GB2579149A - Pharmaceutical composition for preventing or treating cancer containing receptor tyrosine kinase inhibitor as active ingredient - Google Patents

Pharmaceutical composition for preventing or treating cancer containing receptor tyrosine kinase inhibitor as active ingredient Download PDF

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GB2579149A
GB2579149A GB2001368.6A GB202001368A GB2579149A GB 2579149 A GB2579149 A GB 2579149A GB 202001368 A GB202001368 A GB 202001368A GB 2579149 A GB2579149 A GB 2579149A
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compound
cancer
chemical formula
cell
active ingredient
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GB202001368D0 (en
GB2579149B (en
Inventor
Yeon Ann Ji
Young Song Jie
Choi Hyun-Kyoung
Ni Ryu Hwa
Gu Hwang Sang
Nam Ky-Youb
Jung In-Sung
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Korea Inst Radiological & Medical Sciences
Korea Institute of Radiological and Medical Sciences
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Korea Inst Radiological & Medical Sciences
Korea Institute of Radiological and Medical Sciences
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The present invention relates to a receptor tyrosine kinase activity inhibiting compound represented by Chemical Formula 1 and Chemical Formula 2, wherein the compound represented by Chemical Formula 1 and Chemical Formula 2 has been confirmed to inhibit the growth of cancer cells through inhibiting kinase activity and has been confirmed to enhance cancer cell apoptosis when used in combination with existing anticancer drugs or radiation therapy. Accordingly, the compound represented by Chemical Formula 1 and Chemical Formula 2 can be provided as a pharmaceutical composition for preventing or treating cancer, or as a composition for increasing the anti-cancer treatment effect of anti-cancer treatments and radiation therapy.

Description

[DESCRIPTION]
[Invention Title]
PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING CANCER CONTAINING RECEPTOR TYROSINE KINASE INHIBITOR AS ACTIVE INGREDIENT
[Technical Field]
The present invention relates to a pharmaceutical composition for preventing or treating cancer, a composition for enhancing anticancer effect or a health food for preventing or improving cancer, comprising a receptor tyrosine kinase activity inhibiting compound as an active ingredient.
[Background Art]
Receptor tyrosine kinases (RTKs) are transmembrane proteins that penetrate the cell membrane and are one of the most important receptor groups responsible for the cellular signaling system that regulates cell proliferation, cell migration, cell cycle and cell differentiation, and human RTKs are classified into about 20. Among them, the platelet-derived growth factor receptor (PDGFR) may be activated by ligand platelet-derived growth factor (PDGF), mitogen-activated protein kinases (MAPK), phosphatidyl inositol 3-kinase (P13K) and STAT3 (signal transducer and activator of transcription 3) can activate the downstream signaling pathways. Activation of PDGFR, including mutations, is observed in gastrointestinal stromal tumors (GIST), glioblastoma multiforme, and chronic myelogenous leukemia. Internal tandem duplication (IDT) mutations in the juxtamembrane domain of the FLT3 (FMS-like tyrosine kinase 3) gene in approximately 30% of patients with acute myeloid leukemia (AML) are found in about 3% of patients with acute lymphoblastic leukemia (ALL), and as patients with this mutation are known to have a poor prognosis, FLT3 inhibition may help treat acute myeloid leukemia and acute lymphocytic leukemia A c-Kit can be activated by the ligand stem cell factor (SCF) and point mutants such as D816V or V560G can be constantly activated without ligand to have their resistance against the cell proliferation, the cell survival and the apoptosis. In particular, c-Kit activates mast cells to induce mastocytosis and increases the expression in various organs (skin, liver, gastrointestinal tract, genitals, etc.) to induce autoimmune diseases, leukemia, gastrointestinal stromal tumor (GIST), small cell lung cancer, testicular cancer, polymorphic glioblastoma and the like. About 70-80% of GISTs patients have a gain-of-function mutation of c-Kit. It has been reported that the increase of SCE by nicotine activates c-Kit of non-small cell lung cancer, thereby enabling rapid growth and metastasis of non-small cell lung cancer.
