Soc Nephrol,2009(20):In 2556-2569 ".It builds and authentication step is as follows：First, in Pkd2 genes
3 exon both sides insert two loxP sites, have FRT sites in Positive selectable Neo both sides, due to
The structure does not block the expression of normal Pkd2 genes completely, so being passed through with this carrier caused by gene targeting
Pkd2nf3Mouse can avoid dying from embryonic period, embryonic phase；Again by Pkd2nf3Mouse and ACTB-Flep mouse hybrids, that is, produce and do not have
There is the Pkd2 of Neo elementsf3/f3Mouse.In view of in Pkd2f3/f3More capsule phenotypes, PC2 table are not observed in mouse
Up to also not changing, it is believed that this Pkd2f3Allele will not cause Pkd2 expression to inactivate.
The transgenic mice with Vil-Cre recombinases in following embodiments is purchased from The Jackson Laboratory,
Strain Name：B6.SJL-Tg (Vil-cre) 997Gum/J, Stock Number：004586, refer to network address：
http://jaxmice.jax.org/strain/004586.html。
LGK974 in following embodiments is the product of Selleck companies, catalog number S7143.Molecular weight：
396.44；Chemical formula：C23H20N6O；No. CAS：1243244-14-5；Dissolubility (25 DEG C)：DMSO 79mg/mL,
Water<1mg/mL, ethanol<1mg/mL；Stability：3 years -20 DEG C of powderies, -80 DEG C of June are dissolved in solvent.
Wnt-C59 in following embodiments is the product of Selleck companies, catalog number S7037.Molecular weight：
379.45；Chemical formula：C25H21N3O；No. CAS：1243243-89-1；Dissolubility (25 DEG C)：DMSO 76mg/mL,
Water<1mg/mL, ethanol<1mg/mL；Stability：3 years -20 DEG C of powderies, -80 DEG C of June are dissolved in solvent.
Embodiment 1, Vil-Cre；Pkd2f3/f3The structure of mouse model and identification
Vil-Cre；Pkd2f3/f3Mouse is the mouse mould that Pkd2 can be knocked out with conditionity established using Cre-loxP systems
Type, it can produce and mankind's kidney of patients with autosomal dominant polycystic kidney disease (Autosomal Dominant Polycystic Kidney
Disease, ADPKD) similar to clinical phenotypes, and kidney failure is died from early days, ADPKD animal models can be used as.Its
Structure and qualification process are as follows：
First, Vil-Cre；Pkd2f3/f3The structure of mouse model
By Pkd2f3/f3Mouse and the transgenic mice (B6.SJL-Tg (Vil-cre) 997Gum/J) with Vil-Cre recombinases
Hybridized, obtaining F1 generation, (genotype for having 1/2 offspring in theory is Vil-Cre:Pkd2+/f3；The gene of 1/2 offspring
Type is Pkd2+/f3)；By Vil-Cre in F1 generation:Pkd2+/f3Mouse (enters performing PCR identification, specific side for Cre genes
Method see below, identified to obtain the F1 generation mouse that size is 650bp purpose bands) and Pkd2f3/f3Mouse is returned
Hand over, obtain backcross progeny.
From backcross progeny obtained as above, screening obtains Pkd2 gene pures, while can express Vil-Cre mouse,
Concrete operations are as follows：
Backcross progeny rat-tail genome is extracted, using it as template, performing PCR is entered to Pkd2 genes and Cre genes respectively
Identification, wherein the PCR the primers sequence for Pkd2 genes is following three：
5 '-TCTGACTTGCAGACTGTGGG-3 ',
5’-AGGTAGGGGAAGGTCAGGGTT GG-3’；
5'-TTTACGTCCAGCCAAGCT-3'；
PCR the primers sequence for Cre genes is following two：
5’-CCAGGTTACGGATATAGTTCATG-3’；
5’-TGCCACGACCAAGTGACAGC-3’。
When entering performing PCR amplification in same reaction system using three primers for Pkd2 genes, if obtained
Size is respectively 650bp and 350bp two bands, then corresponding backcross progeny mouse is Pkd2 genetic heterozygosis
(Pkd2+/f3), if obtaining the single band that size is 650bp, corresponding backcross progeny mouse is Pkd2 genes
Homozygosis (Pkd2f3/f3)；When entering performing PCR amplification using two primers for Cre genes, it is if obtaining size
650bp purpose band, then corresponding backcross progeny mouse expression Vil-Cre, if it is 650bp not obtain size
Purpose band, then corresponding backcross progeny mouse do not express Vil-Cre.
