CN109336836A - The compound and purposes of CARM1 micromolecular inhibitor - Google Patents
The compound and purposes of CARM1 micromolecular inhibitor Download PDFInfo
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- CN109336836A CN109336836A CN201811407624.XA CN201811407624A CN109336836A CN 109336836 A CN109336836 A CN 109336836A CN 201811407624 A CN201811407624 A CN 201811407624A CN 109336836 A CN109336836 A CN 109336836A
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Abstract
The compound and purposes of CARM1 micromolecular inhibitor, are related to new medicine use.By analyzing the crystal structure model of CARM1,24 compounds and application thereof for adhering to the CARM1 micromolecular inhibitor of various structures type separately are provided by in-vitro screening model in conjunction with virtual screening and random screening method.The officinal salt of the compound of the CARM1 micromolecular inhibitor, acid-addition salts including being formed with following acid are one of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, P-TOLUENE SULFO ACID 99, naphthalene sulfonic acids, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, tussol, it further include the acid salt of inorganic base, the acid salt of inorganic base includes one of alkali metal cations, alkaline earth metal cation, ammonium cation salt.Pharmacological testing shows that 24 be related to compound all has CARM1 inhibitory activity and anti-tumor activity.
Description
Technical field
The present invention relates to new medicine uses, change more particularly, to the officinal salt of 24 small molecule compounds, containing these
The Pharmaceutical composition and their medical application for closing object, especially as arginine methyltransferase CARM1 inhibition of enzyme activity
The anticancer purpose of agent.
Background technique
In China, cancer has become one of highest disease of the death rate and the fastest-rising country of cancer morbidity
One, and age of onset is also in the trend of gradually rejuvenation, thus find the regulation that plays a crucial role to cancer occurrence and development because
Son simultaneously designs effective and special micromolecular inhibitor as drug target, with important learning value and society's effect
Benefit.
The posttranslational modification of histone is as one of regulatory mechanism important in epigenetic.Such modification includes histone
Phosphorylation, acetylation, methylation, ubiquitination, SUMOization, ADP- ribosylation etc. usually occur in histone amino terminal, shadow
The processes such as genetic transcription and DNA damage reparation of sound.Histone methylated is one of presently found most commonly seen modification, is occurred
On the arginine or lysine residue of histone amino terminal.Histone methyltransferase, histone demethylase and methyl
Change identification albumen and undertakes histone methylated " writing ", " wiping " and " reading " function respectively, the common methylation shape for adjusting histone
State.Arginine methylation is the important posttranslational modification occurred extensively into the cell, by protein-arginine methyltransferase (N-
Arginine methyltransferases, PRMTs) mediate the methyl by the co-factor SAM that methylates to be transferred to arginine side chain
Nitrogen-atoms on.PRMTs can both methylate histone, can also methylate nonhistones.According to the difference of methylation pattern, smart ammonia
Acid methyltransferase is broadly divided into three classes:
I type is responsible for being catalyzed monomethylation and asymmetric double methylations, including PRMT1, PRMT2, PRMT3, PRMT4
(CARM1), PRMT6 and PRMT8；
II type is responsible for monomethylation modification and the double methylations of symmetry, including PRMT5 and PRMT9；
Type III is only catalyzed arginic monomethylation, is PRMT7.
In addition, the substrate of PRMT10 and PRMT11 has not been reported.The study found that arginine methylation participates in gene expression tune
Control, cell signalling regulation, albumen positioning, DNA damage reparation and RNA processing etc. one is bioprocess.The exception table of PRMTs
Up to related to a variety of diseases to dysfunction, important work has been played in the occurrence and development and invasion transfer process of malignant tumour
With.