A cyclin-dependent kinase (CDK) is a serine/threonine protein kinase which is very important in the cell cycle. The complex consists of catalytic small molecule cyclin-dependent kinase (CDK) and a regulatory small molecule cyclin, and each CDK is activated by forming the complex with a specific cyclin. The progression of each cell cycle can be regulated by specific CDK/cyclin complex, in particular CDK1/cyclin B1, CDK2/cycle E and CDK2/cyclin A are important factors for cell cycle progression.
In clinical trials, many RTK inhibitors showed an initial clinical response, which was identified as transient reactions and problems of the rapid resistance. In addition, RTK inhibitors can cause D816V mutations in KIT, D842V mutations in PDGFR, and D835V mutations in FLT3, and these mutations can hinder the binding of the RTK inhibitors to targets.
Accordingly, because RTK activation and rapid cell cycle progression in various cancer species are involved in abnormal cell regulation, there is a need for the development of inhibitors targeting CDK1/cyclin B, CD1C/cyclin A, and CDK5/p35 complex kinase activity together with the RTK activity.
[Disclosure]
[Technical Problem] The object of the present invention is to provide a composition comprising a compound capable of effectively inhibiting the activity of receptor tyrosine kinase (RTK) as an active ingredient in various cancer species as an anticancer agent, and a composition for enhancing the anticancer therapeutic effect in combination with other anticancer agents or radiation to improve the therapeutic effect.
[Technical Solution] The present invention can provide a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] in Chemical Formula 1, X may be any one selected from nitrogen and carbon.
The present invention provides a pharmaceutical composition for preventing or treating cancer comprising a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical Formula 1] In Chemical Formula 1, X may be any one selected from nitrogen and carbon.
to The present invention provides a composition for enhancing anticancer effect comprising a compound represented by the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
In addition, the present invention provides a health food for preventing or improving cancer comprising a compound represented by the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
[Advantageous Effects] According to the present invention, it was confirmed that the compound represented by the above Chemical Formula 1 inhibits the growth of the cancer cells by the inhibition of kinase activity and the combined treatment with conventional anticancer agents or radiation therapy improves the apoptosis effect of cancer cells and thus the compound represented by the above Chemical -----.../Th \ \ _ -80aet Formula 1 may be provided as a pharmaceutical composition for preventing or treating cancer or as a composition for enhancing the anticancer therapeutic effect of anticancer and radiation therapy.
[Description of Drawings]
FIG. 1 shows a result confirming that when human leukemia MV4-11 cell line was treated with 10 pM Compound 11 (Chemical Formula 1) and Compound 12 (Chemical Formula 2), the phosphorylation of STAT5 (Signal Transducer and Activator of Transcription 5) which is a sub-signaling system matrix protein of FLT3, was inhibited.
FIG. 2 is a result confirming that when human leukemia MV4-11 cell line was treated with 10pM Compound 11 (Chemical Formula 1) and Compound 12 (Chemical Formula 2), the cell death due to apoptosis occurs.
FIG. 3 is a result confirming that when human leukemia MV4-11 cell line was treated with 2pM Compound 11 (Chemical Formula 1) and Compound 12 (Chemical Formula 2) in combination with 5pM anticancer drug cisplatin, the cell proliferation was inhibited.
FIG. 4 is a result confirming that when human leukemia MV4-11 cell line was treated with 10pM Compound 11 (Chemical Formula 1) and Compound 12 (Chemical Formula 2) in combination with the radiation at 1Gy, the cell death was 20 increased [Best Mode] The present invention provides a compound represented by a following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] in Chemical Formula 1, X may be any one selected from nitrogen and carbon.
The present invention can provide a pharmaceutical composition for preventing or treating cancer comprising a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical Formula 1] in Chemical Formula 1, X may be any one selected from nitrogen and carbon.
