WO2024247648A1 - Agent thérapeutique tumoral et complexe - Google Patents

Agent thérapeutique tumoral et complexe Download PDF

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WO2024247648A1
WO2024247648A1 PCT/JP2024/017295 JP2024017295W WO2024247648A1 WO 2024247648 A1 WO2024247648 A1 WO 2024247648A1 JP 2024017295 W JP2024017295 W JP 2024017295W WO 2024247648 A1 WO2024247648 A1 WO 2024247648A1
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group
site
tumor
carbon atoms
acrolein
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Japanese (ja)
Inventor
昌幸 永橋
康雄 三好
克典 田中
浩二 盛本
アンバラ ラクマット プラディプタ
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Hyogo Medical University
RIKEN
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Hyogo Medical University
RIKEN
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a tumor treatment agent and a complex.
  • S1P Sphingosine-1-phosphate
  • Fingolimod also known as "FTY720”
  • FTY720 an S1P receptor modulator
  • FTY720 is covered by health insurance in Japan as a treatment for multiple sclerosis.
  • in vitro experimental systems have shown that FTY720 effectively suppresses cancer growth and metastasis (Non-Patent Document 8).
  • S1P receptor modulators such as FTY720 exert a strong immunosuppressive effect in the body, which causes problems with side effects on normal cells.
  • the immunosuppressive effect of S1P receptor modulators contradicts one of the methodologies of cancer treatment, which is to remove anti-tumor immunity against cancer cells.
  • Non-Patent Document 9 discloses sphingosine kinase inhibitors.
  • Patent Document 1 describes a complex that reacts with acrolein to release an active substance, and a tumor treatment agent that contains the complex.
  • Acrolein (CH 2 ⁇ CHCHO) is the smallest unsaturated aldehyde molecule and is a highly reactive molecule. It is known that acrolein is generated when organic matter is burned, and it is also thought to be generated in vivo as a metabolic product of lipids or polyamines in diseases related to oxidative stress, such as cancer, Alzheimer's disease, and cerebral infarction. It has been reported that acrolein is generated in tumor cells in greater amounts than in normal cells, and the amount is more than 1,000 times that of normal cells at the site of inflammation (Non-Patent Documents 10 to 12).
  • Patent Document 1 describes that by incorporating an existing antitumor compound into a complex to make it in a prodrug state, the antitumor activity (toxicity) of the compound can be attenuated, and that the complex can react with acrolein present around tumor cells to release the antitumor compound. In this way, the technology of Patent Document 1 makes it possible to control the antitumor activity of existing antitumor compounds that have been established as anticancer drugs so that they are exerted around tumor cells.
  • Patent Document 1 only describes complexes with existing antitumor compounds (existing anticancer drugs).
  • One aspect of the present invention aims to provide a novel drug for tumor treatment that targets the S1P signaling pathway.
  • a tumor therapeutic agent comprising a complex including an acrolein reactive site and a detachment site having a chemical structure represented by formula (1), wherein the detachment site is bound to the acrolein reactive site via a linker that is cleavable upon reaction of the acrolein reactive site with acrolein, and the detachment site includes the chemical structure of a compound having activity of inhibiting sphingosine-1-phosphate signaling in cells.
  • R1 and R2 each independently represent a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom, provided that at least one of R1 and R2 is an alkyl group having 1 to 5 carbon atoms;
  • R3 and R4 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a thiol group, an amino group which may have a substituent, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, or an alkyl group having 1 to 5 carbon atoms (wherein a hydrogen atom constituting the alkyl group may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and an amino group which may have a substituent); * indicates the binding site with the linker.
  • the present invention also includes the following aspects.
  • a therapeutic agent for multidrug-resistant tumors comprising as an active ingredient a compound having activity of inhibiting sphingosine-1-phosphate signal transduction in cells.
  • the present invention also includes the following aspects.
  • a complex having an acrolein reactive site and a release site the complex having a chemical structure represented by formula (1), the detachment site is bonded to the acrolein reactive site via a linker that is cleavable by a reaction between the acrolein reactive site and acrolein;
  • a conjugate, wherein the release moiety comprises the chemical structure of a sphingosine-1-phosphate receptor modulator.
  • R1 and R2 each independently represent a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom, provided that at least one of R1 and R2 is an alkyl group having 1 to 5 carbon atoms;
  • R3 and R4 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a thiol group, an amino group which may have a substituent, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, or an alkyl group having 1 to 5 carbon atoms (wherein a hydrogen atom constituting the alkyl group may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and an amino group which may have a substituent); * indicates the binding site with the linker.
  • a novel drug for tumor treatment that targets the S1P signaling pathway can be provided.
  • FIG. 1 shows the results of comparing the growth inhibitory effects of each drug of Comparative Examples 1 to 3 and Example 1 on a normal breast cancer line and a multidrug resistant breast cancer line.
  • FIG. 1 shows the results of comparing the growth inhibitory effects of each of the drugs of Examples 2 to 5 on normal breast cancer lines and multidrug resistant breast cancer lines.
  • FIG. 1 shows the results of comparing tumor weight, percentage of lymphocytes in blood samples, and lymphocyte count.
  • FIG. 1 shows the results of comparing the concentrations of FTY-720, phosphorylated FTY-720, and Prodrug-FTY-720 in plasma.
  • FIG. 1 shows the results of comparing the concentrations of FTY-720, phosphorylated FTY-720, and Prodrug-FTY-720 in tissues.
  • FIG. 1 shows the results of comparing the proliferation inhibitory effects of each drug of Comparative Examples 1 to 3 and Example 2 on organoids derived from breast cancer patients.