As a result as shown in figure 1, Pkd2 in Figure 1Af3/f3For Pkd2 gene pures, Vil-Cre in Figure 1B is can
Express Vil-Cre.Identified more than, the Pkd2 gene pures obtained from backcross progeny, while Vil-Cre can be expressed
Mouse, as Vil-Cre:Pkd2f3/f3Mouse.Vil-Cre is the Cre enzymes for being controlled by Villin1 promoters, wherein Villin1
Promoter is expressed in the enterocyte of the 12.5th day mice embryonic phase, and mouse, can be in cell in the presence of Cre enzymes
Pkd2 is produced in leveld3/d3, due to Pkd2d3/d33 exons on allele have been cut away, and then are produced
Frameshift mutation, cause 3 exon downstreams nearby to produce terminator, and then turn into Pkd2 gene outcomes PC2
Truncated protein.
2nd, Vil-Cre；Pkd2f3/f3The identification of mouse model
The Vil-Cre that conventinal breeding step 1 obtains；Pkd2f3/f3Mouse, observe its existing state.The monthly age of mouse four is treated,
Its kidney, liver, pancreas are taken, observes lesion situation；Carrying out HE staining analysis to kidney in addition, (concrete operations are joined
See the correlation step of embodiment 2).Pkd2 is set simultaneouslyf3/f3Mouse is as control.
As a result as shown in Fig. 2 wherein, Fig. 2A Vil-Cre；Pkd2f3/f3Mouse kidney form；Fig. 2 B are
Vil-Cre；Pkd2f3/f3Mouse liver form；Fig. 2 C are Vil-Cre；Pkd2f3/f3Mice pancreatic form；Fig. 2 D are
Vil-Cre；Pkd2f3/f3The kidney cross section of mouse；Fig. 2 E are Pkd2f3/f3The kidney cross section of mouse.Can be with from figure
Find out, the Vil-Cre that step 1 obtains；Pkd2f3/f3Mouse is in 4~May or so death, its kidney, liver, pancreas
There is serious tumour, and the HE coloration results of kidney further demonstrate that kidney is serious without kidney essence, renal function
It is impaired, judge Vil-Cre；Pkd2f3/f3Mouse dies from kidney failure caused by renal cyst, and brood Pkd2 of the same agef3/f3It is small
Then phenotype is normal for mouse.
Result above shows, the Vil-Cre that step 1 obtains；Pkd2f3/f3Mouse phenotype is similar to mankind ADPKD patient,
ADPKD animal models can be used as.
The application of embodiment 2, LGK974 and Wnt-C59 in kidney of patients with autosomal dominant polycystic kidney disease is treated
The Vil-Cre that the present embodiment is obtained with embodiment 1；Pkd2f3/f3Mouse is as ADPKD animal models, research point
Analyse applications of the LGK974 and Wnt-C59 in kidney of patients with autosomal dominant polycystic kidney disease is treated.It is specific as follows：
First, experimental method
1st, experiment packet and processing
(1) LGK974 solution
LGK974 is dissolved with solution A, is 3mg/mL to its concentration, after with normal saline dilution to 0.3mg/ml.
The solvent of solution A is water, and solvent is methylcellulose and Tween 80, wherein, methylcellulose is in solution A
Mass fraction is 0.5%, and volume fraction of the Tween 80 in solution A is 0.5%.
(2) Wnt-C59 solution
Wnt-C59 is dissolved with solution A, is 3mg/mL to its concentration, after with normal saline dilution to 1mg/ml.
