CN109223794A - A kind of compound C6 is as histone methyltransferase NSD3 activity inhibitor and its application - Google Patents
A kind of compound C6 is as histone methyltransferase NSD3 activity inhibitor and its application Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
The invention discloses a kind of compound C6 as histone methyltransferase NSD3 activity inhibitor and its medicinal usage.The compound C6 has chemical structure shown in Formulas I:Chemical name are as follows: 6-amino-9- (2- (naphthalen-1-yloxy) ethyl) -9H-purine-8-thiol;The medicinal usage, which refers to using at least one of the compound C6 or its hydrate, pharmaceutically acceptable salt, tautomer, stereoisomer, precursor compound, is used to prepare anti-tumor drug as active constituent.Experiment shows that NSD3 enzymatic activity, the horizontal IC of zymetology can be effectively suppressed in compound C6 of the present invention50Value is 17.97 ± 2.75 μm of ol/L;And it can obviously inhibit the growing multiplication of Lines H460, H1299, H1650.Compound of the present invention has the function of inhibiting tumor cell proliferation, it is expected to be used to prepare anti-tumor drug as active constituent, have prospect in medicine.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are specifically related to a kind of histone methyltransferase NSD3 activity inhibitor
And its application.
Background technique
Histone methylated is one of most important modified mechanism of epigenetic modification.Histone methylated and its regulation person
The generation of a variety of diseases such as the unconventionality expression of histone methyltransferase and hereditary disease, autoimmune disease, aging and cancer
It is closely related, especially it is of great significance in the occurrence and development of tumour.Therefore, histone methyltransferase is considered as potential
Antineoplaston novel targets.
In recent years, it made breakthrough progress by the research and development of the inhibitor of target spot of histone methyltransferase.Currently, group
Protein methyltransferase EZH2 inhibitor EPZ-6438 (Epizyme company) entered I/II clinical trial phase in 2014, was used for
Treat non-Hodgkin lymphoma, advanced malignance and malignant mesothelioma patient;Histone methyltransferase DOT1L inhibitor
EPZ-5676 (Epizyme company) also entered Phase I clinical trial in 2014, for treating acute leukemic patient.In addition, also
There is the micromolecular inhibitor of multiple histone-lysine methyltransferases, such as SETD7 inhibitor PFI-2, G9a (EHMT2) and GLP
(EHMT1) inhibitor UNC0638, A-366, SMYD2 inhibitor LLY-507 etc. is in the preclinical study stage, these researchs pair
It is most important in the research and development of antineoplastic target therapeutic agent, it has broad application prospects.Histone methyltransferase NSD3 (also known as
WHSC1L1, Wolf-Hirschhorn syndrome candidate1-like1) the 36th lysine of histone H 3 can be made
(H3K36) di-methylation (me2) and tri-methylated (me3).The NSD3 assignment of genes gene mapping on the position human chromosome 8p11.23, with
The occurrence and development of Several Kinds of Malignancy have important relationship.Firstly, 8p11-12 chromosome interval where NSD3 is in breast cancer,
It is highly expanded in the cancers such as lung cancer, cancer of pancreas and neoplastic hematologic disorder, disclosing the section and tumor development has strong correlation.
Secondly, multiple studies have shown that NSD3 gene itself plays a significant role in the occurrence and development of malignant tumour.In breast cancer, bladder
NSD3 is found highly to express in the tumours such as cancer, Head and neck squamous cell carcinoma, has the function of promoting tumour formation;Acute myelogenous
T (8 is found in leukaemic;11)(p11.2;P15) NUP98-NSD3 fusion, specific mechanism of action are unclear;
Find that NSD3-NUT fusion, the fusion protein of expression pass through in NUT center line cancer (NUT midline carcinoma)
It plays an important role in terms of tumor cell differentiation retardance and proliferation in conjunction with BRD4 albumen;In acute myelocytic leukemia
(AML) in cell, the NSD3 isomers for containing only first, the end N PWWP structural domain mediates BRD4-CHD8 protein to combine, directly
Connect the proliferation and differentiation for influencing tumour cell.
