CN111297862B - Necrotic apoptosis inhibitor KW-2449 and application thereof as medicine - Google Patents
Necrotic apoptosis inhibitor KW-2449 and application thereof as medicine Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a necrotic apoptosis inhibitor KW-2449 and application thereof as a medicine, in particular to application thereof in preparing necrotic apoptosis inhibitors and medicines for resisting tumor, ischemic or cisplatin-induced acute kidney injury, Alzheimer disease, ischemic cardiomyopathy, ischemic stroke, atherosclerosis, acute pancreatitis, inflammatory bowel disease, sepsis, salmonella infection, Listeria infection, vaccinia virus infection and other inflammation and infection related diseases.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a necrotic apoptosis inhibitor KW-2449 and application thereof as a medicine.
Background
Necrotic apoptosis is a recently discovered regulated mode of programmed cell death that is morphologically characterized by necrosis. Research shows that protein kinases RIPK1 and RIPK3 form a complex and activate MLKL protein, and MLKL is polymerized to be directly positioned on a cell membrane and cause the cell membrane to break, so that the key mechanism for inducing programmed cell necrosis is realized. Necrotic apoptosis can cause infiltration of a large number of inflammatory cells in the body due to the release of cellular contents, thereby inducing a severe inflammatory response. Necrotic apoptosis, as a new type of programmed cell death mode, plays an important role in the pathophysiological processes of various diseases such as ischemic injury, acute kidney injury, neurodegenerative disease, malignant tumor, viral infection, immunological disease and the like. The identification and discovery of small molecule inhibitors of necrotic apoptosis are of great importance in the clinical treatment of diseases associated with necrotic apoptosis.
The Chinese alias [4- [2- (1H-indazol-3-yl) ethenyl ] KW-2449]Phenyl radical]-1-piperazinylmethanone of formula C20H20N40The inhibitor strongly inhibits Flt3 (related to chronic granulocytic leukemia and myelodysplasia), has moderate inhibition on FGFR1, Bcr-Abl and Aurora A, has no inhibition on PDGFR beta, IGF-1R and EGFR, and does not find the application report of the inhibitor directly serving as an inhibitor of RIPK1 and RIPK3 kinase to resist necrosis and apoptosis at present.
Disclosure of Invention
Aiming at the existing problems, the invention provides a necrotic apoptosis inhibitor KW-2449 and application thereof as a medicament, and aims to provide a novel anti-necrotic apoptosis inhibitor, in particular to a compound KW-2449 and a medicinal salt thereof, wherein the compound can be used as an inhibitor of RIPK1 and RIPK3 kinase to play an anti-necrotic apoptosis activity. The invention also aims to provide a new application of the compound KW-2449 in preparing medicaments for treating inflammation and infection related diseases such as tumor, acute kidney injury, Alzheimer disease, ischemic cardiomyopathy, ischemic stroke, atherosclerosis, acute pancreatitis, inflammatory bowel disease in children, sepsis, salmonella infection, Listeria infection and vaccinia virus infection.
The invention obtains the necrotic apoptosis inhibitor with a brand-new structure by screening the self compound library.
The specific technical scheme of the invention is as follows:
as a first aspect of the invention, a compound KW-2449 and a medicinal salt thereof have a structure shown in a formula (I), and the compound is: use of [4- [2- (1H-indazol-3-yl) vinyl ] phenyl ] -1-piperazinylmethanone or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament against cell necrosis;
the compound of the invention can be prepared into a form of medicinal salt according to a conventional method, and comprises organic acid salt and inorganic acid salt thereof: inorganic acids include, but are not limited to, hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, nitric acids, and the like, and organic acids include, but are not limited to, acetic, maleic, fumaric, tartaric, succinic, lactic, p-toluenesulfonic, salicylic, oxalic, and the like.
In a preferred embodiment, the compound shown in the formula (I) or the isomer, solvate or precursor thereof, or the pharmaceutically acceptable salt thereof has a drug action target of RIPK1/RIPK3, and inhibits cell necrosis by inhibiting the kinase activity of RIPK1/RIPK 3.
In another aspect of the invention, there is provided the use of a compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for RIPK1/RIPK3 inhibitors.
In another aspect of the invention there is provided the use of a compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for a disease associated with a RIPK1/RIPK3 kinase disorder, overactivation or overactive interaction.