More specifically, the compound represented by Chemical Formula 1 may inhibit receptor tyrosine kinase activity.
The cancer may be selected from the group consisting of lung cancer, tz) leukemia, breast cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, 402Et kidney cancer, blood cancer and rectal cancer, and the leukemia may be selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia.
According to one embodiment of the present invention, Compound 11 and Compound 12, which are compounds represented by Chemical Formula 1, exhibited the effect of inhibiting the kinase activities of 23 kinds as shown in Table 2, in particular, despite the concentration of 0.1 pM, cKit (V560G), FLT1, FLT3, FLT3 (D835Y), FLT3 (ITD), FLT4 kinases were confirmed to show a very superior inhibitory effect.
In addition, as a result of confirming the anticancer effect of Compound 11 and Compound 12 in various cancer disease cells, as shown in Table 4, both Compound 11 and Compound 12 showed excellent proliferation inhibitory effect in lung cancer, breast cancer, colon cancer and leukemia cells, since the cell viability of normal cells of CCD18-Co was not inhibited at the same concentration, selective cancer cell proliferation inhibitory effect was confirmed.
In one embodiment of the present invention, the pharmaceutical composition for preventing or treating cancer comprising the compound represented by Chemical Formula 1 or a pharmaceutically usable salt thereof as an active ingredient may be used as any one formulation selected from the group consisting of injections, granules, powders, tablets, pills, capsules, suppositories, gels, suspensions, emulsions, drops or solutions according to the conventional method.
Another embodiment of the invention may further comprise at least one additive selected from the group consisting of carriers, excipients, disintegrants, sweeteners, coating agents, swelling agents, slip modifiers, flavors, antioxidants, buffers, bacteristats, diluents, dispersants, surfactants, binders and lubricants, which are conventionally used for the preparation of the pharmaceutical composition.
Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Solid to formulations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid formulations may contain at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin and the like in addition to the composition. Furthermore, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the to liquid formulations for oral administration include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used as simple diluents. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories and the like. Examples of the non-aqueous solution and the suspension include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurinum, glycerogelatin and the like can be used.
According to one embodiment of the invention, the pharmaceutical composition may be administered intravenously, intraarterially, intraperitoneally, intramuscularly, intraarterially, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, orally, intraocularlly or intradermally to the subject in the conventional manner.
The preferred dosage of the compound represented by Chemical Formula 1 may vary depending on the condition and weight of the subject, the type and extent of the disease, the drug form, the route of administration, and the duration, and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dosage may be, but is not limited to, 0.01 to 200 mg/kg, specifically 0.1 to 200 mg/kg, more specifically 0.1 to 100 mg/kg. Administration may be administered once a day or divided into several times, and the scope of the invention is not limited thereto.
In the present invention, the 'subject' may be a mammal including a human, but it is not limited thereto.
The present invention can provide a composition for enhancing anticancer effect comprising a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
[Chemical Formula 1] In Chemical Formula 1, X may be any one selected from nitrogen and carbon.
The composition for enhancing anticancer effect may be treated in combination with an anticancer agent or radiation.
The anticancer agent may be any one or more selected from the group consisting of cisplatin, 5-fluorouracil, paclitaxel, doxorubicin, daunorubicin, vinblastine, vincristine, actinomycin D, teniposide, etoposide, cyclophosphamide, epirubicin, adriamycin, daunomycin and mitomycin-C.
The composition may include 1 to 99 parts by weight of the anticancer agent and 1 to 99 parts by weight of the compound represented by Chemical Formula 1 based on 100 parts by weight of the total composition.
The composition may enhance the anticancer effect against any one cancer selected from the group consisting of lung cancer, leukemia, breast cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, blood cancer and rectal cancer.
The leukemia may be selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and chronic 402Et lymphocytic leukemia.
