CN109232573A - A kind of compound B-11 is as histone methyltransferase NSD3 activity inhibitor and its application - Google Patents
A kind of compound B-11 is as histone methyltransferase NSD3 activity inhibitor and its application Download PDFInfo
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- CN109232573A CN109232573A CN201810971341.1A CN201810971341A CN109232573A CN 109232573 A CN109232573 A CN 109232573A CN 201810971341 A CN201810971341 A CN 201810971341A CN 109232573 A CN109232573 A CN 109232573A
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- compound
- nsd3
- inhibitor
- histone methyltransferase
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
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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
- A61K31/52—Purines, e.g. adenine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a kind of compound B-11s as histone methyltransferase NSD3 activity inhibitor and its medicinal usage.The compound B-11 has chemical structure shown in Formulas I:Chemical name are as follows: 6-amino-9- (2-phenoxyethyl) -9H-purine-8-thiol；The medicinal usage, which refers to using at least one of the compound B-11 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 can be effectively suppressed in compound B-11 of the present invention, and the horizontal IC50 value of zymetology is 28.58 ± 12.68 μm of ol/L, has good NSD3 enzyme inhibitory effect.Effective inhibitor of the compound of the present invention as the important target spot NSD3 of tumour, it is expected to be used to prepare anti-tumor drug as active constituent, there is 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[1-4].Therefore, histone methyltransferase is considered as latent
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[5,6]；Histone methyltransferase DOT1L inhibits
Agent EPZ-5676 (Epizyme company) also entered Phase I clinical trial in 2014, for treating acute leukemic patient[7,8].This
Outside, there are also the micromolecular inhibitors of multiple histone-lysine methyltransferases, such as SETD7 inhibitor PFI-2, G9a (EHMT2)
With GLP (EHMT1) inhibitor UNC0638, A-366, SMYD2 inhibitor LLY-507 etc. is in the preclinical study stage, these
Research is most important for the research and development of antineoplastic target therapeutic agent, has broad application prospects.Histone methyltransferase
NSD3 (also known as WHSC1L1, Wolf-Hirschhorn syndrome candidate1-like1) can make histone H 3 the 36th
Lysine (H3K36) di-methylation (me2) and tri-methylated (me3).The NSD3 assignment of genes gene mapping is in the position human chromosome 8p11.23
On, the occurrence and development with Several Kinds of Malignancy have important relationship.Firstly, the 8p11-12 chromosome interval where NSD3 is in cream
It is highly expanded in the cancers such as gland cancer, lung cancer, cancer of pancreas and neoplastic hematologic disorder, disclosing the section and tumor development has strong phase
Guan Xing.Secondly, multiple studies have shown that NSD3 gene itself plays a significant role in the occurrence and development of malignant tumour.In mammary gland
NSD3 is found highly to express in the tumours such as cancer, bladder cancer, Head and neck squamous cell carcinoma, has the function of promoting tumour formation；?
T (8 is found in patients with acute myeloid leukemia；11)(p11.2；P15) NUP98-NSD3 fusion, specific mechanism of action
It is unclear；NSD3-NUT fusion is found in NUT center line cancer (NUT midline carcinoma), expression is melted
Hop protein is by combining BRD4 albumen to play an important role in terms of tumor cell differentiation retardance and proliferation[20]；In acute marrow
In chronic myeloid leukemia (AML) cell, the NSD3 isomers for containing only first PWWP structural domain of N-terminal mediates BRD4-CHD8 albumen
Matter combines, and directly affects the proliferation and differentiation of tumour cell[21]。
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 the 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 B1) can inhibit NSD3 enzymatic activity, and the anti-tumor activity of combination cell experimental verification compound,
Although the research also prematurity about inhibitor B1 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 B1 (chemical name: 6-amino-9- (2-
Phenoxyethyl) -9H-purine-8-thiol), the horizontal IC of zymetology50Value is 28.58 ± 12.68 μm of ol/L；With good
NSD3 enzyme inhibitory effect.
Detailed description of the invention
Fig. 1: the B1 IC on NSD3 protein level50Value figure.
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.ChemDiv database is carried out using Discov ery Studio 2.5
The pretreatment of compound, including duplicate removal, removal salt ion and inorganic matter, and carry out construction standard.Using
LigPrep module in 9.0 generates the possibility ionization state and tautomer of compound under the conditions of pH=7.4.
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 B1) has preferable histone methyltransferase inhibitory activity.
Compound of formula I chemical structural formula (compound of formula I hereinafter referred to as B1)
The external Enzyme assay experimental procedure of 1.2NSD3
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,
After being sequenced and identifying, conversion inducing expression in Escherichia coli Rossetta (after 0.5mM IPTG induction, is persistently trained at 16 DEG C
Support 20 hours), purified with GST resin, obtains the NSD3 albumen of GST label.
2) the external Enzyme assay step of NSD3:
1. compound B-11 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 be 1.0 μM), and 50mM Tris-HCl pH8.5,50mM NaCl,
In 5mM MgCl2,1mM DTT and 0.01%Tween reaction solution, 30 DEG C are reacted 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.
2. experimental result
Determine the activity inhibition that B1 is directed to histone methyltransferase NSD3 on albumen and cellular level.
As shown in Figure 1, B1 has good NSD3 enzyme inhibitory effect, IC in albumen zymetology level in vitro50Value is
28.58±12.68μM。
To sum up, compound B-11 of the present invention is effective histone methyltransferase NSD3 inhibitor, can be had in vitro
Effect inhibits its enzymatic activity.Due to important function of the NSD3 in kinds of tumors, the compounds of this invention B1 is as NSD3 inhibitor, tool
There is potential antitumor action, it is expected to become as activity and be used to prepare anti-tumor drug, especially be expected to be used to prepare anti-lung cancer
Drug, have 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. histone methyltransferase NSD3 activity inhibitor according to claim 1 is in preparation tumor
Using.
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 its hydrate of compound of formula I, pharmaceutically may be used
Salt, tautomer, stereoisomer or the precursor compound of receiving and one or more pharmaceutically acceptable carriers are made
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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| CN201810971341.1A CN109232573A (en) | 2018-08-24 | 2018-08-24 | A kind of compound B-11 is as histone methyltransferase NSD3 activity inhibitor and its application |
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| CN201810971341.1A CN109232573A (en) | 2018-08-24 | 2018-08-24 | A kind of compound B-11 is as histone methyltransferase NSD3 activity inhibitor and its application |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2018
- 2018-08-24 CN CN201810971341.1A patent/CN109232573A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Application publication date: 20190118 |