(3) it is grouped and handles
It is divided into LGK974 treatment groups, Wnt-C59 treatment groups and control group (placebo) according to whether treated with medicaments,
Every group randomly selects at least 20 Vil-Cre:Pkd2f3/f3Mouse.After mouse is born the 30th day, carry out continuous
Bimestrial gastric infusion, daily administration is until the monthly age of mouse three is discontinued, and every mouse for the treatment of group is by 3mg/kg (per kg
Body weight gives 3mg LGK974) and 10mg/kg (giving 10mg Wnt-C59 per kg body weight) dosage administration；Control
The injection daily of every mouse of group it is isometric containing the methylcellulose of equivalent 0.5%/0.5% Tween 80 physiological saline.
2nd, each group mouse treatment is analyzed
(1) the renal cyst phenotype of two groups of mouse of HE staining analysis
After the monthly age of mouse two is discontinued, every group randomly selects no less than 10 mouse, after execution, extracts bilateral renal.
It is precisely weighed on electronic balance, calculates kidney weight ratio (g/g), i.e. bilateral renal weight (g)/weight (g).
Bilateral renal is cut along sagittal plane afterwards, fixes 24 hours with 10% neutral formalin solution, rear graded ethanol
Dehydration, then routinely embedded with paraffin wax embedding, wax stone row section and HE dyeing after.
A. dehydration embedding
Specific steps：1. it is dehydrated：Ethanol 1h → 90% of the ethanol 1h of the ethanol 1h of 70% ethanol 1h → 75% → 80% → 85%
The ethanol 1h of the ethanol 1h of ethanol 1h → 95% → 100% → dimethylbenzene 15min × 2；2. embed：Paraffin wax embedding is wrapped
Bury.
B. cut into slices
Kidney wax stone is made to the continuous renal histotomy of 3 μ m thicks on cycle type slicer, gently propped up with writing brush,
It is sufficiently spread out in warm water, then the slide treated with poly-D-lysine picks up nephridial tissue and cut into slices, electric air drier
Dry, in being then put in electric heating constant-temperature blowing drying box, 70 DEG C of constant temperature toast 1 hour, so that histotomy and glass
Piece close adhesion, it is placed in standby in box.
C.HE pathological stainings
Principle：Haematine (hematoxylin) dye liquor for alkalescence, mainly make endonuclear chromatin with it is intracytoplasmic
Ribosomes hyacinthine；Yihong (eosin) is acid dyes, mainly the composition in cytoplasm and extracellular matrix
It is red.
Step：
1. dimethylbenzene dewaxes, washed away afterwards with 100% ethanol；
2. the ethanol of various concentrations aquation successively；
Washed 5 minutes 3. phosphate buffer shaking table is slow；
4. haematine extracts 8 times；
5. flowing water rinses 5 minutes；
6. hydrochloride alcohol extracts 8 times；
7. flowing water rinses 2 minutes；
8. eosin stains 10 minutes；
9. the ethanol of various concentrations is dehydrated successively；
10. dimethylbenzene is transparent, neutral gum mounting is used afterwards；Micro- sem observation.
(11) result is shown：Cytoplasm is red, nucleus bluish violet.
(2) measure of the renal cystis index of mouse
After the Kidney sections of LGK974 treatment groups, Wnt-C59 treatment groups and control group mice HE dyeing are taken pictures, figure
Piece runs on GNU Image Manipulation Program.Picture is converted into gray-scale map first, then adjusts picture
Pixel is to 800 × 598.By after adjustment picture operation addition grid program, set each grid as size be 22 × 22
Pixel.Calculate tumour area grid quantity and the total number of grid ratio in kidney region can obtain tumour index.
(3) LGK974 treatment groups, the survey of Wnt-C59 treatment groups and control group mice ADPKD related biochemical indicators
It is fixed
The present inventor goes out the improvement degree for the treatment of group's Mouse Kidney liver function for accurate response, further right
Urea nitrogen (BUN) and creatinine (Cr) in LGK974 treatment groups, Wnt-C59 treatment groups and control group mice blood
Content be determined, with the situation of change of this precise reaction renal function, reflect the order of severity of tumour.Specifically
Operation is as follows：
At three monthly age of mouse, by LGK974 treatment groups, Wnt-C59 treatment groups and control group mice etherization,
Mouse blood is extracted from inferior caval vein, it is serum that supernatant is obtained after centrifugation.Creatinine can be measured by carrying out chemical examination to serum
And urea nitrogen content.
