WO2024035085A1 - Nouveau composé et composition pour prévenir ou traiter le cancer her2-positif le comprenant - Google Patents

Nouveau composé et composition pour prévenir ou traiter le cancer her2-positif le comprenant Download PDF

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WO2024035085A1
WO2024035085A1 PCT/KR2023/011697 KR2023011697W WO2024035085A1 WO 2024035085 A1 WO2024035085 A1 WO 2024035085A1 KR 2023011697 W KR2023011697 W KR 2023011697W WO 2024035085 A1 WO2024035085 A1 WO 2024035085A1
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hydroxyphenyl
cancer
dihydropyrazol
ethanone
compound
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PCT/KR2023/011697
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Korean (ko)
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권영주
황수연
나영화
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이화여자대학교 산학협력단
차의과학대학교 산학협력단
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Priority claimed from KR1020220135133A external-priority patent/KR20240020636A/ko
Application filed by 이화여자대학교 산학협력단, 차의과학대학교 산학협력단 filed Critical 이화여자대학교 산학협력단
Publication of WO2024035085A1 publication Critical patent/WO2024035085A1/fr

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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
    • A61K31/12—Ketones
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • It relates to a novel compound and a composition containing the same for preventing or treating HER2-positive cancer.
  • PPI Protein-protein interaction
  • HER2 a member of the HER family, plays a key role in various tumorigenic processes by regulating cell survival, proliferation and differentiation.
  • HER2 overexpression was first observed in breast cancer and was evaluated as a classic therapeutic marker for breast cancer, but today many reports show its association with cancer, suggesting a negative prognostic role in gastrointestinal cancer, especially gastric cancer.
  • chemotherapy is usually administered with trastuzumab (TZMB), an antibody drug that targets the extracellular domain of the HER2 protein.
  • TZMB trastuzumab
  • trastuzumab although it is a clinically successful drug, there is a problem in that treatment becomes difficult when resistance develops (Cancer Res (2008) 68 (5): 1471-1477). Therefore, there is a need to develop small molecule drugs that can solve these problems.
  • One aspect is to provide a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen
  • R 2 and R 3 are independently hydrogen or a hydroxy group
  • R 4 is p-methoxynaphthalenyl, or ego
  • a 1 is nitrogen, oxygen or sulfur
  • a 2 is halogen or C 1-3 alkoxy.
  • Another aspect is to provide a compound represented by the following formula (2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 5 to R 7 are independently hydrogen or a hydroxy group
  • R 8 is p -Methoxynaphthalenyl ( p -methoxynaphthalenyl), 1-Methoxynaphthalenyl (1-Methoxynaphthalenyl), , or ego;
  • R 9 is C 1-3 alkyl
  • a 1 is nitrogen, oxygen or sulfur
  • a 2 is halogen or C 1-3 alkoxy.
  • Another aspect is to provide a composition for inhibiting protein-protein interaction, comprising the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another aspect is to provide a pharmaceutical composition for preventing or treating cancer, comprising the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another aspect is to provide a health functional food composition for preventing or improving cancer, comprising the compound, a stereoisomer thereof, or a foodologically acceptable salt thereof as an active ingredient.
  • One aspect provides a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen
  • R 2 and R 3 are independently hydrogen or a hydroxy group
  • R 4 is p-methoxynaphthalenyl, or ego
  • a 1 is nitrogen, oxygen or sulfur
  • a 2 is halogen or C 1-3 alkoxy.
  • halogen is a fluorine, chlorine, bromine, or iodine atom.
  • C 1-3 alkoxy is an OR group in which R is C 1-3 in -OR form.
  • R is C 1-3 in -OR form.
  • it may be methoxy, ethoxy, propoxy, or 1-methylethoxy.
  • the compound may be any one selected from the group consisting of the following compounds:
  • Another aspect provides a compound represented by the following formula (2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 5 to R 7 are independently hydrogen or a hydroxy group
  • R 8 is p -Methoxynaphthalenyl ( p -methoxynaphthalenyl), 1-Methoxynaphthalenyl (1-Methoxynaphthalenyl), , or ego;
  • R 9 is C 1-3 alkyl
  • a 1 is nitrogen, oxygen or sulfur
  • a 2 is halogen or C 1-3 alkoxy.
  • the compound of Formula 2 may be any one selected from the group consisting of the following compounds:
  • stereoisomer refers to molecules that have the same chemical formula and the same bonding order between constituent atoms, but have different three-dimensional structures, and are divided into enantiomers and diastereomers.
  • stereochemical isomeric form of the pyridone derivative compound defines all possible compounds that the compound of Formula 1 may have.
  • chemical name of a compound refers to a mixture of all possible stereochemical isomeric forms, which mixture includes all diastereomers and enantiomers of the basic molecular structure.
  • the stereogenic center can have the R- or S-configuration and the substituents on the divalent cyclic (partially) saturated radical can have the cis- or trans-configuration.
  • Compounds containing a double bond may have E or Z-stereochemistry at the double bond.
  • Stereochemical isomeric forms of the compound represented by Formula 1 are intended to be included within the scope of the invention.
  • compositions for inhibiting protein-protein interaction comprising a compound represented by Formula 1 or Formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • protein-protein interaction refers to an established high molecular weight relationship between two or more protein molecules as a result of biochemical events mediated by interactions involving electrostatic forces, hydrogen bonding, and hydrophobic effects. It means physical contact of singularity. This is most often observed in certain biomolecular contexts, which refers to physical contact with molecular bonds between chains that occur in cells or living organisms.
