CN116327887B - Application of LSD1 inhibitor as antitumor drug - Google Patents
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- CN116327887B CN116327887B CN202310448696.3A CN202310448696A CN116327887B CN 116327887 B CN116327887 B CN 116327887B CN 202310448696 A CN202310448696 A CN 202310448696A CN 116327887 B CN116327887 B CN 116327887B
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- HSSLDCABUXLXKM-UHFFFAOYSA-N resorufin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3N=C21 HSSLDCABUXLXKM-UHFFFAOYSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
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Abstract
The invention discloses an LSD1 inhibitor and application thereof in anti-tumor drugs. The invention discovers that the structural compound shown in the formula I has obvious inhibition effect on histone lysine specific demethylase LSD1, and opens up a new way for searching anti-tumor drugs based on histone lysine specific demethylase LSD1 targets.
Description
Technical Field
The invention belongs to the field of anti-tumor medicine and aims to provide an application of a histone lysine specific demethylase LSD1 inhibitor in an anti-tumor medicine.
Background
Epigenetic and genetic errors cooperate to promote the development and progression of cancer by altering gene activity without altering DNA sequences, DNA and DNA-related protein modification regulation have become a popular research area, and enzymes involved in these processes are also considered as popular targets for drug development, with histones being one of them. Histone tails are affected by a variety of post-translational modifications, such as: phosphorylation, acetylation, methylation and ubiquitination, where acetylation and methylation play an important role in the regulation of gene expression, and are often deregulated in cancer.
Histone lysine-specific demethylase LSD1 can specifically remove mono-and di-methylation of lysine 4 (H3K 4) and lysine 9 (H3K 9) of histone H3, methylation of H3K4 is usually associated with gene activation, methylation of H3K9 is associated with transcriptional inhibition, and related processes are closely related to tumor development and progression.
Histone lysine-specific demethylase LSD1 is a highly conserved protein, present in many organic organisms, with three major domains: an N-terminal SWIRM domain (small alpha-helical domain), a C-terminal amine oxidase domain (AOL), and a centrally protruding TOWER domain that facilitates protein stabilization. The TOWER domain divides AOL into two subdomains, a FAD binding region and a substrate binding region. The active center of histone lysine-specific demethylase LSD1 is located in the middle of the AOL domain at the intersection between FAD and substrate binding region.
Histone lysine-specific demethylase LSD1 is overexpressed in various tumors including rhabdomyosarcoma, ewing's sarcoma, osteosarcoma, prostate cancer, breast cancer, neuroblastoma cells, lymphoma, lung cancer, gastric cancer, colorectal cancer, bladder cancer, esophageal cancer or acute and chronic leukemia, etc., and thus it is an important target for antitumor drugs. Inhibition of histone lysine-specific demethylase LSD1 may be an effective strategy for the re-expression of epigenetic silenced tumor suppressor genes, capable of inhibiting tumor growth and metastasis. Therefore, the design and development of a histone lysine-specific demethylase LSD1 inhibitor with strong selectivity, high efficiency and low toxicity is a new way for treating cancers.
Several histone lysine-specific demethylase LSD1 inhibitors have been reported at present, but their selectivity is poor, and the inhibitory activity against enzymes is low, so further development of efficient, highly selective histone lysine-specific demethylase LSD1 inhibitors remains a promising target.
Disclosure of Invention
The invention aims to provide application of a histone lysine specific demethylase LSD1 inhibitor in an anti-tumor drug, and provides guidance for LSD1 inhibitor drug design.
The above object of the present invention is achieved by the following technical scheme:
the LSD1 inhibitor shown in the formula I is:
the compounds of formula I according to the invention have been reported in the ZINC20 compound library (https:// zinc20. Dock. Org /), and are known compounds.
The invention provides application of an LSD1 inhibitor shown in a formula I or pharmaceutically acceptable salt thereof in preparation of histone lysine specific demethylase LSD1 inhibitor medicines.
The invention provides application of an LSD1 inhibitor shown in a formula I or pharmaceutically acceptable salt thereof in preparing a medicament for inhibiting tumor growth.
The invention provides application of an LSD1 inhibitor shown in a formula I or pharmaceutically acceptable salt thereof in preparation of a medicament for inhibiting tumor metastasis.
The invention provides application of an LSD1 inhibitor shown in a formula I or pharmaceutically acceptable salt thereof in preparation of a medicament for inhibiting tumor invasion.
The tumor comprises rhabdomyosarcoma, ewing sarcoma, osteosarcoma, prostatic cancer, breast cancer, neuroblastoma cells, lymphoma, lung cancer, gastric cancer, colorectal cancer, bladder cancer, esophageal cancer or acute and chronic leukemia.
The pharmaceutically acceptable salts of the present invention may be the usual salts of these compounds, including for example but not limited to acetate, sulfate, hydrochloride, oxalate or phosphate.
The histone lysine specific demethylase LSD1 inhibitor has good anti-rhabdomyosarcoma effect.
Drawings
FIG. 1 is a two-dimensional graph of molecular docking results for compounds of formula I and LSD1 proteins.