Arginine methyltransferase 4 (protein arginine methyltransferase 4, PRMT4)/co-activation
Relevant 1 (the coactivator-associated arginine methyltransferase of arginine methyltransferase of the factor
1, CARM1) it is one of the PRMTs family member found earliest, exists simultaneously in nucleus and cytoplasm, methylated substrate
Including histone and nonhistones.Although CARM1 can be by relying on from the non-methylation such as methylation and protein-protein interaction
Mode play biological function, but its methylase activity has vital influence to biological function.On the one hand,
Histone methylated (H3R17me2a and H3R26me2a) activation nuclear receptor that CARM1 is generated or the gene that transcription factor mediates
Transcription.On the other hand, CARM1 can also be transcribed by the nonhistones substrate controlling gene that methylates, and be adjusted after influencing the transcription of mRNA
Delay, glutamine metabolism and DNA damage reparation of radioactivity induction etc. in control and core.For cellular level, the first of CARM1
Baseization activity controllable cell cycle, cell Proliferation, cell differentiation, cell autophagy and stem cell versatility, etc..The table of CARM1
Up to dysfunction, (breast cancer, colon cancer, lung cancer, cancer of pancreas, liver cancer, oophoroma, osteosarcoma, acute marrow are thin with kinds cancer
Born of the same parents' leukaemia etc.) occurrence and development it is closely related.By taking breast cancer as an example, CARM1 include estrogen positive, the HER-2 positive with
And high expression in three breast cancer including feminine gender.Also, the expression of CARM1 and the grade malignancy of breast cancer are positively correlated.CARM1
As estrogen co-activation transcription factor, it is enriched in the promoter region of estrogen receptor alpha (ER α) target gene, is turned by combining
Record the expression of co-activation factor p160 up-regulation estrogen target gene.Recent research is shown, thin in the breast cancer of estrogen stimulation
CARM1 can also raise the expression of E2F1 and CCND1 by transcriptional factors AIB1 in born of the same parents, promote growth of tumour cell.
CARM1 methylation transcription co-activation factor p/CIP, increases the activity and stability of p/CIP.In the MCF7 cell of estrogen induction
In, the ER α of p/CIP and activation interacts, and activates the downstream p/CIP JAK/STAT signal path, enhances tumor cell proliferation energy
Power.In addition, CARM1 can also activate ER α with cancer protein PELP1 interaction is promoted, the gene expression that activation PELP is mediated promotes cream
The invasion of adenocarcinoma cell MCF7 and transfer ability.In breast cancer cell, it was found that the estrogen receptor regulated and controled by CARM1 is non-
Dependent signals access.CARM1 methylation BAF155, improves the oncogene c-Myc table that chromatin remodeling factors SWI/SNF is mediated
It reaches, promotes the proliferation of triple negative breast cancer cell MDA-MB-231.Meanwhile the CARM1 methylation MED12 in this cell, it can
The transcriptional expression for inhibiting cell cycle inhibitor p21, reduces breast cancer to the drug resistance of chemotherapeutics.Positive in HER-2
CARM1 overexpression is had also discovered in breast cancer cell matter.The p300 however, CARM1 methylates, promotes tumor suppressor BRCA1
The transcription of target gene shows the function of tumor suppressor gene.From the above it can be seen that although work of the CARM1 in breast cancer occurrence and development
It need to be gone into seriously with mechanism, but generally CARM1 shows the facilitation to breast cancer (especially ER positive breast cancer), it is special
The potential carcinogenicity not shown in the invalid breast cancer of conventional medication, so that it is designated as cracking as tumor drug target
The predicament that current breast cancer treatment faces brings new hope.
In conclusion CARM1 has a variety of biological functions as epigenetic regulation, arginine methylation is in cancer
Functional study in disease shows that epigenetic regulation is potential anti-tumor drug target, therefore it is proposed that targeted inhibition
CARM1 enzyme function is used for the imagination of oncotherapy.
Summary of the invention
It is an object of the invention to the crystal structure models by analysis CARM1, in conjunction with virtual screening and random screening side
Method provides 24 compounds and its use for adhering to the CARM1 micromolecular inhibitor of various structures type separately by in-vitro screening model
On the way.
