CN107349202B - Application of the LGK974 in the product of preparation treatment polycystic kidney disease - Google Patents
Application of the LGK974 in the product of preparation treatment polycystic kidney disease Download PDFInfo
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- CN107349202B CN107349202B CN201610301472.XA CN201610301472A CN107349202B CN 107349202 B CN107349202 B CN 107349202B CN 201610301472 A CN201610301472 A CN 201610301472A CN 107349202 B CN107349202 B CN 107349202B
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
Abstract
The invention discloses application of the LGK974 in the product of preparation treatment polycystic kidney disease.The present invention is with Vil-Cre;Pkd2f3/f3Mouse is as ADPKD animal model, 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 all has significance for treating the research and development of drug of ADPKD.
Description
Technical field
The invention belongs to biomedicine fields, and in particular to LGK974 answering in the product of preparation treatment polycystic kidney disease
With application of the in particular to LGK974 in the product of preparation treatment kidney of patients with autosomal dominant polycystic kidney disease disease.
Background technique
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 formed for bilateral renal
The spherical fluidity tumour largely to differ in size, and progressive increases, and destroys the structure and function of kidney, eventually leads to renal function and decline
It exhausts.ADPKD usually falls ill in adult, disease incidence 1:500-4000, is the fourth-largest of current terminal kidney failure in the world
Main cause.In addition to nephrosis phenotype, the non-renal tract lesion phenotype of ADPKD patient is also fairly obvious: 83% ADPKD patient
There is hepatic cyst, pancreatic cyst occurs in 10% ADPKD patient, and cerebral aneurysm occurs in 16% patient.Other Pathology packets
Aortic root is included, Thoracic arteries are abnormal, mitral valve prolapse and stomach wall hernia.About 50% patient will occur eventually after 60 years old
Last kidney failure.Urea nitrogen (BUN) term of reference of normal person is 2.14-7.14mmol/L, and serum creatinine (Cr) term of reference is 44-
133 μm of ol/L are the inflammation damnification phase when serum creatinine is more than 133 μm of ol/L, and more than 186 μm ol/L are the renal impairment phase, are more than
451umol/L is renal failure stage.Current research the result shows that, the missing of ADPKD Disease-causing gene PKD1 and PKD2 can be led
The abnormal activation of classical Wnt signal path is caused, classical Wnt/β-catenin signal path is likely to close participation the renal cystis
The adjusting of forming process.
LGK974 is the inhibitor of effective specificity Porcn, IC50 4nM.LGK974 inhibits Porcn by specificity
The acylation modification of mediation is to inhibit the secretion of Wnt ligand molecular such as Wnt-3a.LGKP74 can inhibit mammal Porcn acyl
Based transferase activity inhibits the activation of Wnts ligand and reduces the phosphorylation of Wnt receptor LPR6 to promote Wnt signal path target
Gene expression reduces, and then inhibits the activity of classical Wnt access.LGK974 is current as effective Porcn specific inhibitor
The malignant tumour of Wnt ligand is relied in treatment.Currently, the medicine has been used for clinical I phase experiment.Wnt-C59 is also specific Porcn
Inhibitor, act on Wnt3A mediation poly TCF binding site driving luciferase activation.Wnt-C59 can rub receiving
You are horizontal to inhibit mammal Porcn acyltransferase activity.IC50 is 74pM in HEK293 cell.
Summary of the invention
It is an object of the present invention to provide the new applications of LGK974.
The present invention provides application of the LGK974 in the product of preparation treatment kidney of patients with autosomal dominant polycystic kidney disease.
The present invention also provides LGK974 to prepare the application in the product of at least one of following (1)-(4):
(1) weaken the product of sickened body renal cyst degree;
(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 products.
The active constituent of product provided by the invention is LGK974;The purposes of the product be in following (a)-(e) extremely
Few one kind:
(a) kidney of patients with autosomal dominant polycystic kidney disease is treated;
(b) weaken sickened body renal cyst degree;
(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 drug.