In a preferred embodiment, the RIPK1/RIPK3 kinase disorder, overactivation or overactive interaction-related disease is an inflammatory, infectious, ischemic and degenerative related disease or tissue injury.
In another preferred embodiment, the inflammatory, infectious, ischemic and degenerative related diseases are mediated by RIPK1/RIPK3 kinase, or are triggered by cellular necrosis (inhibition of inflammatory and infectious related diseases by inhibition of cellular necrosis).
In another preferred embodiment, the inflammatory, infectious, ischemic and degenerative related diseases include, but are not limited to: tumor, Alzheimer's disease, ischemic cardiomyopathy, ischemic stroke, atherosclerosis, acute pancreatitis, inflammatory bowel disease in children, sepsis, Salmonella infection, Listeria infection, or vaccinia virus infection.
In another preferred embodiment, the tumor includes cancers of the esophagus, stomach, intestine, rectum, oral cavity, pharynx, larynx, lung, colon, breast, uterus, endometrium, ovary, prostate, testis, bladder, kidney, liver, pancreas, bone, connective tissue, skin, eye, brain and central nervous system, as well as thyroid cancer, leukemia, hodgkin's disease, lymphoma and myeloma.
In another aspect of the present invention, there is provided a method of inhibiting cell necrosis, comprising: treating cells with a compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, the method of inhibiting cell necrosis is a method that does not aim at treating a disease; such as in vitro cell culture methods.
In a preferred embodiment, the compound shown in the formula (I) or the isomer, solvate or precursor thereof, or the pharmaceutically acceptable salt thereof has excellent anti-necrotic apoptosis effect when the cells are treated in vitro.
In a preferred embodiment, the compound shown in the formula (I) or an isomer, a solvate or a precursor thereof, or a pharmaceutically acceptable salt thereof is used for preparing a medicament for inhibiting the systemic inflammatory syndrome (SIRS) caused by TNF-alpha, acetaminophen (APAP) -induced hepatotoxicity, cisplatin-induced acute kidney injury, ischemic kidney injury and breast cancer metastasis.
In another aspect of the present invention, there is provided a method for preventing, alleviating or treating inflammatory, infectious, ischemic and degenerative related diseases, comprising: a compound represented by the formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof is administered to a subject in need of prevention, alleviation or treatment of inflammation and infectious related diseases.
Other aspects of the invention will be apparent to those skilled in the art in view of the disclosure herein.
Drawings
FIG. 1 is a graph showing the results of screening an inhibitor against necrotic apoptosis using a self-constructed drug library in example 1 of the present invention;
FIG. 2 is a graph of the inhibitory effect of KW-2449 on HT-29 necrotic apoptosis following TSZ stimulation at various concentrations in example 2 of the present invention;
FIG. 3 is a graph showing the effect of KW-2449 on the inhibitory activity of necrotic apoptosis in different cells in example 3 of the present invention;
FIG. 4 is a graph of KW-2449 inhibiting phosphorylation and preventing interaction of RIPK1 and RIPK3 in example 4 of the present invention;
FIG. 5 is a graph showing the recognition of KW-2449 binding target in example 5 of the present invention;
FIG. 6 is a graph of the protection of mice by KW-2449 from TNF- α induced systemic immune syndrome (SIRS) in example 7 of the present invention;
FIG. 7 is a graph of the protection of KW-2449 in vivo against acetaminophen (APAP) -induced hepatotoxicity in mice of example 8 of the present invention;
FIG. 8 is a graph showing that the necrotic apoptosis inhibitor KW-2449 in example 9 of this invention protects against Cisplatin-induced acute kidney injury in vivo;
FIG. 9 is a graph showing that the necrotic apoptosis inhibitor KW-2449 of example 10 of the present invention inhibits lung metastasis of breast cancer tumor in mice.
Detailed Description
The following description is of preferred embodiments of the present invention, and it should be understood that the preferred embodiments described herein are for purposes of illustration only and are not intended to limit the invention.
Example 1
Screening of anti-necrotic apoptosis inhibitors from the own compound library:
each compound was dissolved in DMSO to 10mM stock solution, human colon cancer cells HT-29 were plated in 96-well plates and pre-stimulated with 10. mu.M of one compound for 30min per well, and then necrotic apoptotic stimulation was induced by TNF-. alpha., Smac mimetic and z-VAD-fmk (TSZ) for 6 h, and cell survival was determined by assay for activated cell ATP content (using Promega corporation)
Luminescab Cell vitality Assay kit test catalog number: g7570) In that respect
As shown in figure 1, the results show that most of 120 screened compounds have no protective effect on necrotic apoptosis induced by TSZ stimulation, and only KW-2449 obviously inhibits necrotic apoptosis induced by TSZ stimulation.