According to another embodiment of the present invention, MV4-11 leukemia cells were co-treated with 2 pM of Compound 11 and 12 and 5 pM of cisplatin (5 pM), a known anticancer agent for 48 hours, and subjected to MTT assay for the analysis of the cell viability and as shown in FIG. 3, the cell proliferation inhibitory effect of the experimental group in which cisplatin and Compound 11 were co-administered was 40% or more higher than that of the control group treated with cisplatin as an anticancer agent alone, and the experimental group in which cisplatin and Compound 12 were administered in lo combination was confirmed to increase at least 60%.
In addition, the cultured human blood cancer cell MV4-11 cell line was treated with 10 pM Compound 11 and Compound 12 and irradiation at 1Gy of radiation and then cultured for 48 hours and analyzed by using FACSort flow cytometer (Becton dickinson, USA) for apoptosis-induced cells and the cell death by the apoptosis in the MV4-11 human blood cancer cell line was induced at least 2.1-fold and 1.8-fold, respectively, as compared with the radiation alone group as shown in FIG. 4.
From the above results, it was confirmed that Compound 11 and Compound 12 of the present invention can be treated in combination with the conventional anticancer treatment or radiation therapy to increase anticancer effect.
In addition, the present invention can provide a health food for preventing or improving cancer comprising a compound represented by the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
[Chemical Formula 1]
N r \\ so:Et
-\ 0 N I-1 \ J1 x --
In Chemical Formula 1, X may be any one selected from nitrogen and carbon.
The cancer may be any one selected from the group consisting of lung cancer, leukemia, breast cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, breast cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer and rectal cancer.
The leukemia may be selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia.
The health food may be used with other foods or food additives in addition to the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and may be appropriately used according to the conventional method. The mixed amount of the active ingredient may be appropriately determined depending on the purpose of use thereof, for example, prophylactic, health or therapeutic treatment.
The effective dose of the compound contained in the health food 20 composition may be used in accordance with the effective dose of the therapeutic agent, but in the case of prolonged intake for the purpose of health and hygiene or health control, it may be less than the above range and since the active ingredient has no problem in terms of safety, it is evident that the active ingredient may be used in an amount above the above range.
There is no particular limitation on the kind of the health food, for example, meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic drinks, vitamin complexes, etc. Hereinafter, the present invention will be described in detail with reference to the following examples. The examples are only for describing the present invention in more detail and it is obvious to those skilled in the art that that the scope of the present invention is not limited by these examples embodiments in accordance with the gist of the present invention.
<Reference Example> Materials and instruments The melting point of the synthesized compound was determined using a Kruess M5000 Melting Point apparatus, and the value was not corrected. Proton NMR spectra were recorded on Avance-300 (Bruker) at 300 MHz. Chemical shifts were recorded in ppm and Me4Si was used as the reference standard.
Mass spectra were recorded in JEOL, JMS-600W VG Trio-2 GC-MS.
The reaction product was purified by clean column chromatography using silica gel 60 (230-400 mesh, Merck) and was subjected to trace observation by thin layer chromatography using pre-coated silica gel 60 F254 (E. Merch, Mumbai, India). Spots were stained using phosphomolybdic acid (PMA) or Hanesian's solution and visualized under UV light (254 nm).
<Example 1> Compound synthesis Compounds shown in Table 1 were synthesized in the same manner as in Reaction Scheme 1 below.
[Reaction Scheme 1] P.1.-Dv(w r Iryt.rkr-rrtkk 2a4 At, Hekk HR2.
Ii tr-WH ar.
R 31t4 C fr c Sr -B.2 L'H'RR.R'R/RRR-0 H000H,,Arrr H r; RS0HtE a ar, R2. keE;
EWt * as,HH H: H xt, R H NICL," 4411441 fat:NrcHkrkkkr 3.6144 1. Azide synthesis 4'-Bromophenacyl bromide (1.0 eq) or 2-bromo-4'-fluoroacetophenone was dissolved in 0.2 M acetone and sodium azide (3.0 eq) was added. After reacting for 16 hours at room temperature with stirring, the mixture was filtered and concentrated under vacuum to obtain an azide compound (la-b) (93% yield).