  • a tumor therapeutic agent according to one embodiment of the present invention (hereinafter also referred to as "first tumor therapeutic agent”) comprises a complex having an acrolein reactive site and a detachable site having a chemical structure represented by formula (1), wherein the detachable site is bound to the acrolein reactive site via a linker that is cleavable upon reaction of the acrolein reactive site with acrolein, and the detachable site comprises a chemical structure of a compound having activity of inhibiting sphingosine-1-phosphate signaling in cells.
  • treatment includes causing the tumor cells in tumor tissue to regress or decrease compared to before administration of the tumor therapeutic agent according to one embodiment of the present invention, eliminating (eliminating) tumor cells in tumor tissue, or preventing tumor progression in a subject (hereinafter simply referred to as "subject") to whom the tumor therapeutic agent according to one embodiment of the present invention has been administered.
  • a complex contained in a tumor treatment agent includes an acrolein reactive site having a chemical structure represented by formula (1) and a detachable site, and the detachable site is bonded to the acrolein reactive site via a linker that is cleavable upon reaction of the acrolein reactive site with acrolein.
  • this complex reacts sensitively with acrolein, cleaving the linker and releasing the detachment site. This is because the azide group ( N3 group) in the acrolein-reactive site of this complex acts as a 1,3-dipole and undergoes a 1,3-dipolar cycloaddition reaction (click reaction) with acrolein, a dipolarophile, to produce a five-membered ring (1,2,3-triazoline) intermediate.
  • the 1,2,3-triazoline produced by the click reaction (1,3-dipolar cycloaddition reaction) between the acrolein reaction site and acrolein then undergoes an isomerization reaction to form an imine, followed by decarboxylation (release of carbon dioxide) to cleave the linker between the acrolein reaction site and the release site, and the diazo compound derived from the acrolein reaction site and the active substance derived from the release site are separated.
  • the above reaction can proceed under mild conditions, such as in vivo, and shows high reaction specificity. Therefore, by administering this complex to the body, endogenous acrolein reacts with this complex, and the active substance derived from the release site can be released into the body.
  • R1 and R2 each independently represent a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom, provided that at least one of R1 and R2 is an alkyl group having 1 to 5 carbon atoms.
  • halogen atoms examples include fluorine atoms, chlorine atoms, and bromine atoms. Note that fluorine atoms may be isotopes.
  • the alkyl group having 1 to 5 carbon atoms may be either linear or branched.
  • the alkyl group may have its hydrogen atoms substituted with at least one of the above-mentioned halogen atoms, or may be unsubstituted.
  • Examples of alkyl groups having 1 to 5 carbon atoms with unsubstituted hydrogen atoms include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, and sec-pentyl groups.
  • R1 and R2 may be the same or different, but from the viewpoint of improving reactivity with acrolein, it is preferable that both R1 and R2 are alkyl groups having 1 to 5 carbon atoms, which may or may not be substituted with at least one halogen atom, and it may be more preferable that they are the same alkyl group.
  • the number of carbon atoms constituting the alkyl group may be preferably 1 to 4, and may be more preferably 2, 3, or 4.
  • one of R1 and R2 is an alkyl group having 1 to 5 carbon atoms, which may or may not be substituted with at least one halogen atom, and the other of R1 and R2 is a halogen atom (particularly fluorine or an isotope).
  • the number of carbon atoms constituting the alkyl group may be preferably 1 to 4, and more preferably 2, 3, or 4.
  • R3 and R4 are each independently a hydrogen atom, a halogen atom, a hydroxy group, a thiol group, an amino group which may have a substituent, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, or an alkyl group having 1 to 5 carbon atoms, provided that the hydrogen atom constituting the alkyl group may be substituted with a substituent selected from a halogen atom, a hydroxy group, and an amino group which may have a substituent.
  • halogen atoms are the same as those described for R1 and R2.
  • amino groups that may have a substituent include unsubstituted amino groups, alkylamino groups, and (hetero)arylamino groups.
  • the number of carbon atoms constituting each alkyl group contained in the alkylamino group is, for example, 1 to 5.
  • a (hetero)arylamino group refers to a group in which at least one hydrogen atom constituting the amino group is substituted with an aryl group (i.e., an aryl group or a heteroaryl group) that may have a heteroatom.
  • Each (hetero)aryl group contained in the (hetero)arylamino group may, for example, have a ring structure skeleton formed by 3 to 20 atoms (preferably 4 to 12 atoms).
  • heteroatoms contained in the heteroaryl group include a sulfur atom, a nitrogen atom, and an oxygen atom.
  • alkoxy groups having 1 to 5 carbon atoms examples include methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups.
  • alkylthio groups having 1 to 5 carbon atoms examples include methylthio, ethylthio, propylthio, butylthio, and pentylthio groups.
  • alkyl groups having 1 to 5 carbon atoms in which hydrogen atoms are not substituted are the same as those described for R1 and R2.
  • the number of carbon atoms constituting the alkyl group may preferably be 1 to 4, and more preferably 1 to 3.
  • at least one of the hydrogen atoms constituting the alkyl group may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and an amino group which may have a substituent.
  • examples of the halogen atom and the amino group which may have a substituent include the same ones as those described for R3 and R4.
  • R3 and R4 may be the same or different, but it may be preferable that R3 and R4 are the same.
  • R3 and R4 are each independently a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom.
  • the definition and examples of the alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom are the same as those described for R1 and R2.
  • R1, R2, R3, and R4 each independently represent a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom, provided that at least one of R1 and R2 is an alkyl group having 1 to 5 carbon atoms.
  • Example combination ⁇ 2> In formula (1), R3 and R4 each independently represent a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom, and R1 and R2 each independently represent an alkyl group having 1 to 5 carbon atoms.
  • Example combination ⁇ 4> In the above example combination ⁇ 1> or ⁇ 2>, R3 and R4 are each independently a hydrogen atom or a halogen atom, and R1 and R2 are each an alkyl group having 1 to 5 carbon atoms.