The structure of the compound of the CARM1 micromolecular inhibitor is as follows:
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt, including with it is following acid formed acid-addition salts be hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, to benzene
Sulfonic acid, naphthalene sulfonic acids, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenyl
One of acetic acid, tussol etc..
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt, further includes the acid salt of inorganic base, and the acid salt of the inorganic base includes alkali metal cations, alkaline-earth metal sun
One of ion, ammonium cation salt etc..
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt is a kind of pharmaceutical composition, wherein any compound 1-1,1-2,1-3,1-4,2-5,2- containing therapeutically effective amount
6、2-7、2-8、2-13、2-14、3-9、4-10、5-11、6-12、7-15、7-16、7-17、7-21、7-22、8-18、9-19、10-
20,11-23,12-24 or its officinal salt and at least one pharmaceutically acceptable carrier or excipient etc..
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt, the purposes in the drug for preparing CARM1 dependence disease.
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt pharmaceutical composition, the purposes in the drug for preparing CARM1 dependence disease.
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt, the purposes in the drug that preparation inhibits CARM1.
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt pharmaceutical composition, the purposes in the drug that preparation inhibits CARM1.
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt, the purposes in the drug of preparation treating cancer, wherein the cancer can be selected from breast cancer, colon cancer, lung cancer, pancreas
One of gland cancer, liver cancer, oophoroma, osteosarcoma, acute myelocytic leukemia etc..
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt pharmaceutical composition, the purposes in the drug of preparation treating cancer, wherein the cancer can be selected from breast cancer, colon
One of cancer, lung cancer, cancer of pancreas, liver cancer, oophoroma, osteosarcoma, acute myelocytic leukemia etc..
Pharmacological testing shows that 24 compounds of the present invention all have different degrees of CARM1 inhibitory activity and one
Fixed anti-tumor activity.
Specific embodiment
The present invention is further illustrated for following embodiment.
The structure of the compound of the CARM1 micromolecular inhibitor is as follows:
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt, including with it is following acid formed acid-addition salts be hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, to benzene
Sulfonic acid, naphthalene sulfonic acids, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenyl
One of acetic acid, tussol etc..
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt, further includes the acid salt of inorganic base, and the acid salt of the inorganic base includes alkali metal cations, alkaline-earth metal sun
One of ion, ammonium cation salt etc..
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt is a kind of pharmaceutical composition, wherein any compound 1-1,1-2,1-3,1-4,2-5,2- containing therapeutically effective amount
6、2-7、2-8、2-13、2-14、3-9、4-10、5-11、6-12、7-15、7-16、7-17、7-21、7-22、8-18、9-19、10-
20,11-23,12-24 or its officinal salt and at least one pharmaceutically acceptable carrier or excipient.
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt, the purposes in the drug for preparing CARM1 dependence disease.
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt pharmaceutical composition, the purposes in the drug for preparing CARM1 dependence disease.
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt, the purposes in the drug that preparation inhibits CARM1.
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt pharmaceutical composition, the purposes in the drug that preparation inhibits CARM1.
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt, the purposes in the drug of preparation treating cancer, wherein the cancer can be selected from breast cancer, colon cancer, lung cancer, pancreas
One of gland cancer, liver cancer, oophoroma, osteosarcoma, acute myelocytic leukemia etc..
Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2- of the CARM1 micromolecular inhibitor
14,3-9,4-10,5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24
Officinal salt pharmaceutical composition, the purposes in the drug of preparation treating cancer, wherein the cancer can be selected from breast cancer, colon
One of cancer, lung cancer, cancer of pancreas, liver cancer, oophoroma, osteosarcoma, acute myelocytic leukemia etc..
Specific embodiment is given below.
