CN108186644A - The purposes of compound - Google Patents
The purposes of compound Download PDFInfo
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- CN108186644A CN108186644A CN201810067209.8A CN201810067209A CN108186644A CN 108186644 A CN108186644 A CN 108186644A CN 201810067209 A CN201810067209 A CN 201810067209A CN 108186644 A CN108186644 A CN 108186644A
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- pi3k
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- inositol
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
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Abstract
The present invention relates to the purposes of field of medicaments, more particularly to compound.The present invention provides compound shown in formula I as the application in the inhibitor of 3 kinases of phosphatidylinositols.The compound can effectively inhibit PI3K γ, and reference is provided for the target drug design with PI3K γ.In addition, the screening technique of the inhibitor of 3 kinases of phosphatidylinositols provided by the invention, has the ability of deposition activity molecule, and it is highly practical, it can be applied to quickly find active drug molecule.
Description
Technical field
The present invention relates to the purposes of field of medicaments, more particularly to compound.
Background technology
Phosphatidyl-inositol 3-kinase (Phosphatidylinositol-4,5-bisphosphate 3-kinase,
PI3K), it is the intracellular lipoid for participating in regulation and control and including the important vital movement such as cell Proliferation, survival, growth, transfer, apoptosis
Matter kinases.PI3K can be divided mainly into three classes, wherein research is most widely I class PI3K, such PI3K is by a catalytic subunit
(P110) subunit (P85) composition catalytic subunits are adjusted and can be divided into four kinds of hypotypes again with one：PI3K α, PI3K β, PI3K δ and
PI3K γ, four play an important role in tumour, thrombus, immune and inflammatory process respectively, and design synthesis is using PI3K as target spot
The drugs such as antithrombotic, antitumor have become the research hotspot of medicinal chemistry art.
Some researches show that PI3K γ play an important role in immune and inflammation, and participate in allergy, cardiovascular disease
Disease, the development of chronic inflammation and autoimmune disease.So the inhibition of PI3K γ can be used as treatment inflammation and itself
The good approach of immunity disease.Two researchs being published on Nature magazines, which demonstrate PI3K γ, is improving immunotherapy
Key effect is played in validity.Study 1 (topic：Overcoming resistance to checkpoint
Blockade therapy by targeting PI3K γ in myeloid cells) it mentions, it is blocked using experimental drug
After PI3K γ molecules in inhibitory cells, the balance of this kind of immunosupress cellule changes, and promotes antineoplastic immune
Activation.Research 2 is found, the PI3K γ signals of macrophage (from University of California Santiago branch school, Moores Cancer centers)
Immunosupress is promoted by the activation for inhibiting antitumor T cell.PI3K γ is blocked to have activated immune response, significantly suppress transplanting
The growth of knurl.Meanwhile PI3K γ is blocked to also improve certain tumours and enhance existing to having the sensibility of anticancer drug, collaboration
The ability of immunotherapy for cancer tumor eradication.
Therefore it provides the PI3K gamma inhibitors molecules of high activity, provide reference for the target drug design with PI3K γ, have
There is important realistic meaning.
Invention content
In view of this, the present invention provides a kind of purposes of compound.The compound can effectively inhibit PI3K γ, be with
The target drug design of PI3K γ provides reference.
In order to achieve the above-mentioned object of the invention, the present invention provides following technical scheme：
The present invention provides compound shown in formula I as the application in the inhibitor of phosphatidyl-inositol 3-kinase.
The SPEC ID of the compound are AK-968/15605213, smi：C12n (ncc1C (=O) N/N=C (/c1cc (NC
(=O) C (C) C) ccc1) and C) c (cc (n2) c1ccccc1) C, Drug-likeness modelscore：0.54.
In some specific embodiments of the present invention, the phosphatidyl-inositol 3-kinase is PI3K γ.
The present invention some specific embodiments in, the PI3K γ include PDB ID such as 1e8w, 2a5u, 2chw,
3dbs, 3l16,3l17,3ml8,3prz, 3qaq, 3r7q, 3s2a, 4dk5,4ezk, 4f1s, 4fad, 4fjy, 4flh, 4hle or
The albumen of 4hvb.