  • * is a binding site for a linker for linking the release site, as described above.
  • This linker can be cleaved by a reaction between the acrolein reaction site and acrolein. More specifically, this linker has a structure in which cleavage is promoted by a 1,3-dipolar cycloaddition reaction between the acrolein reaction site and acrolein to generate a five-membered ring.
  • Linker An example of a linker that can be cleaved by reaction of the acrolein reactive site with acrolein is a linker having a chemical structure represented by formula (2).
  • R are each independently a hydrogen atom, a halogen atom, a hydroxy group, a thiol group, an amino group which may have a substituent, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, or an alkyl group having 1 to 5 carbon atoms, provided that a hydrogen atom constituting the alkyl group may be substituted with a substituent selected from a halogen atom, a hydroxy group, and an amino group which may have a substituent.
  • halogen atoms are the same as those described for R1 and R2.
  • alkoxy groups having 1 to 5 carbon atoms examples include methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups.
  • alkylthio groups having 1 to 5 carbon atoms examples include methylthio, ethylthio, propylthio, butylthio, and pentylthio groups.
  • alkyl groups having 1 to 5 carbon atoms in which hydrogen atoms are not substituted are the same as those described for R1 and R2.
  • the number of carbon atoms constituting the alkyl group may preferably be 1 to 4, and more preferably 1 to 3.
  • at least one of the hydrogen atoms constituting the alkyl group may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and an amino group which may have a substituent.
  • substituents selected from a halogen atom, a hydroxyl group, and an amino group which may have a substituent.
  • examples of halogen atoms and amino groups which may have a substituent include the same ones as those described for R3 and R4.
  • the R's bonded to the same carbon atom may be the same or different, but it may be preferable for the R's to be the same.
  • R may preferably be, independently of one another, a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms (wherein the hydrogen atom constituting the alkyl group may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and an amino group which may have a substituent), and may more preferably be, independently of one another, a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom.
  • the definition and examples of the alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom are the same as those described for R1 and R2.
  • ** is a bonding site with the release site. From the viewpoint of rapid cleavage of the linker, ** may be preferably a bonding site with a nitrogen atom, a sulfur atom, or an oxygen atom contained in the release site (i.e., -N(-)-, -S-, or -O-), and may be more preferably a bonding site with a nitrogen atom contained in the release site.
  • a specific example of the complex having the chemical structure represented by formula (3) above is a complex of the release site and 4-azidobenzylcarbamate (hereinafter also simply referred to as "ABC") represented by formula (4) below (release site-ABC).
  • ABC 4-azidobenzylcarbamate
  • ** is a bonding site with a nitrogen atom contained in the leaving site.
  • ⁇ is a bonding site with a nitrogen atom contained in the separation site
  • the chemical structures shown in the above formulas (3) and (4) can also be regarded as a protecting group for the amino group contained in the separation site that can be deprotected by acrolein.
  • reaction mechanism of linker cleavage As an example of a conjugate according to one embodiment of the present invention, a conjugate having a linker bound to a nitrogen atom contained in the release site is given below.
  • the detachment site of this complex contains the chemical structure of a compound having activity of inhibiting sphingosine-1-phosphate signaling in cells (hereinafter also referred to as "S1P signaling inhibitor compound").
  • S1P signaling inhibitor compound a compound having activity of inhibiting sphingosine-1-phosphate signaling in cells.
  • the detachment site contains the chemical structure of the S1P signaling inhibitor compound means that at least a part of the chemical structure of the detachment site contains the chemical structure of the S1P signaling inhibitor compound.
  • sphingosine-1-phosphate is known to be involved in angiogenesis, lymphatic vessel formation, etc. by binding to the S1P receptor expressed in endothelial cells.
  • S1P sphingosine-1-phosphate
  • tumor cells sphingosine-1-phosphate (S1P) is known to be involved in tumor cell proliferation, migration, survival, etc. (Non-Patent Documents 1 to 7).
  • Non-Patent Documents 10-12 tumor cells produce more acrolein than normal cells, with the amount being more than 1,000 times that of inflammatory sites in normal cells. Therefore, this complex, which has an S1P signaling inhibitory compound as a release site, can react with acrolein present around tumor cells to release the S1P signaling inhibitory compound, and can therefore be suitably used as a tumor treatment agent.
  • any compound that has the activity of inhibiting sphingosine-1-phosphate signaling in cells can be used without limitation, including S1P signaling inhibitor compounds used in clinical or clinical trials and S1P signaling inhibitor compounds to be developed in the future.
  • the S1P signaling inhibitor compound is preferably a compound having a nitrogen atom, a sulfur atom, or an oxygen atom as a binding site with the linker so that it can be rapidly cleaved from the linker.
  • These functional groups may be functional groups that the S1P signaling inhibitor compound originally has, or may be functional groups that are added later to serve as a binding site with the linker.
  • the bond between the S1P signaling inhibitor compound and the linker is preferably one that can be rapidly cleaved by the reaction of the acrolein reactive site with acrolein. From this perspective, the bond between the release site and the linker is preferably a carbamate bond, a thiocarbamate bond, an ester bond, or a thioester bond.
  • the S1P signaling inhibitor compound is preferably a hydrophobic compound from the viewpoint of ease of uptake into tumor cells.
  • the molecular weight of the S1P signaling inhibitor compound is not particularly limited, but is preferably low enough to reach tumor cells, for example, 15,000 Da or less, preferably 10,000 Da or less, and more preferably 500 Da or less.
  • the lower limit of the molecular weight of the S1P signaling inhibitor compound is not particularly limited, but is, for example, 100 Da or more, and preferably 300 Da or more.
  • the S1P signaling inhibitor compound When the S1P signaling inhibitor compound is bound to the acrolein reactive site via a linker, its S1P signaling inhibitory activity (toxicity) is reduced compared to when it is not bound, i.e., it is preferably in a prodrug state.