The present invention is with Vil-Cre;Pkd2f3/f3Mouse has carried out the inhibition of Wnt signal path as ADPKD animal model
The effect disquisition that agent-LGK974 and Wnt-C59 treats kidney of patients with autosomal dominant polycystic kidney disease (ADPKD), the results showed that,
Wnt signal path inhibitor-LGK974 for treatment kidney of patients with autosomal dominant polycystic kidney disease have the effect of it is certain, specifically
It is embodied in: (1) Vil-Cre can be weakened;Pkd2f3/f3The renal cyst degree of mouse;(2) Vil-Cre can be reduced;Pkd2f3/f3Mouse
Kidney weight ratio;(3) Vil-Cre can be reduced;Pkd2f3/f3The content of creatinine and/or urea nitrogen in the blood of mouse.The present invention
Analysis for kidney of patients with autosomal dominant polycystic kidney disease (ADPKD) pathogenesis, for treating autosomal dominant
The research and development of the drug of polycystic kindey (ADPKD) all have significance.
Detailed description of the invention
Fig. 1 is the PCR testing result of backcross progeny murine genes type.Wherein, Figure 1A is to detect to tie for Pkd2 gene PCR
Fruit, Pkd2f3/f3For Pkd2 gene pure, Pkd2+/f3For Pkd2 genetic heterozygosis;Figure 1B is the PCR detection knot for Cre gene
Fruit, Vil-Cre are expression Vil-Cre;WT is not express Vil-Cre.
Fig. 2 is Vil-Cre;Pkd2f3/f3The disease phenotype of mouse simulation mankind ADPKD.Wherein, Fig. 2A Vil-Cre;
Pkd2f3/f3Mouse kidney form;Fig. 2 B is Vil-Cre;Pkd2f3/f3Mouse liver form;Fig. 2 C is Vil-Cre;Pkd2f3/f3
Mice pancreatic form;Fig. 2 D is Vil-Cre;Pkd2f3/f3The kidney cross section of mouse;Fig. 2 E is Pkd2f3/f3The kidney of mouse is horizontal
Section.
Fig. 3 is that the kidney of two groups of mouse visually observes and HE coloration result.Wherein, Fig. 3 a is that control group visually observes knot
Fruit;Fig. 3 b is treatment group's visual results;Fig. 3 c is control group HE coloration result;Fig. 3 d is treatment group HE coloration result.
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 is
Creatinine content;Fig. 6 B is urea nitrogen content.
Specific embodiment
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.
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 is constructed and authentication step is as follows: firstly,
Two sites loxP are inserted into 3 exon two sides of Pkd2 gene, have the site FRT in the two sides of Positive selectable Neo, due to this
Structure does not block the expression of normal Pkd2 gene completely, so the Pkd2 generated with this carrier by gene targetingnf3
Mouse can avoid dying of embryonic period, embryonic phase;Again by Pkd2nf3Mouse and ACTB-Flep mouse hybrid, that is, be produced without Neo element
Pkd2f3/f3Mouse.In view of in Pkd2f3/f3More capsule phenotypes are not observed in mouse, also no change has taken place for the expression of PC2, recognizes
For this Pkd2f3Allele not will lead to the expression inactivation of Pkd2.
The transgenic mice with Vil-Cre recombinase in following embodiments is purchased from The Jackson
Laboratory, Strain Name:B6.SJL-Tg (Vil-cre) 997Gum/J, Stock Number:004586, is detailed in net
Location: http://jaxmice.jax.org/strain/004586.html.
LGK974 in following embodiments is the product of Selleck company, 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,
Ethyl alcohol < 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 company, 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,
Ethyl alcohol < 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 building and identification of mouse model
Vil-Cre;Pkd2f3/f3Mouse is the mouse mould that Pkd2 can be knocked out with conditionity using the foundation of Cre-loxP system
Type 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 early stage dies of kidney failure, can be used as ADPKD animal model.It is constructed and identification
Process is as follows:
One, Vil-Cre;Pkd2f3/f3The building of mouse model
By Pkd2f3/f3Mouse and the transgenic mice (B6.SJL-Tg (Vil-cre) for having Vil-Cre recombinase
997Gum/J) hybridized, obtaining F1 generation, (genotype for theoretically having 1/2 offspring is Vil-Cre:Pkd2+/f3;1/2 offspring's
Genotype is Pkd2+/f3);By Vil-Cre:Pkd2 in F1 generation+/f3Mouse (carries out PCR identification, specific method ginseng for Cre gene
It sees below, identified to obtain the F1 generation mouse that size is 650bp purpose band) and Pkd2f3/f3Mouse is returned, and is returned
Offspring.