In some specific embodiments of the present invention, the IC to PI3K γ of compound shown in the formula I50It is worth and is
2047.3±5nM。
The present invention also provides a kind of screening techniques of the ligand of phosphatidyl-inositol 3-kinase, include the following steps：
The albumen of phosphatidyl-inositol 3-kinase is obtained as receptor；
Untested compound is taken to be docked with described by weight；
By root mean square deviation (RMSD) value and/or enrichment factor (EF), obtain whether the untested compound is phosphatidyl
The result of the ligand of inositol 3-kinase.
In some specific embodiments of the present invention, during root mean square deviation≤2.0 angstrom, the untested compound is phosphorus
The ligand of acyl inositol 3-kinase.
In some specific embodiments of the present invention, the enrichment factor ＞ 1, the untested compound is phosphatidyl-4
The ligand of alcohol 3- kinases.
The present invention also provides a kind of screening techniques of the inhibitor of phosphatidyl-inositol 3-kinase, include the following steps：
The albumen of phosphatidyl-inositol 3-kinase is obtained as receptor；
Untested compound is taken to be docked with described by weight；
By root mean square deviation (RMSD) value and/or enrichment factor (EF), obtain whether the untested compound is phosphatidyl
The result of the ligand of inositol 3-kinase；
The ligand of acquisition is taken, the protein binding with phosphatidyl-inositol 3-kinase obtains inhibiting rate, when inhibiting rate is not more than 10
μM when, the ligand be phosphatidyl-inositol 3-kinase inhibitor.
The present invention provides compound shown in formula I as the application in the inhibitor of phosphatidyl-inositol 3-kinase.
The compound can effectively inhibit PI3K γ, and reference is provided for the target drug design with PI3K γ.In addition, this hair
The screening technique of the inhibitor of the phosphatidyl-inositol 3-kinase of bright offer has the ability of deposition activity molecule, highly practical, can
To be applied to quickly find active drug molecule.
Description of the drawings
In order to illustrate more clearly about the embodiment of the present invention or technical scheme of the prior art, to embodiment or will show below
There is attached drawing needed in technology description to be briefly described.
Fig. 1 (A) shows that PI103 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 1 (B) shows that compound 1 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 1 (C) shows that compound 2 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 1 (D) shows that compound 3 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 1 (E) shows that compound 4 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 1 (F) shows that compound 5 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 1 (G) shows that compound 6 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 1 (H) shows that compound 7 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 1 (I) shows that compound 8 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 1 (J) shows that compound 9 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 1 (K) shows that compound 10 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 1 (L) shows that compound 11 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 1 (M) shows that compound 12 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 1 (N) shows that compound 13 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 1 (O) shows that compound 14 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 1 (P) shows that compound 15 is to the dose-effect curve of PI3K γ in test board 1；
Fig. 2 (A) shows that PI103 is to the dose-effect curve of PI3K γ in test board 2；
Fig. 2 (B) shows that compound 16 is to the dose-effect curve of PI3K γ in test board 2；
Fig. 2 (C) shows that compound 17 is to the dose-effect curve of PI3K γ in test board 2；
Fig. 2 (D) shows that compound 18 is to the dose-effect curve of PI3K γ in test board 2；
Fig. 2 (E) shows that compound 19 is to the dose-effect curve of PI3K γ in test board 2；
Fig. 2 (F) shows that compound 20 is to the dose-effect curve of PI3K γ in test board 2；
Fig. 2 (G) shows that compound 21 is to the dose-effect curve of PI3K γ in test board 2；
Fig. 2 (H) shows that compound 22 is to the dose-effect curve of PI3K γ in test board 2；
Fig. 2 (I) shows that compound 23 is to the dose-effect curve of PI3K γ in test board 2；
Fig. 2 (J) shows that compound 24 is to the dose-effect curve of PI3K γ in test board 2；
Fig. 2 (K) shows that compound 25 is to the dose-effect curve of PI3K γ in test board 2；
Fig. 2 (L) shows that compound 26 is to the dose-effect curve of PI3K γ in test board 2；
Fig. 2 (M) shows that compound 27 is to the dose-effect curve of PI3K γ in test board 2；
Fig. 2 (N) shows that compound 28 is to the dose-effect curve of PI3K γ in test board 2；
Fig. 2 (O) shows that compound 29 is to the dose-effect curve of PI3K γ in test board 2；
Fig. 3 shows 64 albumen that PI3K γ are included.