NSD3 is by 1 SET (Su (var), Enhancer of zeste, and Trithorax) structural domain, 2 PWWP
(Pro-Trp-Trp-Pro motif) structural domain and 4 PHD structural domain (Plant Homeodomain) compositions.Wherein SET is tied
Structure domain is catalytic center, PWWP and PHD structural domain usually participates in many biologies such as the relevant transcriptional control of chromatin and DNA reparation
Process.
So far, about more than 60 kinds of the histone methyltransferase of discovery rely ammonia including more than 50 kinds of histones
Acid methyltransferase.In the histone-lysine methyltransferase having found, there is 50% methyl transferase activity to pass through reality
Proved recipe method is verified, and most of closely related with tumour generation.However, in histone-lysine methyltransferase inhibitor
In research field, most of research focuses primarily upon the histones such as EZH1 and EZH2, DOT1L, SETD7, EHMT1 and EHMT2 and relies
Propylhomoserin transmethylase has been found the histone methyltransferase closely related with human tumor occurrence and development for other
It studies in contrast less.Histone methyltransferase NSD3 is particularly significant during tumor development, is one potential
Antineoplastic new target.Consequently found that the NSD3 inhibitor of high activity is especially heavy for application of the NSD3 in targeting cancer therapy
Will with it is urgent, for these histone methyltransferase find high activity Non-specific inhibitor for antineoplastic target medicine
Object research and development are of great significance.
Summary of the invention
The present invention provides a kind of histone methyltransferase NSD3 activity inhibitor, the inhibitor be compound of formula I or
Its pharmaceutically acceptable salt
The present invention also provides new opplication of the compound of formula I in preparation tumor.
Preferred tumour of the present invention is lung cancer, breast cancer, cancer of pancreas, osteosarcoma, head-neck carcinoma, and sent lung cancer is preferred
For non-small cell lung cancer.
Preferred drug of the present invention be compound of formula I, its hydrate, pharmaceutically acceptable salt, tautomer,
Drug made of stereoisomer or precursor compound and one or more pharmaceutically acceptable carriers.The carrier includes medicine
The diluent of field routine, excipient, filler, adhesive, wetting agent, disintegrating agent, sorbefacient, surfactant,
Absorption carrier, lubricant etc..
Injection, tablet, pulvis, granule, pill, capsule, oral solution, paste, creme can be made in drug of the present invention
Etc. diversified forms.The drug of above-mentioned various dosage forms can be prepared according to the conventional method of pharmaceutical field.
The drug is to treat tumour by inhibition of histone transmethylase NSD3 activity, can by injection, injection,
Collunarium, eye drip, infiltration, absorption, the method physically or chemically mediated import body such as muscle, intradermal, subcutaneous, vein, mucous membrane group
It knits;Or body is imported after other material mixings or package.
Virtual screening is integrated in present invention use and the method for measuring is found and found from from ChemDiv compound library
Compound of formula I (hereinafter referred to as C6) can inhibit NSD3 enzymatic activity, and the anti-tumor activity of combination cell experimental verification compound,
Although the research also prematurity about inhibitor C 6 is to clinical stage is entered, these researchs are for finally developing anti-NSD3 medicine
Object is most important, with important application prospects.
The present invention carries out prior assessment using validity of the computer simulation method to drug molecule, and real using biology
Proved recipe method detects and verifies activity, obtains effective NSD3 enzyme inhibitor C6 (chemical name: 6-amino-9- (2-
(naphthalen-1-yloxy)ethyl)-9H-purine
- 8-thiol), the horizontal IC50 value of zymetology is 17.97 ± 2.75 μm of ol/L;To a variety of non-small cell lung cancer cells
System has antiproliferative effect, and IC50 value in 50~100 μm of ol/L, has good NSD3 enzyme inhibitory effect respectively.