The compound of CARM1 micromolecular inhibitor is as follows to the external inhibitory activity test of CARM1:
Using MTase-GloTMThe rejection ability that method test compound acts on CARM1 methylase
MTase-GloTMIt is a kind of detection system based on biloluminescence method, by monitoring reaction product S-adenosyl
The formation of homocysteine (SAH), so as to monitor transmethylase (methyltransferases, MTases) activity
With small molecule under various flux to the activity regulation of MTases.Basic principle are as follows: transmethylase after reaction, is added
MTase-GloTMSAH is converted to ADP by Reagent, adds MTase-GloTMDetection Solution turns ADP
ATP is turned to, then ATP is detected by a pair of of luciferase reaction.Luminous signal can be by having the plate reader of detection light-emitting function
Detection, is then associated using SAH standard curve and SAH concentration, and the half-life period of luminous signal is greater than 4h.Longer half-life period
Make to examine time keeping instrument without configuring sample injector, and batch detection can be carried out.
The specific method is as follows: being tried using the MTase-Glo Methyltransferase Assay that Promega company produces
Agent box, first step methylation reaction system include 4Xreaction buffer (80mM Tris-HCl 8.0,200mM NaCl,
4mM EDTA,12mM MgCl2, 0.4mg/ml BSA), 20uM SAM, 25uM histone substrates, the transmethylase of 0.5ng and
Compound DMSO solution with a certain concentration gradient is added MTase-Glo Reagent and methylates under the conditions of 37 DEG C
1h is reacted, after the completion of methylation reaction, MTase-Glo Detection Solution is added, and the reaction was continued under the conditions of 37 DEG C
30min is transferred in 96 hole plates and measures fluorescence intensity (negative control being not added of system with GloMax Discover System
Object is closed, blank control system is not enzyme and compound).Then existed with 6 software of GraphPad Prism to experimental group and control group
Fluorescent intensity angle value under concentration gradient is analyzed, and the 503nhibiting concentration IC of compound is calculated50。
Shown in the experimental data are shown in the following table:
| Compound | IC50(μM) | Compound | IC50(μM) |
| 1-1 | 100.60 | 5-11 | 45.10 |
| 1-2 | 55.39 | 6-12 | 4.68 |
| 1-3 | 163.50 | 7-15 | >200 |
| 1-4 | >200 | 7-16 | 1.30 |
| 2-5 | 15.94 | 7-17 | >200 |
| 2-6 | 8.54 | 7-21 | 1.69 |
| 2-7 | 16.09 | 7-22 | 10.80 |
| 2-8 | 43.26 | 8-18 | >200 |
| 2-13 | 73.30 | 9-19 | 13.07 |
| 2-14 | 6.13 | 10-20 | 77.40 |
| 3-9 | >200 | 11-23 | 4.45 |
| 4-10 | 102.00 | 12-24 | >200 |
(but it is living to be not limited to inhibition to breast cancer to the inhibitory activity of breast cancer for the compound of CARM1 micromolecular inhibitor
Property):
Using the influence of MTS method detection compound cell proliferation
By taking breast cancer cell MCF7 cell as an example, cell is laid in 96 orifice plates, plating density is 20%~30%.
After for 24 hours, compound DMSO solution is added, including positive control (adding positive drug), blank control (add DMSO), experimental group (test
Drug), set up 6 drug concentration gradients: 100 μM, 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM.Each concentration gradient includes 3 weights
It is multiple parallel.Cell changes liquid before dosing.After 48h, with (CellTiterThe mono- Solution Cell Proliferation detection reagent of AQueous
Box) with colorimetric determination cytotoxicity.CellTiterThe mono- solution reagent of AQueous includes a kind of tetrazole compound [3-
(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-
Tetrazo-lium, inner salt；MTS] and an electronics coupled reagent (second sulphur azophenlyene, PES).20 μ l are added in every 100 μ l culture medium
CellTiterAQueous solution reagent, at 37 DEG C, 5%CO21h is cultivated in incubator.25 μ l 10%SDS termination is added
Reaction.Using Thermo Multiskan MK3 microwell plate microplate reader, the extinction Value Data being recorded at wavelength 490nm.It arranges
Data, with the IC of 6 software of GraphPad Prism analysis drug50Value.