  • the S1P signaling inhibitor compound exerts an immunosuppressive effect by inhibiting S1P signaling. By reducing the immunosuppressive effect on normal cells, it is possible to reduce the impact on normal tissues and alleviate side effects.
  • the type of S1P signaling inhibitor is not particularly limited.
  • sphingosine-1-phosphate receptor modulators, S1P-producing enzyme inhibitors, etc. can be suitably used.
  • the S1P signaling inhibitor is a sphingosine-1-phosphate receptor modulator.
  • S1P receptor modulators suitable for use as the release site include, but are not limited to, Fingolimod (also called “FTY720"), Siponimod, Ozanimod, and Ponesimod.
  • the S1P receptor modulator is preferably Fingolimod, Siponimod, Ozanimod, or Ponesimod.
  • S1P production enzyme inhibitors suitable for use as the release site include, but are not limited to, SK1-I ((2R, 3S, 4E)-N-methyl-5-(4'-pentylphenyl)-2-aminopent-4-ene-1,3-diol.HCl, also called "BML258").
  • the S1P production enzyme inhibitor is preferably SK1-I.
  • FTY720-ABC which has the following chemical structure:
  • siponimod-ABC which has the following chemical structure:
  • Siponimod-ABC is an analogue in which 2-ethanolamine is added as an additional linker to the carboxyl group of siponimod, taking into consideration stability when retained in the blood. In this way, a linker may be added to an S1P signaling inhibitor compound as the release site.
  • siponimod active substance
  • Siponimod-ABC does not become “siponimod” directly through fragmentation after reacting with acrolein, but first becomes “siponimod-2-ethanolamide", which is then rapidly converted by amidase in the blood into the active form, siponimod.
  • ozanimod-ABC which has the following chemical structure:
  • ponesimod-ABC which has the following chemical structure:
  • the complex can be produced by any method for synthesizing a carbamate bond. Such methods include reacting an isocyanate with an alcohol, and reacting an amine with a carbonate ester.
  • an isocyanate for example, an amino group of a compound used as a leaving site is reacted with triphosgene in the presence of a suitable solvent to obtain an isocyanate, and then the obtained isocyanate is reacted with an alcohol represented by formula (5) to produce the present complex having a carbamate bond.
  • an alcohol shown in formula (5) is reacted with a chloroformate ester in the presence of a suitable solvent to obtain a carbonate ester, and then the obtained carbonate ester is reacted with the amino group of a compound used as a release site to produce the present complex forming a carbamate bond.
  • Non-Patent Document 5 the method of producing FTY720-ABC, whose chemical structural formula is shown above, is as shown in the Examples.
  • ozanimod has a secondary amine
  • ozanimod-ABC whose chemical structural formula is shown above
  • ponesimod has a hydroxy group
  • ponesimod-ABC whose chemical structural formula is shown above, can be produced by the same method as FTY720-ABC.
  • BAF312-ABC siponimod-ABC
  • BAF312-ABC whose chemical structure is shown above, is an analogue of siponimod with 2-ethanolamine as an additional linker attached to the carboxy group of siponimod.
  • siponimod-2-ethanolamide is synthesized by adding 2-ethanolamine to siponimod (BAF312), and then (4-azido-3,5-diisopropylphenyl)-methanol is added to the siponimod-2-ethanolamide to obtain BAF312-ABC.
  • the first tumor therapeutic agent may contain, in addition to the present complex, a pharma- ceutically acceptable carrier, such as water, an electrolyte solution, or a sugar solution, within a range that does not inhibit the activity of the present complex.
  • a pharma- ceutically acceptable carrier such as water, an electrolyte solution, or a sugar solution
  • the first tumor therapeutic agent may contain an auxiliary agent.
  • auxiliary agents include a buffering agent, a soothing agent, a stabilizer, a preservative, an antioxidant, a coloring agent, etc.
  • buffering agent examples include buffer solutions of phosphate, acetate, carbonate, citrate, and the like.
  • soothing agent examples include propylene glycol, lidocaine hydrochloride, benzyl alcohol, benzalkonium chloride, and procaine hydrochloride.
  • Stabilizers include human serum albumin, polyethylene glycol, and the like.
  • Preservatives include benzyl alcohol, phenol, and the like.
  • Antioxidants include sulfites, ascorbates, and the like.
  • Suitable examples of the coloring agent include water-soluble colored tar dyes (e.g., food dyes such as Food Red Nos. 2 and 3, Food Yellow Nos. 4 and 5, Food Blue Nos.
  • insoluble lake dyes e.g., aluminum salts of the above-mentioned water-soluble edible tar dyes
  • natural dyes e.g., ⁇ -carotene, chlorophyll, red iron oxide
  • the first tumor therapeutic agent may contain additives such as binders, excipients, lubricants, sweeteners, flavoring agents, preservatives, disintegrants, suspending agents, solvents, solubilizers, isotonicity agents, and swelling agents.
  • additives such as binders, excipients, lubricants, sweeteners, flavoring agents, preservatives, disintegrants, suspending agents, solvents, solubilizers, isotonicity agents, and swelling agents.
  • Binders include gelatin, corn starch, tragacanth, gum arabic, pregelatinized starch, sucrose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, white sugar, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.
  • Excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, alpha-starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, gum arabic, pullulan, soft anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, xylitol, sorbitol, erythritol, etc.
  • Lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, polyethylene glycol, etc.
  • Sweetening agents include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, etc.
  • Flavouring agents include peppermint, rose oil, cherry etc.
  • Preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.
  • Disintegrants include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethylstarch, low-substituted hydroxypropylcellulose, soft anhydrous silicic acid, calcium carbonate, etc.