Detailed description of the invention
Fig. 1: the C6 IC50 value figure on NSD3 protein level.
Fig. 2: the H3K36me3 expression in Lines.
Fig. 3: C6 inhibits NSD3 enzymatic activity in the cell.
Fig. 4: C6 to the growth inhibition ratios of Lines.
Fig. 5: C6 inhibits the growing multiplication of non-small cell lung cancer cell.
Specific embodiment
In order to confirm the antitumous effect of the compounds of this invention, the present invention is done below in conjunction with the accompanying drawings and the specific embodiments
Further description out.
1. experimental method
1.1 virtual screenings based on receptor
It uses firstAlbumen preparation module Protein Preparatio n Wizard in software package
The crystal structure (PDB:4YZ8) of NSD3 is handled.Using Discov ery Studio 2.5 to ChemDiv database into
The pretreatment of row compound, including duplicate removal, removal salt ion and inorganic matter, and carry out construction standard.UsingLigPrep module in 9.0 generated under the conditions of pH=7.4 compound possibility ionization state and mutually
Tautomeric.
Before carrying out virtual screening using molecular docking method, it is necessary first to Glide interconnection method used by verifying
Validity, define NSD3 active site, with the matter of ligand molecular S-adenosyl methionine (SAM) in crystal structure
Centered on the heart, setting Square body region, using the SP (Standard of Glide software
Precision) parameter setting after similarly using LigPrep to handle ligand molecular SAM, is docked to NSD3 activity again
In pocket, discovery Glide can preferably reappear the combination conformation in crystal structure.
Using Glide HTVS (High Throughput Virtual Screening) mode to the library ChemDiv chemical combination
Object is docked and is given a mark, and 300,000 forward compounds of giving a mark are selected;It is docked again using Glide SP mode again
And marking, retain 30,000 forward small molecule binding patterns of giving a mark.In the crystal structure of the combination of SAM and NSD3, with activity
Region residue HIS1224, HIS1274 form three crucial interaction of hydrogen bond.30,000 small molecules generated for docking
Binding pattern takes hydrogen bond criteria as screening conditions, selects and HIS1224, HIS1274 form the combination of 2 or more hydrogen bonds
Mode obtains 697 qualified compound molecules.In order to fully consider the structure diversity of compound, use
Canvas module in Schrodinger carries out clustering, selects a collection of compound and carries out measuring.Discoverable type Iization
Object is closed, (hereinafter referred to as C6) has preferable histone methyltransferase inhibitory activity.
Compound of formula I chemical structural formula (compound of formula I hereinafter referred to as C6)
The external Enzyme assay experimental procedure of 1.2 NSD3
1) it the expression and purification of NSD3 albumen: is expanded from HEK293 cell line cDNA by PCR method and obtains the part NSD3
Gene (1021-1320aa), is subcloned in prokaryotic expression carrier pGEX-4T1, constructs the recombinant plasmid with GST label, warp
It is sequenced after identifying, conversion inducing expression in Escherichia coli Rossetta (after 0.5mM IPTG induction, is persistently cultivated at 16 DEG C
20 hours), purified with GST resin, obtains the NSD3 albumen of GST label.
2) the external Enzyme assay step of NSD3:
1. compound and 2.3 μ g NSD3 albumen are mixed, and placed 15 minutes at 30 DEG C;
2. being separately added into histone H 3 K36me1 polypeptide fragment (ATKAARKSAPATGGV-K (Me1)-KPHRYRPG-GK
(Biotin)) (ultimate density is 0.2 μM) and S-adenosyl methionine SAM (ultimate density is 1.0 μM), and
In 50mM Tris-HCl pH8.5,50mM NaCl, 5mM MgCl2,1mM DTT and 0.01%Tween reaction solution, 30 DEG C anti-
It answers 1 hour;
3. in conjunction with cisbio HTRF histone methyltransferase detection kit, using multi-function microplate reader in 620nm and
The corresponding fluorescence values of 665nm wavelength detecting calculate NSD3 activity.