2. Isothiocyanate synthesis Aniline, p-anisidine, 2,5-dimethoxyaniline, 1-naphthylamine or 3-amino-4-methoxyphenyl ethyl sulfone of 1.0 eq, as an amine solution was dissolved in dichloromethane (DCM), respectively and treated with thiophosgene of 1.2 eq and stirred for 4 hours. After the reaction was completed, the mixture was diluted with saturated K2CO3 solution and extracted with DCM in each time.
The combined organic layers were dried under anhydrous MgSO4, filtered and concentrated under vacuum to obtain isothiocyanate compound (2a-l).
3. lsooxazole synthesis Triphenylphosphine (PPhs; 1.0 eq) was added into a solution in which 1.0 eq of azide compound (1 a-b) synthesized by the above method and isothiocyanate compound (2a-l; 1.0 eq) dissolved in 0.2 M dioxane were mixed and stirred.
The mixture was stirred for 4 hours while heating to 90 °C and after the reaction was completed, the temperature was cooled to room temperature and the solvent was removed under pressure.
After removal of solvent, the residue was purified by clean column chromatography on silica gel using ethyl acetate (Et0Ac)/hexane (1:10) as mobile phase to obtain as eluent (3a-j, 32% yield).
4. Cross coupling Pd(dppf)C12 (0.5 mol%) was added into a solution in which the synthesized 3e compound, 3-pyridinylboronic acid (1.5 eq) or phenylboronic acid (1.5 eq) and K2COs dissolved in 0.2M DMF were mixed, the mixed solution was stirred at 90 °C for 10 hours and then extracted with ethyl acetate and water at each time.
The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under vacuum. The residue was purified by clean column chromatography on silica gel using Et0Ac/hexane (1:5) as mobile phase to obtain the following Compounds 11(3k) and Compound 12 (31) as eluents (3k and 31, 35% yield, respectively).
[Compound 11] El la N-(5-(ethylsulfonyI)-2-methoxypheny1)-5-(4-(pyridin-3-yl)phenyl) oxazol-2-amine (Compound (3k)) White solid, mp = 183-185 °C, 1H NMR (300 MHz, DMSO-c16)5 10.52 (s, 1H), 9.86 (br s, 1H), 8.68-9.02 (m, 1H), 7.41-7.88 (m, 9H), 7.08-7.38 (m, 1H), 3.83-4.20 (m, 3H), 3.24 (br d, J=7.70 Hz, 2H), 1.15 (br t, J=7.34 Hz, 3H); MS (FAB) m/z 436 (MN) [Compound 12] 5-(bipheny1-4-y1)-N-(5-(ethylsulfony1)-2-methoxyphenyl)oxazol-2-amine (Compound (31)) Yellow solid, mp = 203.0-203.2 °C, 1H NMR (300 MHz, DMSO-c16)5 10.52 (s, 1H), 9.81 (s, 1H), 8.70-8.84 (m, 1H), 7.18-7.85 (m, 11H), 3.90-4.06 (m, 3H), 3.14-3.28 (m, 2H), 1.05-1.18 (m, 3H); MS (FAB) m/z 435 (MH+).
<Example 2> Confirmation of kinase activity inhibitory effect The RTK kinase activity inhibitory effect of Compound 11 and Compound 12 synthesized as in Example 1 was confirmed.
The kinase profiling services of Eurofins (England) and Reaction Biology (USA) were used to measure the inhibition effects of various kinase activities of Compounds 11 and Compound 12 at concentrations of 0.1 pM and shown in Table 2 below.