Example 2
KW-2449 has anti-HT-29 cell necrosis activity:
the protective effect of KW-2449 on TNF-alpha induced necroptosis in HT-29 cells at different concentrations was further investigated. We found that KW-2449 concentration-dependent inhibition of TSZ-induced necrotic apoptosis, its EC50Comprises the following steps: 0.95. mu.M (FIG. 2A). At the same time, KW-2449 had no significant toxic effect on HT-29 cells at concentrations of 1-100. mu.M (FIG. 2B). In addition, KW-2449 did not protect against TNF-. alpha.and Smac mimetic (TS) -induced apoptosis (FIG. 2C).
Example 3
KW-2449 has inhibitory activity on necrotic apoptosis of different cells:
another human-derived cell line (U937) and a mouse-derived cell line (L929) were used to investigate the inhibitory activity of GNF-on necrotic apoptosis in different cell lines induced by TNF- α. In which U937 cells were stimulated with TNF-. alpha.Smac mimetic and z-VAD-fmk (TSZ) for 6 hours and L929 cell line with TNF-. alpha.and z-VAD-fmk (TZ) for 4 hours. The results are shown in FIG. 3, where KW-2449 concentration-dependently inhibited the development of necrotic apoptosis in both cell lines.
Example 4
KW-2449 inhibits necrotic apoptosis by inhibiting phosphorylation of RIPK1 and RIPK 3:
HT-29 cells are treated for 30min by KW-2449(1 mu M), and the expression of RIPK1, RIPK3, MLKL and phosphorylated proteins thereof is examined by stimulating different time points with TSZ, as shown in figure 4A, KW-2449 can obviously inhibit the phosphorylation of RIPK1, RIPK3 and MLKL, but has no influence on the expression amount of RIPK1, RIPK3 and MLKL proteins. Further, using the method of co-Immunoprecipitation (IP), we investigated whether KW-2449 could inhibit the interaction of RIPK1 and RIPK3 after TSZ necrosis activation, and the results showed that KW-2449 could directly inhibit the interaction of intracellular RIPK1 and RIPK3 after 4h of TSZ treatment (fig. 4A and B).
Example 5
Target validation of necrotic apoptosis inhibitor KW-2449:
drug affinity response target stability assays (DARTS) were used to detect potential interactions between KW-2449 and RIPK1/3 kinase, relying on a decrease in protease sensitivity of the target protein to drug binding. As shown in FIG. 5, both RIPK1 and RIPK3 proteins were protected by digestion with 0.01% protease, whereas no protection of MLKL was detected in the same samples in extracts of KW-2449 cells, suggesting that KW-2449 may interact with RIPK1 and RIPK 3.
Example 6
KW-2449 inhibits kinase activity of RIPK1 and RIPK 3:
further in vitro by ligand kinase binding assay (KinomeScan, Ambit Co., Ltd.)TM) The inhibition effect of KW-2449 on the binding capacity of RIPK1 and RIPK3 kinase and substrate is tested. KW-2449 inhibits the kinase activity of RIPK1 and RIPK3, and the Kd value of the inhibition effect is 157 nm.
Example 7
The necrotic apoptosis inhibitor KW-2449 protected mice in vivo against TNF-induced systemic immune syndrome (SIRS):
to test whether KW-2449 could protect against RIP kinase-driven inflammation in vivo, its activity was first tested in a TNF-. alpha.induced SIRS model. Mice were given KW-2449(10mg/kg) by gavage 3 hours prior to model establishment, and then induced to develop SIRS by intravenous mTNF- α (400 μ g/kg) plus intraperitoneal injection of z-VAD-fmk (200 μ g). KW-2449 significantly protected mice from death (FIG. 6A). Furthermore, when these mice were examined at 6 hours, the concentration levels of IL-6 in serum were significantly reduced by KW-2449 treatment (fig. 6B). Thus, these results indicate that KW-2449 protects mice in vivo from TNF-. alpha.induced SIRS.