From backcross progeny obtained as above, screening obtains Pkd2 gene pure, while can express the mouse of Vil-Cre, has
Gymnastics is made as follows:
Backcross progeny rat-tail genome is extracted, using it as template, PCR mirror is carried out to Pkd2 gene and Cre gene respectively
It is fixed, wherein the PCR the primer sequence for Pkd2 gene is following three:
5 '-TCTGACTTGCAGACTGTGGG-3 ',
5'-AGGTAGGGGAAGGTCAGGGTT GG-3';
5'-TTTACGTCCAGCCAAGCT-3';
PCR the primer sequence for Cre gene is following two:
5'-CCAGGTTACGGATATAGTTCATG-3';
5’-TGCCACGACCAAGTGACAGC-3’。
When carrying out PCR amplification in same reaction system using three primers for Pkd2 gene, if obtained big
Small is respectively two bands of 650bp and 350bp, then corresponding backcross progeny mouse is Pkd2 genetic heterozygosis (Pkd2+/f3), such as
Fruit obtains the single band that size is 650bp, then corresponding backcross progeny mouse is Pkd2 gene pure (Pkd2f3/f3);When adopting
When carrying out PCR amplification with two primers for Cre gene, if obtaining the purpose band that size is 650bp, corresponding time
Progeny mice is handed over to express Vil-Cre, if not obtaining the purpose band that size is 650bp, corresponding backcross progeny mouse
Do not express Vil-Cre.
As a result as shown in Figure 1, Pkd2 in Figure 1Af3/f3For Pkd2 gene pure, the Vil-Cre in Figure 1B is that can express
Vil-Cre.By identifying above, the Pkd2 gene pure obtained in the backcross progeny, while the mouse of Vil-Cre can be expressed,
As Vil-Cre:Pkd2f3/f3Mouse.Vil-Cre is the Cre enzyme for being controlled by Villin1 promoter, wherein Villin1 promoter
It is expressed in the mice embryonic phase the 12.5th day enterocyte, mouse can generate on a cellular level under the action of Cre enzyme
Pkd2d3/d3, due to Pkd2d3/d33 exons on allele have been cut away, and then generate frameshift mutation, lead to No. 3
Exon downstream nearby generates terminator, and then Pkd2 gene product PC2 is made to become truncated protein.
Two, Vil-Cre;Pkd2f3/f3The identification of mouse model
The Vil-Cre that conventinal breeding step 1 obtains;Pkd2f3/f3Mouse observes its existing state.To four monthly age of mouse,
Its kidney, liver, pancreas are taken, lesion situation is observed;In addition carrying out HE staining analysis to kidney, (concrete operations are referring to embodiment 2
Correlation step).Pkd2 is set simultaneouslyf3/f3Mouse is as control.
As a result as shown in Figure 2, wherein Fig. 2A Vil-Cre;Pkd2f3/f3Mouse kidney form;Fig. 2 B is Vil-Cre;
Pkd2f3/f3Mouse liver form;Fig. 2 C is Vil-Cre;Pkd2f3/f3Mice pancreatic form;Fig. 2 D is Vil-Cre;Pkd2f3/f3
The kidney cross section of mouse;Fig. 2 E is Pkd2f3/f3The kidney cross section of mouse.It can be seen from the figure that step 1 obtained
Vil-Cre;Pkd2f3/f3For mouse in 4~May or so death, there is serious tumour, and kidney in kidney, liver, pancreas
Dirty HE coloration result further demonstrates that kidney without kidney essence, and renal function is badly damaged, and determines Vil-Cre;Pkd2f3/f3Mouse is dead
The kidney failure caused by renal cyst, and brood Pkd2 of the same agef3/f3Then phenotype is normal for mouse.