[Table 2]
Kinase Compound 11(0.1 pM) Compound 12 activity % (0.1 pM) activity % Abl 68 72 ARK5 73 71 CDK1/cyclinB 78 77 CDK5/p35 75 72 cKit(h) 74 78 cKit(D816H)(h) 64 88 cKit(V560G)(h) 41 57 Flt1(h) 18 28 F1t3(D835Y)(h) 6 11 F1t3(1TD)(h) 8 15 F1t3(h) 8 20 F1t4(h) 2 1 PDGFRa(h) 78 77 PDGFRp(h) 79 84 As shown in the Table 2, Compound 11 and Compound 12 showed the effect of inhibiting kinase activity of 23 kinds, in particular, despite the concentration of 0.1 pM cKit (V560G), FLT1, FLT3, FLT3 (D835Y), FLT3 (ITD), FLT4 kinases showed a very excellent inhibitory effect.
In addition, with respect to the kinase exhibited a significant inhibitory effect, the half maximal inhibitory concentration (IC5o) of the Compound 11 and Compound 12 was confirmed, as shown in Table 3.
[Table 3]
IC50 Compound 11 (pM) Compound 12 (pM) FLT3 0.025 0.008 FLT3(D835Y) 0.009 0.007 FLT3(ITD) 0.004 0.016 As shown in the above Table 3, Compound 11 and Compound 12 showed an excellent inhibitory effect of 50% inhibitory concentration as nM level for FLT3 and D835Y in FLT3 genes, ITD mutant FLT3 kinase.
<Example 3> Confirmation of effects on various human cancer cell lines With respect to the cell proliferation rate of various cancer cell lines, the cancer cell proliferation inhibitory effect of Compound 11 and Compound 12 synthesized in Example 1 was confirmed.
First, human lung cancer cell line H1299, human breast cancer cell line 20 MDA-MB231, human colon cancer cell line HCT116, human acute leukemia cell line MV4-11, human normal colon cell line CCD18-Co purchased from the American Type Culture Collection (ATCC) were incubated in DMEM (Dulbecco's modified Eagle's medium, WELGENE), RPM! (WELGENE) or MEM (MV4-11; WELGENE) medium containing 10% fetal bovine serum (FBS, WELGENE, Korea), 100 pg/ml streptomycin and 100 unit/mIpenicillin (GIBCO, UK) under 5% CO2 and 37 °C, respectively, and used for the experiment.
1. Confirmation of STAT5 phosphorylation inhibitory effect After treatment with Compound 11 and Compound 12 in cultured MV4-11 leukemia cells, it was confirmed by Western blot whether the phosphorylation of STAT5, a sub-signaling system of FLT3, was inhibited.
After treatment with Compound 11 or Compound 12 at 0.1, 1, 2, 5 or 10 pM concentrations for 1 hour, cells were obtained and cell lysates were obtained by methods commonly used in the art. The cell lysates were separated by electrophoresis using 9% gradient SDS-PAGE and transferred to nitrocellulose membranes (BioRad, Hercules, CA, USA). The membrane was blocked with 5% skim milk, followed by reacting anti-phospho-STAT5 antibody (Santa Cruz Biotechnology, USA) as the primary antibody and anti-13-actin (Santa Cruz Biotechnology) as a control for 1 hour. Thereafter, horseradish peroxidase conjugated anti-mouse IgG antibody (Santa Cruz Biotechnology) was incubated and visualized using an ECL system (GE, USA).
As a result, as shown in FIG. 1, it was confirmed that phosphorylation of STAT5, which is a substrate protein of FLT3 kinase, was suppressed from 1 hour in MV4-11 leukemia cells treated with Compound 11 or Compound 12.
2. Confirmation of survival inhibition effect of cancer cell line Various cell lines cultured by the above method were incubated for 24 hours after dispensing in 96-well plates with the number of 3 x 103, respectively, and then treated with Compounds 11 and Compound 12 synthesized as in Example 1 at 10 pM concentrations, respectively, and incubated for 48 hours. Then 0.5 mg/m L MTT (3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide solution was added to each well and further incubated for 3 hours at 37°C. After incubation, the supernatant was removed, and the formed formazan crystals were dissolved in DMSO and measured at 590 nm using a spectrometer (Labsystems, USA) and the control group was treated with DMSO.