  • Suspending agents include, for example, surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, etc.
  • surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate
  • hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethy
  • solvents include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil, etc.
  • solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, etc.
  • isotonicity agents include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, xylitol, fructose, etc.
  • the first tumor therapeutic agent can be administered as an oral preparation, an injection, or a transdermal preparation.
  • oral preparations include tablets (including sublingual tablets and oral disintegrants), capsules (including soft capsules and microcapsules), powders, granules, lozenges, syrups, emulsions, suspensions, and the like.
  • injections include intradermal injections, subcutaneous injections, intravenous injections, intramuscular injections, intraspinal injections, epidural injections, local injections, and the like.
  • transdermal preparations include patches, ointments, dusting agents, and the like. These preparations may be controlled-release preparations such as immediate-release preparations or sustained-release preparations (e.g., sustained-release microcapsules).
  • the first tumor therapeutic agent is preferably formulated as an injection.
  • Sterile compositions for injections can be formulated according to common formulation practices, such as dissolving or suspending an active substance in a vehicle (aqueous solution for injection; naturally occurring vegetable oils such as sesame oil, coconut oil, etc.).
  • aqueous solution for injection for example, physiological saline, isotonic solutions containing glucose or other auxiliary drugs (e.g., D-sorbitol, D-mannitol, sodium chloride, etc.) are used, and may be used in combination with appropriate solubilizing agents, such as alcohol (e.g., ethanol), polyalcohol (e.g., propylene glycol, polyethylene glycol), nonionic surfactants (e.g., polysorbate 80TM, HCO-50), etc.
  • solubilizing agents such as alcohol (e.g., ethanol), polyalcohol (e.g., propylene glycol, polyethylene glycol), nonionic surfactants (e.g., polysorbate 80TM, HCO-50), etc.
  • oily solution for example, sesame oil, soybean oil, etc. are used, and may be used in combination with solubilizing agents such as benzyl benzoate, benzyl alcohol, etc.
  • the injection can be sealed in a container such as an ampule or a vial, in a unit dose or multiple doses.
  • a container such as an ampule or a vial
  • the active ingredient and a pharma- ceutical acceptable carrier can be freeze-dried and stored in a state in which it is sufficient to dissolve or suspend them in an appropriate sterile vehicle immediately before use.
  • the content of the present complex in the first tumor therapeutic agent varies depending on the form of the preparation, but is usually about 10 to 25% by mass, preferably about 15% by mass or more, and more preferably about 20% by mass or more, based on the total amount of the preparation.
  • the dosage of the first tumor therapeutic agent can be appropriately determined in consideration of the type of subject, the administration method, the type of S1P signal transduction inhibitor compound, the type and site of tumor cells, and the like.
  • the appropriate dosage for humans can be determined from the results of animal experiments.
  • the dosage is preferably 0.1 to 5 mg, more preferably 0.3 mg or more, and even more preferably 1 mg or more, in terms of the amount of FTY720 per kg of body weight.
  • the appropriate dosage for humans based on the human equivalent dosage is preferably 0.008 to 0.4 mg, more preferably 0.024 mg or more, and even more preferably 0.08 mg or more, in terms of the amount of FTY720 per kg of body weight. These effective amounts can be administered once or in several divided doses.
  • the first tumor therapeutic agent can be applied to tumors in any mammal.
  • the type of mammal can be a non-human mammal or a human.
  • non-human mammals include rodents such as mice, rats, hamsters, and guinea pigs, laboratory animals such as rabbits, livestock such as pigs, cows, goats, horses, sheep, and minks, pets such as dogs and cats, and primates other than humans such as humans, monkeys, rhesus monkeys, marmosets, orangutans, and chimpanzees.
  • the subject to which the first tumor therapeutic agent is administered is the subject having a tumor.
  • the type of tumor is not particularly limited, but examples include lung cancer (e.g., lung adenocarcinoma), uterine cancer (e.g., cervical cancer, uterine body cancer), gastric cancer, colon/rectal cancer, pancreatic cancer, liver cancer, gallbladder/bile duct cancer, breast cancer, bladder tumor, osteosarcoma, malignant melanoma, pheochromocytoma, etc.
  • the first tumor therapeutic agent is also effective against multidrug-resistant tumors. Therefore, the tumor therapeutic agent according to one embodiment of the present invention may be a therapeutic agent for multidrug-resistant tumors.
  • the subject to which the multidrug-resistant tumor therapeutic agent according to one embodiment of the present invention is administered is the subject having a multidrug-resistant tumor.
  • multidrug-resistant tumor means a tumor that is resistant to at least two types of chemotherapy drugs. Resistance to a chemotherapy drug means that the effect of the chemotherapy drug is lower than that of a tumor of the same type that is sensitive to the chemotherapy drug, and for example, means that the growth inhibitory effect of the chemotherapy drug is lower than that of a tumor of the same type that is sensitive to the chemotherapy drug.
  • the at least two types of chemotherapy drugs may be chemotherapy drugs having different chemical structures from each other, or may be chemotherapy drugs having different mechanisms of action against tumors.
  • the chemotherapy drug is, for example, an anticancer drug.
  • the type of multidrug-resistant tumor is not particularly limited, but examples include multidrug-resistant tumors of all kinds of tumors, such as lung cancer (e.g., lung adenocarcinoma), uterine cancer (e.g., cervical cancer, uterine body cancer), gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, gallbladder/bile duct cancer, breast cancer, bladder tumor, osteosarcoma, malignant melanoma, and pheochromocytoma.
  • lung cancer e.g., lung adenocarcinoma
  • uterine cancer e.g., cervical cancer, uterine body cancer
  • gastric cancer colorectal cancer
  • pancreatic cancer pancreatic cancer
  • liver cancer gallbladder/bile duct cancer
  • breast cancer bladder tumor
  • osteosarcoma malignant melanoma
  • pheochromocytoma pheochromocytoma.