The above result shows that the Vil-Cre that step 1 obtains;Pkd2f3/f3Mouse phenotype is similar to mankind ADPKD patient,
It can be used as ADPKD animal model.
The application of embodiment 2, LGK974 and Wnt-C59 in treatment kidney of patients with autosomal dominant polycystic kidney disease
The Vil-Cre that the present embodiment is obtained with embodiment 1;Pkd2f3/f3Mouse is researched and analysed as ADPKD animal model
Application of the LGK974 and Wnt-C59 in treatment kidney of patients with autosomal dominant polycystic kidney disease.It is specific as follows:
One, experimental method
1, experimental group and processing
(1) LGK974 solution
LGK974 is dissolved with solution A, until its concentration is 3mg/mL, after with normal saline dilution to 0.3mg/ml.Solution A
Solvent be water, solvent is methylcellulose and Tween 80, wherein mass fraction of the methylcellulose in solution A be
0.5%, volume fraction of the Tween 80 in solution A is 0.5%.
(2) Wnt-C59 solution
Wnt-C59 is dissolved with solution A, until its concentration is 3mg/mL, after with normal saline dilution to 1mg/ml.
(3) it is grouped and handles
It is divided into LGK974 treatment group, Wnt-C59 treatment group and control group (placebo) according to whether treated with medicaments, every group
Randomly select at least 20 Vil-Cre:Pkd2f3/f3Mouse.After mouse birth the 30th day, carry out continuous bimestrial
Gastric infusion, daily administration is until three monthly age of mouse is discontinued, and (every kg weight is to 3mg by 3mg/kg for every mouse for the treatment of group
LGK974 it) is administered with the dosage of 10mg/kg (every kg weight gives 10mg Wnt-C59);Every mouse of control group such as injects at the bodies daily
Long-pending contains 0.5% methylcellulose of equivalent/0.5% Tween 80 physiological saline.
2, each group mouse treatment condition is analyzed
(1) the renal cyst phenotype of two groups of mouse of HE staining analysis
After two monthly age of mouse is discontinued, every group randomly selects no less than 10 mouse, after execution, extracts bilateral renal.?
It is precisely weighed, calculates kidney weight ratio (g/g), i.e. bilateral renal weight (g)/weight (g) on electronic balance.Afterwards by Bilateral Renal
It is dirty to be cut along sagittal plane, 24 hours are fixed with 10% neutral formalin solution, rear graded ethanol dehydration, then with paraffin packet
It buries machine routinely to embed, wax stone row slice and HE dyeing after.
A. dehydration embedding
Specific steps: it is 1. dehydrated: 70% ethyl alcohol of ethyl alcohol 1h → 75% ethyl alcohol of 1h → 80% ethyl alcohol 1h → 90% of 1h → 85%
The ethyl alcohol of ethyl alcohol 1h → 95% ethyl alcohol of 1h → 100% 1h → dimethylbenzene 15min × 2;2. embedding: paraffin wax embedding is embedded.
B. it is sliced
Kidney wax stone is made into the continuous renal histotomy of 3 μ m thicks on cycle type slicer, is gently propped up with writing brush,
It being sufficiently spread out in warm water, then picks up nephridial tissue slice with the processed slide of poly-D-lysine, electric air drier is dried,
Then in being put in electric heating constant-temperature blowing drying box, 70 DEG C of constant temperature are toasted 1 hour, so that histotomy and slide close adhesion,
It is placed in spare in box.
C.HE pathological staining
Principle: hematoxylin (hematoxylin) dye liquor is alkalinity, mainly makes endonuclear chromatin and intracytoplasmic core
Sugared body hyacinthine;Yihong (eosin) is acid dyes, mainly makes the ingredient red coloration in cytoplasm and extracellular matrix.
Step:
1. dimethylbenzene dewaxes, washed away afterwards with 100% ethyl alcohol;
2. the ethyl alcohol of various concentration successively aquation;
It is washed 5 minutes 3. phosphate buffer shaking table is slow;
4. hematoxylin 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 ethyl alcohol of various concentration is successively dehydrated;
10. dimethylbenzene is transparent, neutral gum mounting is used afterwards;Micro- sem observation.