Part of compounds is shown in the experimental data are shown in the following table:
The above biological activity test show above compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,
2-14、3-9、4-10、5-11、6-12、7-15、7-16、7-17、7-21、7-22、8-18、9-19、10-20、11-23、12-24
With CARM1 enzyme inhibition activity.Compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2-14,3-9,4-10,
It is more that 5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24 can also be used for treatment
Kind cancer, including breast cancer, colon cancer, lung cancer, cancer of pancreas, liver cancer, oophoroma, osteosarcoma, acute myelocytic leukemia
Deng, wherein can be CARM1 mediation cancer, be also possible to the cancer independent of above-mentioned mechanism.Therefore, of the present invention
Compound can be used for the preparation of anticancer drug.
The test of CARM1 inhibition of enzyme activity shows that compound of the present invention inhibits with apparent CARM1 demethylation
Activity.Since CARM1 has key effect, and the support with vitro enzyme activity experiment, this hair in growth of cancer cells proliferation
The bright compound being related to can be used for preventing or treating in the drug of the related disease of CARM1 inhibitor, especially the drug of cancer
In.
Claims (10)
- The compound of 1.CARM1 micromolecular inhibitor, it is characterised in that its structure is as follows:
- 2. the compound of CARM1 micromolecular inhibitor as described in claim 1, it is characterised in that the CARM1 little molecules in inhibiting Compound 1-1,1-2 of agent, 1-3,1-4,2-5,2-6,2-7,2-8,2-13,2-14,3-9,4-10,5-11,6-12,7-15, The officinal salt of 7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24, including what is formed with following acid Acid-addition salts be hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, P-TOLUENE SULFO ACID 99, naphthalene sulfonic acids, citric acid, tartaric acid, One of lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, tussol.
- 3. the compound of CARM1 micromolecular inhibitor as described in claim 1, it is characterised in that the CARM1 little molecules in inhibiting Compound 1-1,1-2 of agent, 1-3,1-4,2-5,2-6,2-7,2-8,2-13,2-14,3-9,4-10,5-11,6-12,7-15, The officinal salt of 7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24 further include the acid of inorganic base Salt, the acid salt of the inorganic base include one of alkali metal cations, alkaline earth metal cation, ammonium cation salt.
- 4. the compound of CARM1 micromolecular inhibitor as described in claim 1, it is characterised in that the CARM1 little molecules in inhibiting Compound 1-1,1-2 of agent, 1-3,1-4,2-5,2-6,2-7,2-8,2-13,2-14,3-9,4-10,5-11,6-12,7-15, The officinal salt of 7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24 are a kind of pharmaceutical composition, wherein Any compound 1-1,1-2,1-3,1-4,2-5,2-6,2-7,2-8,2-13,2-14,3-9,4-10 containing therapeutically effective amount, 5-11,6-12,7-15,7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24 or its officinal salt with And at least one pharmaceutically acceptable carrier or excipient.
- 5. the compound of CARM1 micromolecular inhibitor as described in claim 1, it is characterised in that the CARM1 little molecules in inhibiting Compound 1-1,1-2 of agent, 1-3,1-4,2-5,2-6,2-7,2-8,2-13,2-14,3-9,4-10,5-11,6-12,7-15, The officinal salt of 7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24, in preparation CARM1 dependence disease Purposes in the drug of disease.
- 6. the compound of CARM1 micromolecular inhibitor as described in claim 1, it is characterised in that the CARM1 little molecules in inhibiting Compound 1-1,1-2 of agent, 1-3,1-4,2-5,2-6,2-7,2-8,2-13,2-14,3-9,4-10,5-11,6-12,7-15, The officinal salt pharmaceutical composition of 7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24, in preparation CARM1 Purposes in the drug of dependence disease.