1.3 intracellular NSD3 Enzyme assay experiments
1) protein immunoblotting (Western Blot) measuring H3K36me3 is in a variety of non-small cell lung cancer cells
Protein expression in system, select H3K36me3 high-expression cell line and it is low or without expression cell system measurement Compound cellular in NSD3
Enzyme inhibition activity.
2) compound is added in 6 orifice plates repopulating cell after 16 hours, and is split after continuing culture 48 hours with RIPA lysate
It solves cell and harvests protein sample;Protein immunoblotting measuring H3K36me3 protein expression.
The experiment of 1.4 cellular level anti-tumor activities
1) growth of tumour cell inhibiting rate: 5000 cells are planted in 96 orifice plates, control DMSO or not is added after 16 hours
With the compound of concentration, continue to cultivate in 37 DEG C, 5% carbon dioxide incubator;Dojindo cell is added after 72 hours
Counting kit-8 reagent, 37 DEG C reaction 1 hour after 450nm measure absorbance, finally obtain the tumour cell of the compound
Inhibiting rate IC50.
2) cell proliferation experiment: 500 cells (H460 and H1299) and 2000 cells are planted respectively in 96 orifice plates
(H1650), DMSO or 25 μM of C6 of control is added after 16 hours to continue to cultivate, culture medium was changed every 2 days (containing corresponding control
DMSO or 25 μM of C6).The the 0th, 1,3,5,7 day (H460 cell line) after planting respectively, the 0th, 1,3,5,7,9 day (H1299
Cell line), it is surveyed with Dojindo cell counting kit-8 reagent within the 0th, 1,4,7,10,13,16 day (H1650 cell line)
Fixed corresponding numerical value.
3) plate clone forms test: planting 5000 cells in 6 orifice plates, it is dense that control DMSO or different is added after 16 hours
The compound of degree continues to cultivate in 37 DEG C, 5% carbon dioxide incubator;Change within every 2 days liquid, stationary culture 7-10 days;It discards
Clear liquid is carefully embathed 2 times with 1mL PBS;The pure methanol of 1mL is added and fixes 20 minutes;Fixer is removed, 1mL Giemsa dye is added
Color liquid is placed 10-30 minutes, is then slowly washed away dyeing liquor with ultrapure water, is air-dried.
2. experimental result
Determine C6 on albumen and cellular level for histone methyltransferase NSD3 activity and C6 in cell
The inhibitory effect and inhibiting rate of non-small cell lung cancer cell growing multiplication are directed in level.
IC in albumen zymetology level in vitro50Dependence Results are that C6 has the suppression of good NSD3 enzyme on protein level
Effect processed, IC50Value is 17.97 ± 2.75 μM, sees Fig. 1.
The most important substrate H3K36me3 of NSD3 is determined in the expression test in Lines,
The selected higher H460 of expression, H1299 and H1650 cell line, which detects C6, in the cell imitates the inhibition of NSD3 enzymatic activity
Fruit sees Fig. 2.
The C6 of 30 μM of concentration handles H460 in inhibiting rate test, H1299 and H1650 cell 48 hours, to substrate
The inhibiting rate that H3K36me3 is generated is respectively 55.89%, 48.96% and 34. 64%;Under the same conditions, 60 μM of concentration generate
Inhibiting rate be respectively 32.25%, 23.58% and 18.84%, illustrate that C6 can also effectively inhibit NSD3 enzyme on a cellular level
Activity is shown in Fig. 3.