(11) as the result is shown: cytoplasm is red, nucleus bluish violet.
(2) measurement of the renal cystis index of mouse
After the Kidney sections of LGK974 treatment group, Wnt-C59 treatment group and control group mice HE dyeing are taken pictures, picture operation
In GNU Image Manipulation Program.Picture is converted into grayscale image first, then adjusts picture pixels to 800
×598.By picture adjusted run addition grid program, set each grid as size be 22 × 22 pixels.Calculate tumour
Tumour index can be obtained in the total number of grid ratio of area grid quantity and kidney region.
(3) LGK974 treatment group, the measurement of Wnt-C59 treatment group and control group mice ADPKD related biochemical indicator
The present inventor goes out the improvement degree for the treatment of group's Mouse Kidney liver function for accurate response, further right
The content of urea nitrogen (BUN) and creatinine (Cr) carry out in LGK974 treatment group, Wnt-C59 treatment group and control group mice blood
Measurement, with the situation of change of this precise reaction renal function, reflects the severity of tumour.Concrete operations are as follows:
At three monthly age of mouse, by LGK974 treatment group, Wnt-C59 treatment group and control group mice etherization, under
Vena cave extracts mouse blood, and it is serum that supernatant is obtained after centrifugation.Creatinine and urea nitrogen can be measured by chemically examining serum
Content.
Two, experimental result
1, the renal cyst phenotype of LGK974 treatment group, Wnt-C59 treatment group and control group mice
It visually observes with HE coloration result as shown in figure 3, it can be seen from the figure that LGK-974 treatment group is compared with control group (peace
Console agent) there are more kidney essence, and renal cyst phenotype is considerably less than control group, but does not have after Wnt-C59 treatment with control group
Significant difference.In addition, the kidney weight ratio (g/g) of LGK974 treatment group, Wnt-C59 treatment group and control group mice measures knot
Fruit as shown in figure 4, as the result is shown the kidney weight ratio (g/g) of LGK974 treatment group significantly less than control group (p=0.000015),
With statistical significance, the kidney weight ratio (g/g) of Wnt-C59 treatment group but is not united though compared with control group compared to there is decline
Meter learns meaning (p=0.11).
2, the renal cystis index of LGK974 treatment group, Wnt-C59 treatment group and control group mice
The renal cystis assessment of indices result such as Fig. 5 institute of LGK974 treatment group, Wnt-C59 treatment group and control group mice
Showing, LGK974 treatment group significantly reduces (p=0.000019) compared to the renal cystis index compared with control group, there is statistical significance,
Though but the renal cystis index of Wnt-C59 treatment group compared with control group compared to there is decline, be not statistically significant (p=0.09).
3, LGK974 treatment group, the measurement of Wnt-C59 treatment group and control group mice ADPKD related biochemical indicator
Urea nitrogen (BUN) and creatinine (Cr) in the blood of LGK974 treatment group, Wnt-C59 treatment group and control group mice
Assay result is as shown in fig. 6, the results show that urea nitrogen (BUN) and creatinine (Cr) in the blood of LGK974 treatment group mouse
Content compared compared with control group, have downward trend, urea nitrogen and serum creatinine are significantly less than right in the blood of LGK974 treatment group
According to group (p=0.00005, p=0.00174), there is statistical significance, but the urea nitrogen of Wnt-C59 treatment group and serum creatinine compared with
Though control group is not statistically significant (p=0.08, p=0.012) compared to there is decline.
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) it is had a certain effect in.
Claims (3)
1. application of the LGK974 in the product of preparation treatment kidney of patients with autosomal dominant polycystic kidney disease.
2. application according to claim 1, it is characterised in that: LGK974 has following (1)-(4) at least one effect:
(1) weaken sickened body renal cyst degree;
(2) sickened body kidney weight ratio is reduced;
(3) the renal cystis index of sickened body is reduced;
(4) creatinine and/or urea nitrogen content in sickened body blood are reduced.
3. application according to claim 1 or 2, it is characterised in that: the product is drug.
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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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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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