Specific embodiment
The invention discloses a kind of purposes of compound, those skilled in the art can use for reference present disclosure, be suitably modified
Technological parameter is realized.In particular, it should be pointed out that all similar substitutions and modifications be for a person skilled in the art it is aobvious and
It is clear to, they are considered as being included in the present invention.The method of the present invention and application are retouched by preferred embodiment
It states, related personnel can significantly not depart from the content of present invention, method described herein and application changed in spirit and scope
It is dynamic or suitably change with combining, to realize and using the technology of the present invention.
Agents useful for same and raw material can be bought by market in the application of compound provided by the invention.
With reference to embodiment, the present invention is further explained：
The acquisition and processing of 1 receptor protein of embodiment
Log in sc-PDB databases (http://bioinfo-pharma.u-strasbg.fr/scPDB/), search for PI3K
γ has found that PI3K γ comprising 64 albumen (as shown in Figure 3), choose half therein as research object, PDB ID are shown in altogether
Table 1.
The PI3K γ albumen of 1 experimental study of table
Embodiment 2
Precision test：
Using the binding site centre coordinate that sc-PDB is provided as initial docking parameter, Gridbox is set as 25x25x25,
Exhaustiveness is set as 20.32 target point proteins of PI3K γ are carried out with corresponding eutectic ligand using PyRx softwares
It docks again；Its binding pattern is observed using Pymol softwares, and calculates its root-mean-square-deviation (RMSD) value.It is generally acknowledged that working as RMSD
At≤2.0 angstroms, it is believed that receptor and ligand dock again can preferable playback experiment binding pattern.Docking result is shown again for the first time
Show there are 19 albumen (PDB ID：1e8w、2a5u、2chw、3dbs、3l16、3l17、3ml8、3prz、3qaq、3r7q、3s2a、
4dk5,4ezk, 4f1s, 4fad, 4fjy, 4flh, 4hle or 4hvb) further work can be carried out.
Practicability is verified：
The parameter used in protein number and theoretical calculation that PI3K-gamma hypotypes are related to, (being shown in Table 2~table 5).Greatly
The EF values that Partial Protein calculates are more than 1, illustrate the accumulation ability of the active molecule of screening technique.
The EF values that 2 PI3K γ of table docking calculate
The EF values that 3 PI3K γ of table docking calculate
The EF values that 4 PI3K γ of table docking calculate
The EF values that 5 PI3K γ of table docking calculate
Inhibition of 3 detection compound of embodiment to PI3K kinases (gamma hypotypes) activity
Analysis method:Use the ADP-GLo of Promega companiesTMTechnology carries out IC of the compound for PI3K kinases50It surveys
It is fixed.
Compound test explanation:It is shown in Table 6.
Table 6
Diluted chemical compound：Untested compound 3 is diluted again, totally 10 concentration, final system concentration from 10 μM to
0.5nM。
Every piece of test board is all provided with Positive control wells and negative control hole.
Reference compound:PI-103 is compareed as the positive inhibitor of PI3K；
Data analysis and report:Experimental result is analyzed with XLFIT5 softwares, calculates IC50As a result.
Experiment material：
Experimental procedure：
Diluted chemical compound：Untested compound 3 is diluted again, totally 10 concentration, final system concentration from 10 μM to
0.5nM。
Contain 500mMHEPES, 500mMNaCl and 9mMMgCl in 10 × reaction buffer2.In 1 × reaction buffer
Containing 0.01%BSA, face used time addition.In 5 μ l reaction systems, including 0.4nM PI3Kgamma, 50 μM of PIP2：3PS, 25 μ
MATP is incubated 120 minutes at 23 DEG C.The ADP-Glo reagent that 5 μ l contain 10mMMgCl2 are added in, 60 points are incubated at 23 DEG C
Clock.The Detection reagent of 10 μ l are eventually adding, are incubated 60 minutes at 23 DEG C, Envision readings；
The data that instrument is read are calculated to the inhibiting rate of compound, are then counted with mode 205 in the XLFIT5 of IDBS
Calculate IC50Value.