The C6 of various concentration is to A549, H460, H1299, the inhibition rate of tumor growth of H1650 Lines
Experiment, C6 concentration gradient is 0,12.5,25.0,50.0 μM respectively.In the A549 cell line of low expression H3K36me3,50.0 μM
Concentration is to the growth of A549 lung carcinoma cell without obvious inhibiting effect;Three kind lungs of the C6 in other height expression H3K36me3 in contrast
It is obvious to growth and proliferation of cell inhibitory effect in cancerous cell line (H460, H1299, H1650), see Fig. 4.
Plate clone forms test (Fig. 5) equally announcement C6 and significantly inhibits to the growing multiplication of non-small cell lung cancer cell
Effect.
To sum up, compound C6 of the present invention is effective histone methyltransferase NSD3 inhibitor, and C6 is in the cell
NSD3 enzymatic activity can obviously be inhibited, H3K36me3 level is reduced, also have significantly to the growing multiplication of Lines
Inhibiting effect.It can be seen that C6 compound of the present invention can obviously inhibit tumour as histone methyltransferase inhibitor
Cell Proliferation has potential antitumor action, it is expected to be used to prepare anti-tumor drug as active constituent, especially be expected to be used for
The drug of anti-lung cancer is prepared, there is prospect in medicine.
Claims (8)
1. a kind of histone methyltransferase NSD3 activity inhibitor, which is characterized in that the inhibitor be compound of formula I or its
Hydrate, pharmaceutically acceptable salt, tautomer, stereoisomer, precursor compound
2. application of the inhibitor according to claim 1 in preparation tumor.
3. compound of formula I according to claim 1 or its hydrate, pharmaceutically acceptable salt, tautomer, solid
The application of isomers, precursor compound in preparation tumor.
4. application according to claim 3, which is characterized in that the tumour is lung cancer, breast cancer, cancer of pancreas, bone and flesh
Tumor, head-neck carcinoma.
5. application according to claim 4, which is characterized in that the lung cancer is non-small cell lung cancer.
6. application according to claim 3, which is characterized in that the drug is compound of formula I, its hydrate, pharmaceutically
Acceptable salt, tautomer, stereoisomer or precursor compound and one or more pharmaceutically acceptable carrier systems
At drug.
7. application according to claim 6, which is characterized in that the drug is by inhibition of histone transmethylase
NSD3 activity treats tumour.
8. application according to claim 6, which is characterized in that the dosage form of the drug be tablet, capsule, granule,
Pill or other regular dosage forms that can be prepared.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2021028854A1 (en) * | 2019-08-14 | 2021-02-18 | Novartis Ag | Piperidinyl-methyl-purineamines as nsd2 inhibitors and anti-cancer agents |
Citations (2)
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EP2277595A2 (en) * | 2004-06-24 | 2011-01-26 | Novartis Vaccines and Diagnostics, Inc. | Compounds for immunopotentiation |
CN105198828A (en) * | 2015-08-26 | 2015-12-30 | 中国药科大学 | Heterocyclic anthracene ketone histone methyltransferase inhibitor and medical application thereof |
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2018
- 2018-08-24 CN CN201810971460.7A patent/CN109223794B/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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EP2277595A2 (en) * | 2004-06-24 | 2011-01-26 | Novartis Vaccines and Diagnostics, Inc. | Compounds for immunopotentiation |
CN105198828A (en) * | 2015-08-26 | 2015-12-30 | 中国药科大学 | Heterocyclic anthracene ketone histone methyltransferase inhibitor and medical application thereof |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021028854A1 (en) * | 2019-08-14 | 2021-02-18 | Novartis Ag | Piperidinyl-methyl-purineamines as nsd2 inhibitors and anti-cancer agents |
CN114585622A (en) * | 2019-08-14 | 2022-06-03 | 诺华股份有限公司 | Piperidinyl-methyl-purinamines as NSD2 inhibitors and anticancer agents |
US11420970B1 (en) | 2019-08-14 | 2022-08-23 | Novartis Ag | Piperidinyl-methyl-purineamines as NSD2 inhibitors and anti-cancer agents |
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