The results were shown in Table 4 below as relative proliferation in respect of 100% survival rate.
[Table 4]
Experimental group DMSO (Control) Compound 11 Compound 12 MV4-11 100 ± 10.78 15.15 ± 0.26 14.69 ± 0.82 Blood cancer cells DLD-1 100 ± 2.31 45.15 ± 0.26 44.69 ± 0.82 Colon cancer cells H460 100 ± 5.25 76.40 ± 2.21 58.61 ± 3.42 Lung cancer cells MDA-M B231 100 ± 4.70 72.53 ± 3.84 45.91 ± 4.22 Breast cancer cells CCD18-Co 100 ± 1.25 98.20 ± 4.85 95.52 ± 1.22 Colon normal cells As shown in the Table 4, Compound 11 and Compound 12 according to is the present invention showed an excellent proliferation inhibitory effect in lung cancer, breast cancer, colon cancer and leukemia cells, and because cell survival rate of CCD18-Co normal cells was not inhibited at the same concentration, it was confirmed that the selective cancer cell proliferation inhibitory effect occurred.
In addition, acute leukemia cells MV4-11 were treated with the compounds synthesized in Example 1, i.e. Derivative 2 to Derivative 12 synthesized in Example 1 and the inhibitory effect on the cell survival was confirmed.
Cells were dispensed in 96-well plates with the number of 3 x 103, incubated for 24 hours, and then treated with 10 pM Compound 2 to Compound 12 synthesized in Example 1, respectively, and incubated for 48 hours. Then 0.5 mg/mL of MIT solution was added to each well and further incubated at 37 °C.
for 3 hours. After incubation, the supernatant was removed and the formed formazan crystals were dissolved in DMSO and measured at 590 nm using a spectrometer.
The control group was treated with DMSO, and the cell viability was expressed as a relative value for 100% survival rate as shown in Table 5 below.
[Table 5]
Experimental group Cell viability (%) DMSO 100 ± 4.34 Compound 2 32.43 ± 1.77 Compound 3 59.25 ± 2.09 Compound 4 44.16 ± 1.49 Compound 5 29.30 ± 1.34 Compound 6 30.89 ± 1.00 Compound 7 34.30 ± 0.80 Compound 8 34.58 ± 1.19 Compound 9 65.75 ± 2.11 Compound 10 79.53 ±4.04 Compound 11 29.39 ± 0.53 Compound 12 34.11 ± 1.19 On the other hand, caspase-3 involved in cell death and the cleavage of PARP (poly-ADP ribose polymerase) involved in DNA repair was confirmed by Western blotting. At this time, the protein and cleaved PARP protein were detected with caspase-3 antibody (Cell signaling technology, Inc. USA) and PARP-1 antibody (PARP-1, Cell signaling technology, Inc. USA).
As a result, as shown in FIG. 2, the caspase-3 expression and the cleavage of PARP (poly-ADP ribose polymerase), which are genes related to the cell death due to apoptosis were confirmed to be increased in MV4-11 leukemia cells treated with Compound 11 and Compound 12.
<Example 4> Confirmation of anticancer effect by combined treatment 1. Confirmation of anticancer effect by combination treatment with anticancer agent As in Example 3, the cultured MV4-11 leukemia cells were co-treated with 15 2 pM of Compound 11 or Compound 12 and 5 pM of cisplatin (5 pM), a known anticancer agent for 48 hours, and subjected to MTT assay for the analysis of the cell viability.
As a result, as shown in FIG. 3, the cell proliferation inhibitory effect of the experimental group in which cisplatin and Compound 1 were co-administered was 40% or more higher than that of the control group treated with cisplatin as an anticancer agent alone, and the experimental group in which cisplatin and Compound 2 were administered in combination was confirmed to increase at least 60%.
From the above results, it was confirmed that Compound 11 and Compound 12 according to the present invention can be used as an anticancer agent adjuvant that can enhance the therapeutic effect of anticancer agent.