A concentration of 10 μM of PI3Kgamma participates in test.
PI103 as a control group the results are shown in Table 7, table 8：
Table 7
| PI3K isoforms | Final[Enzyme] | ATP(uM) | PIP2:3PS(uM) | Reactiontime(min) |
| PI3K gamma | 0.4nM | 25 | 50 | 120 |
Table 8
Test results are shown in Table 8.
Table 9
28 untested compounds are to the IC of PI3Kgamma50Value is shown in Table 10：
Table 10
The experimental results showed that IC of the compound 1 to PI3Kgamma50It is worth for 2047.3nM, compound 1 is PI3Kgamma's
Inhibitor.In summary, the integrated use based on virtual screening and biological activity test technology, it can be found that completely new
PI3Kgamma inhibitor, and show a μM horizontal inhibitory activity.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (8)
1. compound is as the application in the inhibitor of phosphatidyl-inositol 3-kinase shown in formula I
2. application according to claim 1, which is characterized in that the phosphatidyl-inositol 3-kinase is PI3K γ.
3. application according to claim 2, which is characterized in that the PI3K γ include PDB ID such as 1e8w, 2a5u,
2chw、3dbs、3l16、3l17、3ml8、3prz、3qaq、3r7q、3s2a、4dk5、4ezk、4f1s、4fad、4fjy、4flh、
The albumen of 4hle or 4hvb.
4. application according to any one of claims 1 to 3, which is characterized in that compound to PI3K γ shown in the formula I
IC50It is worth for 2047.3 ± 5nM.
5. a kind of screening technique of the ligand of phosphatidyl-inositol 3-kinase, which is characterized in that include the following steps：
The albumen of phosphatidyl-inositol 3-kinase is obtained as receptor；
Untested compound is taken to be docked with described by weight；
By root mean square deviation value and/or enrichment factor, obtain whether the untested compound is matching for phosphatidyl-inositol 3-kinase
The result of body.
6. screening technique according to claim 5, which is characterized in that during root mean square deviation≤2.0 angstrom, to be measuredization
Close the ligand that object is phosphatidyl-inositol 3-kinase.
7. screening technique according to claim 5 or 6, which is characterized in that the enrichment factor ＞ 1, the test compounds
Object is the ligand of phosphatidyl-inositol 3-kinase.
8. a kind of screening technique of the inhibitor of phosphatidyl-inositol 3-kinase, which is characterized in that according to such as claim 5 to 7 times
The ligand that screening technique described in one obtains, the protein binding with phosphatidyl-inositol 3-kinase obtain inhibiting rate, work as inhibiting rate
During no more than 10 μM, the ligand is the inhibitor of phosphatidyl-inositol 3-kinase.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810067209.8A CN108186644A (en) | 2018-01-24 | 2018-01-24 | The purposes of compound |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810067209.8A CN108186644A (en) | 2018-01-24 | 2018-01-24 | The purposes of compound |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101678026A (en) * | 2007-05-11 | 2010-03-24 | 诺瓦提斯公司 | 3, 6-disubstituted-imidazo [1, 2-B] pyridazines and 3, 5-disubstituted pyrazolo[1, 5-A] pyrimidines as phosphatidylinositol-3-kinase inhibitors |
-
2018
- 2018-01-24 CN CN201810067209.8A patent/CN108186644A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101678026A (en) * | 2007-05-11 | 2010-03-24 | 诺瓦提斯公司 | 3, 6-disubstituted-imidazo [1, 2-B] pyridazines and 3, 5-disubstituted pyrazolo[1, 5-A] pyrimidines as phosphatidylinositol-3-kinase inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| 朱景宇: "新型PI3K抑制剂的计算机虚拟筛选及其在多发性骨髓瘤治疗中的应用", 《中国博士学位论文全文数据库》 * |
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Application publication date: 20180622 |