  • a multidrug-resistant tumor is breast cancer that is resistant to at least two anticancer drugs selected from the group consisting of eribulin, doxorubicin, and paclitaxel. As shown in the examples below, this complex has an S1P signaling inhibitor compound as a release site, and is therefore effective against the aforementioned multidrug-resistant breast cancer.
  • the first tumor therapeutic agent includes a complex having an S1P signaling inhibitory compound as a release site. Since the first tumor therapeutic agent has an S1P signaling inhibitory compound as an active ingredient, it is expected to have an effect of treating a tumor in a patient by administering the first tumor therapeutic agent to a patient having a tumor. The first tumor therapeutic agent is expected to have an effect of treating a multidrug-resistant tumor that cannot be treated by conventional anticancer drugs.
  • a complex having an S1P signaling inhibitor compound as a release site can react with acrolein present around tumor cells to release the S1P signaling inhibitor compound, making it suitable for use as a tumor treatment.
  • the therapeutic agent for multidrug-resistant tumors according to one embodiment of the present invention (hereinafter also referred to as the "second tumor therapeutic agent”) has an S1P signaling inhibitor compound as an active ingredient.
  • the S1P signaling inhibitor compound which is the active ingredient of the second tumor therapeutic agent, may be incorporated into the above-mentioned complex as a detachment site, or may not be incorporated into the complex.
  • the complex having an S1P signaling inhibitor compound as a detachment site has already been explained in the above section "1. Tumor therapeutic agent", so the explanation will not be repeated here.
  • the S1P signaling inhibitor compound that is not incorporated into the complex is the same as the S1P signaling inhibitor compound that is incorporated into the complex as a detachment site, except that it is not incorporated into the complex.
  • the S1P signaling inhibitor compound that is the active ingredient of the second tumor therapeutic agent may be made into a prodrug by a method different from that of the above-mentioned complex. In other words, it may be made into a prodrug by adding a probe having a chemical structure represented by formula (1) that is different from the acrolein reaction site to the S1P signaling inhibitor compound.
  • the second tumor therapeutic agent is a therapeutic agent for multidrug-resistant tumors. Multidrug-resistant tumors have already been explained in the above section "1. Tumor therapeutic agent”, and therefore the explanation will not be repeated here.
  • Other ingredients contained in the second tumor therapeutic agent, the dosage form of the second tumor therapeutic agent, the manufacturing method, the content of the S1P signaling inhibitor compound in the second tumor therapeutic agent, the dosage, and the subjects of administration are the same as those of the first tumor therapeutic agent, and therefore the explanation will be omitted.
  • the second tumor therapeutic agent contains an S1P signaling inhibitor compound as an active ingredient, and is therefore expected to be effective in treating multidrug-resistant tumors for which conventional anticancer drugs are ineffective, when administered to patients with multidrug-resistant tumors.
  • a tumor therapeutic agent comprising a complex having an acrolein reactive site and a release site, the complex having a chemical structure represented by formula (1), the detachment site is bonded to the acrolein reactive site via a linker that is cleavable by a reaction between the acrolein reactive site and acrolein;
  • the release site comprises the chemical structure of a compound having activity of inhibiting sphingosine-1-phosphate signaling in cells.
  • R1 and R2 each independently represent a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom, provided that at least one of R1 and R2 is an alkyl group having 1 to 5 carbon atoms;
  • R3 and R4 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a thiol group, an amino group which may have a substituent, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, or an alkyl group having 1 to 5 carbon atoms (wherein a hydrogen atom constituting the alkyl group may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and an amino group which may have a substituent); * indicates the binding site with the linker.
  • R each independently represent a hydrogen atom, a halogen atom, a hydroxy group, a thiol group, an amino group which may have a substituent, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, or an alkyl group having 1 to 5 carbon atoms (wherein a hydrogen atom constituting the alkyl group may be substituted with a substituent selected from a halogen atom, a hydroxy group, and an amino group which may have a substituent); * indicates the binding site with the acrolein reaction site.
  • ⁇ is the binding site with the detachment site.
  • R in formula (2) each independently represents a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms (wherein the hydrogen atom constituting the alkyl group may have a substituent selected from a halogen atom, a hydroxyl group, and an amino group which may have a substituent).
  • R1 and R2 in formula (1) each independently represent an alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom.
  • the compound having activity of inhibiting sphingosine-1-phosphate signaling in the cell is a sphingosine-1-phosphate receptor modulator.
  • a complex having an acrolein reactive site and a release site the complex having a chemical structure represented by formula (1), the detachment site is bonded to the acrolein reactive site via a linker that is cleavable by a reaction between the acrolein reactive site and acrolein;
  • a conjugate, wherein the release moiety comprises the chemical structure of a sphingosine-1-phosphate receptor modulator.
  • R1 and R2 each independently represent a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom, provided that at least one of R1 and R2 is an alkyl group having 1 to 5 carbon atoms;
  • R3 and R4 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a thiol group, an amino group which may have a substituent, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, or an alkyl group having 1 to 5 carbon atoms (wherein a hydrogen atom constituting the alkyl group may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and an amino group which may have a substituent); * indicates the binding site with the linker.
  • a pharmaceutical product for tumor treatment comprising the above-mentioned first tumor therapeutic agent or second tumor therapeutic agent is also included in the scope of the present invention.
  • the first tumor therapeutic agent or the second tumor therapeutic agent in the pharmaceutical product for tumor treatment according to one embodiment of the present invention has already been described, and therefore will not be described again here.
  • the pharmaceutical product for tumor treatment is used for treating tumors.
  • the target tumor may be a multidrug resistant tumor.