- 7. the compound of CARM1 micromolecular inhibitor as described in claim 1, it is characterised in that the CARM1 little molecules in inhibiting Compound 1-1,1-2 of agent, 1-3,1-4,2-5,2-6,2-7,2-8,2-13,2-14,3-9,4-10,5-11,6-12,7-15, The officinal salt of 7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24 inhibit the medicine of CARM1 in preparation Purposes in object.
- 8. the compound of CARM1 micromolecular inhibitor as described in claim 1, it is characterised in that the CARM1 little molecules in inhibiting Compound 1-1,1-2 of agent, 1-3,1-4,2-5,2-6,2-7,2-8,2-13,2-14,3-9,4-10,5-11,6-12,7-15, The officinal salt pharmaceutical composition of 7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24 inhibit in preparation Purposes in the drug of CARM1.
- 9. the compound of CARM1 micromolecular inhibitor as described in claim 1, it is characterised in that the CARM1 little molecules in inhibiting Compound 1-1,1-2 of agent, 1-3,1-4,2-5,2-6,2-7,2-8,2-13,2-14,3-9,4-10,5-11,6-12,7-15, The officinal salt of 7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24, in the medicine of preparation treating cancer Purposes in object, wherein the cancer is selected from breast cancer, colon cancer, lung cancer, cancer of pancreas, liver cancer, oophoroma, osteosarcoma, acute One of myelocytic leukemia.
- 10. the compound of CARM1 micromolecular inhibitor as described in claim 1, it is characterised in that the CARM1 little molecules in inhibiting Compound 1-1,1-2 of agent, 1-3,1-4,2-5,2-6,2-7,2-8,2-13,2-14,3-9,4-10,5-11,6-12,7-15, The officinal salt pharmaceutical composition of 7-16,7-17,7-21,7-22,8-18,9-19,10-20,11-23,12-24 are treated in preparation Purposes in the drug of cancer, wherein the cancer is selected from breast cancer, colon cancer, lung cancer, cancer of pancreas, liver cancer, oophoroma, bone and flesh One of tumor, acute myelocytic leukemia.
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| CN112043705A (en) * | 2020-09-16 | 2020-12-08 | 厦门大学 | Application of compound in preparation of small molecule inhibitor or cancer treatment drug, small molecule inhibitor and cancer treatment drug |
| WO2021023609A1 (en) * | 2019-08-02 | 2021-02-11 | Glaxosmithkline Intellectual Property Development Limited | Combination of a type i protein arginine methyltransferase (type i prmt) inhibitor and a methionine adenosyltransferase ii alpha (mat2a) inhibitor |
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| BR112017002260A2 (en) * | 2014-08-07 | 2017-11-21 | Vitae Pharmaceuticals Inc | piperazine derivatives as liver receptor x modulators |
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| CA: "1309078-36-1", 《STN-REGISTRY》 * |
| CA: "1331943-71-5", 《STN-REGISTRY》 * |
| CA: "1331950-59-4", 《STN-REGISTRY》 * |
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| WO2021023609A1 (en) * | 2019-08-02 | 2021-02-11 | Glaxosmithkline Intellectual Property Development Limited | Combination of a type i protein arginine methyltransferase (type i prmt) inhibitor and a methionine adenosyltransferase ii alpha (mat2a) inhibitor |
| CN112043705A (en) * | 2020-09-16 | 2020-12-08 | 厦门大学 | Application of compound in preparation of small molecule inhibitor or cancer treatment drug, small molecule inhibitor and cancer treatment drug |
| CN112043705B (en) * | 2020-09-16 | 2021-10-22 | 厦门大学 | Application of compound in preparation of small molecule inhibitor or cancer treatment drug, small molecule inhibitor and cancer treatment drug |
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