2nd, experimental result
1st, the renal cyst phenotype of LGK974 treatment groups, Wnt-C59 treatment groups and control group mice
Visually observe with HE coloration results as shown in figure 3, it can be seen that LGK-974 treatment groups relatively compare
Group (placebo) has more kidneys essence, and renal cyst phenotype is considerably less than control group, but after Wnt-C59 treatments
There is no significant difference with control group.In addition, LGK974 treatment groups, Wnt-C59 treatment groups and control group mice
Kidney weight ratio (g/g) measurement result is as shown in figure 4, result shows the kidney weight ratio (g/g) of LGK974 treatment groups
Significantly less than control group (p=0.000015), there is statistical significance, but the kidney weight ratio (g/g) of Wnt-C59 treatment groups
Though it is not statistically significant (p=0.11) compared with control group compared to there is decline.
2nd, the renal cystis index of LGK974 treatment groups, Wnt-C59 treatment groups and control group mice
The renal cystis assessment of indices result such as Fig. 5 of LGK974 treatment groups, Wnt-C59 treatment groups and control group mice
Shown, LGK974 treatment groups significantly reduce (p=0.000019) compared with control group compared to the renal cystis index, have statistics
Meaning is learned, though the renal cystis index of Wnt-C59 treatment groups is compared compared with control group decline, but is anticipated without statistics
Adopted (p=0.09).
3rd, the measure of LGK974 treatment groups, Wnt-C59 treatment groups and control group mice ADPKD related biochemical indicators
Urea nitrogen (BUN) and creatinine in the blood of LGK974 treatment groups, Wnt-C59 treatment groups and control group mice
(Cr) assay result is as shown in fig. 6, result is shown, urea nitrogen in the blood of LGK974 treatment groups mouse
(BUN) compared with the content of creatinine (Cr) is compared with control group, there are downward trend, the blood of LGK974 treatment groups
Middle urea nitrogen and serum creatinine have statistical significance significantly less than control group (p=0.00005, p=0.00174), but
Though the urea nitrogen of Wnt-C59 treatment groups is compared with serum creatinine compared with control group decline, it is not statistically significant
(p=0.08, p=0.012).
The experimental result of comprehensive the present embodiment, it is seen that LGK974 is in treatment kidney of patients with autosomal dominant polycystic kidney disease
(ADPKD) there is certain effect in.
Claims (5)
- Applications of the 1.LGK974 in the product for preparing treatment kidney of patients with autosomal dominant polycystic kidney disease.
- Applications of the 2.LGK974 at least one of following (1)-(4) product is prepared：(1) product of sickened body renal cyst degree is weakened；(2) product of sickened body kidney weight ratio is reduced；(3) product of the renal cystis index of sickened body is reduced；(4) product of creatinine and/or urea nitrogen content in sickened body blood is reduced.
- 3. a kind of product, its active component is LGK974；The purposes of the product is in following (a)-(e) It is at least one：(a) kidney of patients with autosomal dominant polycystic kidney disease is treated；(b) sickened body renal cyst degree is weakened；(c) sickened body kidney weight ratio is reduced；(d) the renal cystis index of sickened body is reduced；(e) creatinine and/or urea nitrogen content in sickened body blood are reduced.
- 4. the product described in application according to claim 1 or 2 or claim 3, it is characterised in that：Institute It is the body with kidney of patients with autosomal dominant polycystic kidney disease clinical symptoms to state sickened body.
- 5. the product described in application according to claim 1 or 2 or claim 3, it is characterised in that：Institute It is medicine to state product.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016007775A1 (en) * | 2014-07-11 | 2016-01-14 | Genentech, Inc. | Notch pathway inhibition |
| CN105343096A (en) * | 2014-08-19 | 2016-02-24 | 北京仕林伟业生物科技有限公司 | New uses of Wnt signal pathway inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016007775A1 (en) * | 2014-07-11 | 2016-01-14 | Genentech, Inc. | Notch pathway inhibition |
| CN105343096A (en) * | 2014-08-19 | 2016-02-24 | 北京仕林伟业生物科技有限公司 | New uses of Wnt signal pathway inhibitor |
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