  • the pharmaceutical product according to one embodiment of the present invention includes a package insert describing the dosage, method of use, etc., of the first tumor therapeutic agent or the second tumor therapeutic agent.
  • the package insert preferably describes that when the first tumor therapeutic agent or the second tumor therapeutic agent is administered intravenously to human solid tumors, the amount of the S1P signaling inhibitor compound is preferably 2 to 5 mg, more preferably 3 mg or more, and even more preferably 4 mg or more per kg of body weight, and that these effective amounts can be administered in a single dose or in several divided doses.
  • first tumor therapeutic agent or the second tumor therapeutic agent in the pharmaceutical product for tumor treatment according to one aspect of the present invention may be contained in separate containers (vials, etc.) for each dose, for example.
  • the pharmaceutical product for tumor treatment according to one aspect of the present invention may include containers containing a single dose of the first tumor therapeutic agent or the second tumor therapeutic agent for the number of doses required during the treatment period.
  • Tumor Treatment Methods A method for treating a tumor using the above-mentioned first tumor therapeutic agent or second tumor therapeutic agent is also included in the scope of the present invention.
  • a method for treating a tumor according to one embodiment of the present invention is as follows.
  • a method for treating a tumor comprising administering the tumor therapeutic agent according to any one of [1] to [10] or the multidrug-resistant tumor therapeutic agent according to [21] to a subject (e.g., a non-human mammal or a human).
  • the method for treating a tumor described in [21] further comprising a selection step of selecting a patient having a tumor, wherein the subject of the administration step is the patient selected by the selection step.
  • the tumor treatment method described in [23], wherein the multidrug resistant tumor is a breast cancer having resistance to at least two anticancer drugs selected from the group consisting of eribulin, doxorubicin, and paclitaxel.
  • the first tumor therapeutic agent or the second tumor therapeutic agent in the tumor treatment method according to one embodiment of the present invention has already been described, and so will not be described again here.
  • the recipients, administration route, formulation, and prescription of the first tumor therapeutic agent or the second tumor therapeutic agent are as described above in the section "1. Tumor therapeutic agents.”
  • the selection process is a process for selecting patients with tumors.
  • patients with multidrug-resistant tumors may be selected in particular.
  • the method for selecting patients with tumors is not particularly limited, but, for example, patients with tumors can be selected by a method for selecting patients with metastatic or recurrent tumors.
  • whether a tumor is a multidrug-resistant tumor can be confirmed by a method for judging from the patient's chemotherapy treatment history and clinical course.
  • a first tumor therapeutic agent or a second tumor therapeutic agent is administered to a subject (e.g., a non-human mammal or a human), and thus a tumor in the subject (i.e., a patient) can be treated.
  • a tumor in the subject i.e., a patient
  • a multidrug-resistant tumor that cannot be treated with conventional anticancer drugs can also be treated.
  • a complex having an S1P signaling inhibitor compound as a release site can react with acrolein present around tumor cells to release the S1P signaling inhibitor compound, making it suitable as a method for treating tumors.
  • the use according to one aspect of the present invention is as follows.
  • the conjugate comprising a conjugate having an acrolein reactive site and a release site having a chemical structure represented by formula (1): the detachment site is bonded to the acrolein reactive site via a linker that is cleavable by a reaction between the acrolein reactive site and acrolein;
  • the release moiety comprises the chemical structure of a compound having activity in inhibiting sphingosine-1-phosphate signaling in a cell.
  • R1 and R2 each independently represent a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom, provided that at least one of R1 and R2 is an alkyl group having 1 to 5 carbon atoms;
  • R3 and R4 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a thiol group, an amino group which may have a substituent, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, or an alkyl group having 1 to 5 carbon atoms (wherein a hydrogen atom constituting the alkyl group may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and an amino group which may have a substituent); * indicates the binding site with the linker.
  • [32] The use according to [31], wherein the linker has
  • ⁇ is the binding site with the detachment site.
  • R in formula (2) is each independently a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms (wherein the hydrogen atom constituting the alkyl group may have a substituent selected from a halogen atom, a hydroxyl group, and an amino group which may have a substituent).
  • R1 and R2 in formula (1) each independently represent an alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom.
  • R1 and R2 in formula (1) each independently represent an alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom.
  • R1 and R2 in formula (1) each independently represent an alkyl group having 1 to 5 carbon atoms which may be substituted with at least one halogen atom.
  • the complex reacts with acrolein present around a tumor cell, and the detachment site is detached.
  • the compound having activity of inhibiting sphingosine-1-phosphate signaling in the cell is a sphingosine-1-phosphate receptor modulator.
  • sphingosine-1-phosphate receptor modulator is fingolimod, siponimod, ozanimod, or ponesimod.
  • the tumor is a multidrug resistant tumor.
  • the multidrug resistant tumor is a breast cancer having resistance to at least two anticancer drugs selected from the group consisting of eribulin, doxorubicin, and paclitaxel.
  • MCF-7 breast cancer cell line which is a human breast cancer cell line, was cultured for a long period of time in the presence of low concentrations of eribulin, and the surviving cells were cultured in gradually increasing concentrations of eribulin, thereby finally producing an eribulin-resistant MCF-7 breast cancer cell line that can survive in the presence of a high concentration of eribulin of 675 ⁇ M. It was confirmed that this cell line was resistant to multiple anticancer drugs due to cross-resistance.
  • Example 1 A normal breast cancer cell line (MCF-7 breast cancer cell line) and a multidrug resistant cell line (Eribulin-resistant MCF-7 breast cancer cell line) were seeded on a 96-well plastic plate at 2000 cells/well with 90 ⁇ L/well of medium.
  • the medium used was DMEM/F12 medium (containing phenol red) (Sigma, #D6434) supplemented with 10% FBS, 2.5 mM L-glutamine, and 6 ng/mL insulin.