2. Confirmation of anticancer effect by combined treatment with radiation pM of Compound 11 and Compound 12 were treated in combination of irradiation at 1Gy radiation in cultured human blood cancer cell MV4-11 cell line and cultured for 48 hours and double-stained with annexin V and propidium iodide (P1) and analyzed using a FACSort flow cytometer (Becton dickinson, USA) to determine total apoptosis by summing early and late apoptotic cells.
As a result, it was confirmed that the cell death by the apoptosis in the MV4-1 1 human blood cancer cell line was induced at least 2.1-fold and 1.8-fold, respectively, as compared with the radiation alone group as shown in FIG. 4. From the above results, it was confirmed that Compound 11 and Compound 12 of the present invention can be used as a radiotherapy aid that can enhance the therapeutic effect of radiotherapy.
The following describes an example of the preparation of a composition comprising Compound 11 or Compound 12 according to the present invention, but the present invention is not intended to be limited thereto but merely to be described in detail.
<Prescription Example 1> Prescription example of pharmaceutical composition 1. Preparation of powder A powder was prepared by mixing 20 mg of compound, 100 mg of lactose and 10 mg of talc and filling into an airtight bag.
2. Preparation of tablet A tablet was prepared by mixing 20 mg of compound, 100 mg of corn starch, 100 mg of lactose and 2 mg of magnesium stearate, followed by tablet compression according to a conventional method of preparing the tablets.
3. Preparation of capsule A capsule was prepared by mixing 10 mg of compound, 100 mg of corn starch, 100 mg of lactose and 2 mg of magnesium stearate and filling into gelatin capsules according to a conventional method of preparing the capsules.
4. Preparation of Injection An injection was prepared by mixing 10 mg of compound, appropriate amount of sterile distilled water for injection and appropriate amount of a pH adjusting agent and preparing in the above-described content of ingredients per ampoule (2 ml) according to a conventional method of preparing the injections.
5. Preparation of ointment An ointment was prepared by mixing 10 mg of compound, 250 mg of PEG-4000, 650 mg of PEG-400, 10 mg of white petrolatum, 1.44 mg of paraoxybenzoic acid methyl, 0.18 mg of paraoxybenzoic acid propyl and the remaining amount of purified water according to the conventional method of preparing the ointments.
<Prescription Example 2> Health functional food 1. Preparation of health food A health food was preparing by mixing 1 mg of compound, appropriate amount of vitamin mixture (70 pg of vitamin A acetate, 1.0 mg of vitamin E, 0.13 mg of vitamin B, 0.15 mg of vitamin B2, 0.5 mg of vitamin B6, 0.2 pg of vitamin B12, 10 mg of vitamin C, 10 pg of biotin, 1.7 mg of nicotinic acid amide, 50 pg of folic acid, 0.5 mg of calcium pantothenate) and appropriate amount of mineral mixture (1.75 mg ferrous sulfate, 0.82 mg of zinc oxide, 25.3 mg of magnesium carbonate, 15 mg of potassium monophosphate, 55 mg of dicalcium phosphate, 90 mg of potassium citrate, 100 mg of calcium carbonate, 24.8 mg of magnesium chloride), and preparing granules according to a conventional method.
2. Preparation of health drinks 1 mg of compound, 1000 mg of citric acid, 100 g of oligosaccharide, 2 g of plum concentrate, 1 g of taurine, and purified water were added to make 900 ml in total and after mixing the above components according to a conventional health drinks manufacturing method, and then the mixture was stirred and heated at 85 °C for about 1 hour, the resulting solution was filtered to obtain in a sterilized 2 L container, and followed by sealed sterilization and storing in refrigerated.
While the present invention has been particularly described with reference to specific embodiments thereof, it is apparent that this specific description is only a preferred embodiment and that the scope of the present invention is not limited thereby to those skilled in the art. That is, the practical scope of the present invention is defined by the appended claims and their equivalents.
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