FIG. 2 is a graph showing the inhibition of LSD1 enzyme by compounds of formula I at various concentrations.
FIG. 3 is a graph showing the proliferation assay of the compound of formula I on A673 cells.
Detailed Description
The following describes the essential aspects of the invention in connection with the accompanying drawings and detailed description, but is not intended to limit the scope of the invention.
Example 1: molecular docking validation
The histone lysine-specific demethylase LSD1 protein uses a crystal structure with PDB ID of 2Z6U and has a resolution ofTaking the structure as a receptor in virtual screening, selecting a compound of the formula I for virtual docking, and checking the docking posture and interaction of the compound of the formula I and histone lysine specific demethylase LSD 1. The results show that the compounds of formula I are related to histone lysine-specific demethylase LSD1The interactions of the bonds are shown in FIG. 1.
Example 2 kinetic simulation analysis verification
Molecular dynamics simulations were performed using GROMACS. The ligand and histone lysine specific demethylase LSD1 docking model was used as the initial conformation, the ligand's profile Ambertools was prepared, amber99SB-ILDN force field was used for receptor protein and GAFF force field was used for ligand molecules. The solvent was a TIP3P water model. After energy minimization, the composite was heated from 0K to 300K during 250ps in NVT position restriction, equilibrated at a constant pressure of 1 atmosphere, 300K, and kinetic simulation was performed after 50ps again. The results show that the aldehyde groups form stable hydrogen bond interactions with Ser289, arg310 and Arg 318. Short-range coulombic interactions of proteins and small molecules (Coul-SR: protein-lig) and short-range LJ potentials are shown in Table 1.
Table 1 shows the results of kinetic simulations of the compounds of formula I and LSD1 complexes.
| Energy | Average | RMSD | Tot-Drift |
| Potential | -4.581e+06 | 2306.67 | -182.268(kJ/mol) |
| Total Energy | -3.71418e+06 | 2928.58 | -180.884(kJ/mol) |
| Coul-SR：Protein-lig | -53.4071 | 26.4127 | 28.7022(kJ/mol) |
| LJ-SR：Protein-lig | -269.455 | 15.8264 | -14.1294(kJ/mol) |
Example 3: LSD1 inhibition activity assay
Histone lysine-specific demethylase LSD1 can specifically catalyze the demethylation of histone H3K4 or H3K9, while producing H 2 O 2 . The inhibition assay of histone lysine-specific demethylase LSD1 was based on the horseradish peroxide (horseradish peroxidase, HRP) detection principle, i.e.H in the presence of HRP 2 O 2 The reaction with Amplex Red produces the highly fluorescent compound resorufin. Preparing a compound of formula I into a solution with the concentration of 0-400nM, incubating with human recombinant histone lysine specific demethylase LSD1 enzyme in an experiment buffer (50 mM sodium phosphate pH 7.4) and Flavin Adenine Dinucleotide (FAD) on ice for 15min, adding H3K4me2 peptide substrate, incubating at 37 ℃ for 30min, adding an Amplex Red reagent and horseradish peroxidase (HRP), incubating the mixture in the dark at room temperature for 5min, analyzing the change of fluorescence intensity at an excitation light of 540nM and an emission wavelength of 570nM by using an enzyme-labeled instrument to obtain data, and calculating the IC of the compound by concentration-reaction curve fitting by using GraphPad software 50 Values. The results show that the compounds of formula I have a significant inhibitory effect on histone lysine-specific demethylase LSD1 enzyme in vitro, see figure 2.
Example 4: cell proliferation assay
Culturing A673 cells to logarithmic phase, digesting the cells with trypsin, centrifuging after stopping digestion, preparing single cell suspension, inoculating 5000 MTT solutions per well into 96-well cell culture plates, culturing overnight in an incubator, discarding the culture medium, adding the culture medium into a control group, adding the culture medium containing 100 μg/ml, 50 μg/ml, 25 μg/ml and 12.5 μg/ml of the compound of formula I into LSD1 inhibitor, culturing in the incubator for 72h, adding 10 μl of MTT solution, continuously culturing for 4h, discarding 150 μl of DMSO per well of MTT solution, standing at room temperature for 15min, and detecting optical density at 570nm by using an enzyme-labeling instrument. Inhibition of compounds was calculated via concentration-response curve fitting using GraphPad software. The results show that the compounds of formula I have a significant inhibitory effect on a673 cells and that the results have statistical differences, see figure 3.
Claims (2)
1. Application of LSD1 inhibitor shown in formula I or pharmaceutically acceptable salt thereof in preparation of histone lysine specific demethylase LSD1 inhibitor drug
Formula I.
2. The use according to claim 1, wherein the pharmaceutically acceptable salt is a sulphur acetate, a hydrochloride, an oxalate or a phosphate.
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| CN202310448696.3A CN116327887B (en) | 2023-04-24 | 2023-04-24 | Application of LSD1 inhibitor as antitumor drug |
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| CA3158557A1 (en) * | 2019-11-18 | 2021-05-27 | Javed Khan | Inhibitors of histone demethylases (pfi-63 and pfi-90) for the treatment of cancer and for the inhibition of histone demethylase in cells |
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