  • the absorbance at 450 nm (reference wavelength: 650 nm) was measured using a SPECTRA max PLUS 384 (MOLECULAR DEVICES), and the cell viability at each concentration of FTY720 was calculated, from which the IC 50 was calculated.
  • Example 2 The cell viability at each concentration of Prodrug-FTY-720 was calculated in the same manner as in Example 1, except that Prodrug-FTY-720 (compound 1) synthesized in Production Example 1 was used instead of FTY720, and IC 50 was calculated.
  • Examples 3 to 5 Comparative Examples 1 to 3
  • the cell viability at each concentration of each drug in Examples 3 to 5 and Comparative Examples 1 to 3 was calculated in the same manner as in Example 1, except that the drugs shown in Table 1 were used instead of FTY720, and IC50 was calculated.
  • mice that were not transplanted with the 4T1 cell line or breast cancer model mice, each consisting of 10 mice, were divided into 5 groups, A to E.
  • the mice in groups A to E were given the treatments shown in Table 2.
  • FTY-720 or Prodrug-FTY-720 (compound 1) was administered every 3 days for a total of 3 times.
  • the dose of each drug was 240 nmol per mouse (FTY-720: 81.5 ⁇ g per mouse, Prodrug-FTY-720: 135.8 ⁇ g per mouse).
  • mice were sacrificed the day after (1 day later) or 3 days after the third dose, and blood and tumor samples were taken. The weight and volume of the tumors were measured for each group of mice, and the white blood cell and lymphocyte counts were measured in the blood samples.
  • FIG. 3 is a diagram showing the results of comparing tumor weight, percentage of lymphocytes in blood samples, and lymphocyte count.
  • Ct represents the results of Group A, the control group
  • FTY-720 administration group represents the results of Group B
  • Pro-FTY represents the results of Group C, the Prodrug-FTY-720 administration group.
  • LIM in Figure 3 means lymphocytes.
  • Figure 4 shows the results of comparing the concentrations of FTY-720, phosphorylated FTY-720, or Prodrug-FTY-720 in plasma in each group.
  • “FTY with tumor” represents the results for Group B
  • "Pro-FTY with tumor” represents the results for Group C
  • “Pro-FTY without tumor” represents the results for Group D.
  • Graph B is a graph that extracts the results for only the Prodrug-FTY administration group shown in graph A
  • graph C shows the change over time in the concentrations of FTY-720, phosphorylated FTY-720, or Prodrug-FTY-720 in plasma in Group C.
  • FTY-720 is abbreviated as “FTY”, phosphorylated FTY-720 as “FTY-P”, and Prodrug-FTY-720 as "Prodrug-FTY”.
  • Figure 5 shows the results of comparing the concentrations of FTY-720, phosphorylated FTY-720, or Prodrug-FTY-720 in tissues in each group.
  • “tumor FTY” represents the results for Group B
  • “non-tumor FTY” represents the results for Group B
  • “tumor” represents the results for Group C
  • "normal area with tumor” represents the results for Group C
  • “normal area without tumor” represents the results for Group D.
  • Graph B shows the results of only the Prodrug-FTY administration group shown in graph A
  • graph C shows the changes over time in the concentrations of FTY-720, phosphorylated FTY-720, or Prodrug-FTY-720 in tissues in Group C.
  • FTY-720 is abbreviated as “FTY”, phosphorylated FTY-720 as “FTY-P”, and Prodrug-FTY-720 as "Prodrug-FTY”.
  • converted FTY-720 and phosphorylated FTY-720 were detected in the normal areas surrounding the tumor, but at lower concentrations compared to the tumor area.
  • converted FTY-720 and phosphorylated FTY-720 were still clearly detected in the tissues three days after the third dose.
  • the assay was performed according to the method described in the reference (Cell 172, 373-386, e1-e6, 2018). Specifically, each breast cancer patient-derived organoid was passaged as a single cell, and 5 days after passage, the cells were seeded on a 96 well plastic plate at a cell number of about 1000 to 2000 cells/well with 80 ⁇ L/well of medium.
  • the medium used was a cell culture medium (Type 1 or Type 2 medium containing growth factors added to Advanced DMEM/F12) to which 100% BME2 was added at a volume of 10 ⁇ L per well.
  • the drugs used were Prodrug-FTY-720 (drug in Example 2), eribulin (drug in Comparative Example 1), doxorubicin (drug in Comparative Example 2), and paclitaxel (drug in Comparative Example 3).
  • 3D Cell-Titer Glo assay Five days after the addition of the drug, a 3D Cell-Titer Glo assay was performed.
  • 3D Cell-Titer Glo assay an equal volume of CellTiter-Glo reagent to the medium was added to each well, and the wells were stirred on a shaker. Luminescence was measured using a plate reader, and the number of viable cells in the culture was determined by measuring ATP, an indicator of metabolically active cells.
  • Figure 6 is a diagram showing the results of comparing the proliferation inhibitory effects of each of the drugs in Comparative Examples 1 to 3 and Example 2 on organoids derived from breast cancer patients.
  • the present invention can be used, for example, as a therapeutic agent for tumors, and can be used in life science research, medical applications, and the like.

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Abstract

L'invention concerne un nouveau médicament pour une thérapie tumorale qui cible une voie de signalisation S1P. Un agent thérapeutique tumoral selon un mode de réalisation de la présente invention comprend un complexe qui comprend un site de réaction d'acroléine ayant une structure chimique représentée par la formule (1), et un site de détachement, le site de détachement étant lié au site de réaction d'acroléine par l'intermédiaire d'un lieur qui peut être clivé par une réaction entre le site de réaction d'acroléine et l'acroléine, et le site de détachement comprenant une structure chimique d'un composé qui présente une activité pour inhiber la transduction de signal de sphingosine-1-phosphate dans une cellule.
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