Example 8
Necrotic apoptosis inhibitor KW-2449 protects against acetaminophen (APAP) -induced liver damage in vivo
Previous studies have shown that RIPK1 is essential for APAP to induce hepatotoxicity, and therefore the effect of KW-2449 on tissue injury and inflammation in this model was further investigated. Liver injury in mice was induced by injection of acetaminophen (APAP,300mg/kg) into the mice. As shown in FIG. 7, the liver cells of the mice were significantly necrotic and their serum levels of aspartate Aminotransferase (AST) were elevated. The inventors determined that intragastric administration of KW-2449(10mg/kg) to mice significantly reduced hepatic necrosis (fig. 7B) and plasma AST levels (fig. 7C) in the mice. Overall, the results of this example demonstrate that KW-2449 is able to protect against acetaminophen (APAP) -induced liver injury and in vivo inflammation.
Example 9
Necrotic apoptosis inhibitor KW-2449 protects acute kidney injury induced by cissplatin in vivo:
it has been reported in the literature that necrotic apoptosis is also involved in acute kidney injury induced by Cisplatin (cissplatin), a tumor chemotherapeutic drug. This example further examined the protective effect of the necrotic apoptosis inhibitor KW-2449 on cisplatin-induced acute kidney injury.
The mice were first gavaged with KW-2449(10mg/kg), then intraperitoneally injected with 25mg/kg cisplatin, and 48 hours later, the mice were removed of kidney tissue and serum to examine their degree of loss. Wherein KW-2449 is administered once every 24 hours. As shown in FIGS. 8A and B, cisplatin induced significant pathological necrosis of the kidney, whereas administration of KW-2449 significantly inhibited the renal necrosis induced. At the same time, KW-2449 significantly inhibited the increase in serum Creatinine (Creatinine) and urea nitrogen (BUN) in mice due to cisplatin stimulation (FIGS. 8C and D). Therefore, the necrotic apoptosis inhibitor KW-2449 can protect acute kidney injury induced by Cisplatin in vivo.
Example 10
The necrotic apoptosis inhibitor KW-2449 can inhibit lung metastasis of breast cancer tumor of mice:
it has been reported in the literature that necrotic apoptosis promotes lung metastasis of breast cancer tumors in mice. The embodiment of the invention further detects the inhibition effect of the necrotic apoptosis inhibitor KW-2449 on the lung metastasis of the breast cancer tumor of the mouse. We injected MVT-1 breast cancer cells into the mammary gland of FVB/N mice and examined the level of lung metastasis of breast cancer 4 weeks later. Wherein KW-2449(10mg/kg) was gavaged to mice 2 weeks after breast cancer cell injection, once every 2 days. And detecting the lung metastasis level of the breast cancer of the mouse at 4 weeks. As shown in fig. 9A and B, KW-2449 significantly inhibited lung metastasis of breast cancer in mice. Therefore, the necrotic apoptosis inhibitor KW-2449 can inhibit lung metastasis of breast cancer tumor of mice.
The experimental results show that the compound KW-2449 has excellent anti-cell necrosis activity, can be used as an RIPK1 or RIPK3 inhibitor, can resist TNF-induced systemic immune syndrome (SIRS) and acetaminophen (APAP) induced hepatotoxicity, and is used for preparing medicaments for resisting inflammation or infection related diseases such as tumors, Alzheimer diseases, ischemic cardiomyopathy, ischemic stroke, atherosclerosis, acute pancreatitis, children inflammatory bowel disease, sepsis, salmonella infection, Listeria infection and vaccinia virus infection.
Therefore, the compound and the salt thereof can be used for preparing the anti-necrotic apoptosis inhibitor.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting TNF- α induced systemic inflammatory syndrome;
2. the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting acetaminophen-induced liver damage;
3. the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting cisplatin-induced acute kidney injury;
4. the application of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof in preparing the medicine for inhibiting the lung metastasis of breast cancer tumor;
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Non-Patent Citations (3)
| Title |
|---|
| Inhibitors Targeting RIPK1/RIPK3: Old and New Drugs;Sofie Martens等;《Trends in Pharmacological Sciences》;20200205;第41卷(第3期);第209-224页 * |
| Multi-kinase inhibitors, AURKs and cancer;Jonas Cicenas等;《Med Oncol》;20160401;第33卷(第43期);第1-11页 * |
| 抗细胞坏死小分子化合物的筛选及抗坏死活性的分子机理研究;刘磊;《万方数据知识服务平台》;20171129;第1-102页 * |
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