  • Various reactions within cells proceed by protein-protein interactions, and abnormal protein-protein interactions can be the starting point of various diseases such as cancer, Creutzfeldt-Jakob disease, and Alzheimer's disease.
  • cancer refers to a condition in which problems occur in the normal division, differentiation, and death control functions of cells, causing abnormal hyperproliferation, infiltrating surrounding tissues and organs, forming lumps, and destroying or deforming existing structures. it means.
  • the above cancers include cervical cancer, lung cancer, pancreatic cancer, non-small cell lung cancer, liver cancer, colon cancer, bone cancer, skin cancer, head cancer, cervical cancer, skin melanoma, intraocular melanoma, uterine cancer, ovarian cancer, and rectal cancer.
  • CNS central nervous system
  • prevention refers to any action that suppresses a disease or delays its onset by administering a composition.
  • treatment refers to any action that improves or beneficially changes the symptoms of a disease by administering a composition.
  • the term "pharmaceutically acceptable” means that the benefit/risk ratio is reasonable and is suitable for use in contact with the tissue of a subject (e.g., a human) without excessive toxicity, irritation, allergic reaction, or other problems or complications, and sound medical judgment. It means a composition within the scope of.
  • the term “pharmaceutically acceptable salt” refers to an acid addition salt formed by a pharmaceutically acceptable free acid.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, as well as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodine.
  • a pharmaceutically acceptable metal salt can be prepared using a base.
  • the alkali metal or alkaline earth metal salt can be obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically appropriate to prepare sodium, potassium, or calcium salts as metal salts.
  • the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).
  • the pharmaceutical composition may further include a carrier, excipient, or diluent.
  • Carriers, excipients and diluents include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, not determined. It may contain quality cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil.
  • the pharmaceutical composition may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injection solutions according to conventional methods. When formulated, it can be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
  • the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule.
  • the solid preparation may further include excipients. Excipients may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. Additionally, the solid preparation may further include a lubricant such as magnesium stearate or talc.
  • the liquid preparation for oral administration may be a suspension, oral solution, emulsion, or syrup.
  • the liquid formulation may contain water or liquid paraffin.
  • the liquid formulation may contain excipients such as wetting agents, sweeteners, flavoring agents, or preservatives.
  • preparations for parenteral administration may be sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried products, and suppositories.
  • Non-aqueous solvents or suspensions may contain vegetable oil or ester.
  • the vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil.
  • the ester may be, for example, ethyl oleate.
  • the base of the suppository may be witepsol, macrogol, tween 61, cacao, laurel, or glycerogelatin.
  • the preferred dosage of the pharmaceutical composition varies depending on the individual's condition and weight, degree of disease, drug form, administration route and period, but can be appropriately selected by a person skilled in the art.
  • the compound, its stereoisomer, derivative, solvate, or pharmaceutically acceptable salt may be used in an amount, for example, from about 0.0001 mg/kg to about 100 mg/kg, or from about 0.001 mg/kg to about 100 mg/kg.
  • the amount can be divided into 1 to 24 times per day, 1 to 7 times per 2 days to 1 week, or 1 to 24 times per month to 12 months.
  • the compound, its stereoisomer, or a pharmaceutically acceptable salt may be included in an amount of about 0.0001% by weight to about 10% by weight, or about 0.001% by weight to about 1% by weight based on the total weight of the entire composition.
  • the administration method may be oral or parenteral administration.
  • Methods of administration may be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal.
  • the composition can be administered systemically or topically, alone or in combination with other pharmaceutically active compounds.
  • Another aspect provides a method of preventing or treating cancer, comprising administering the pharmaceutical composition according to one aspect to a subject. Details of the pharmaceutical composition, administration, prevention and treatment are as described above.
  • the subject may be a mammal, for example, a human, cow, horse, pig, dog, sheep, goat, or cat, or may be a mammal other than a human.
  • the individual may be suffering from cancer or may be at high risk of suffering from cancer.
  • the administration method may be oral or parenteral administration.
  • Methods of administration may be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal.
  • the pharmaceutical composition can be administered systemically or topically, alone or in combination with other pharmaceutically active compounds.
  • the dosage of the composition may range, for example, from about 0.0001 mg/kg to about 100 mg/kg, or from about 0.001 mg/kg to about 100 mg/kg.
  • the administration may be divided into 1 to 24 times per day, 1 to 7 times per 2 days to 1 week, or 1 to 24 times per month to 12 months.
  • compositions comprising a compound according to one aspect, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the prevention or treatment of cancer.
  • Another aspect provides a health functional food composition
  • a health functional food composition comprising the compound according to one aspect, a stereoisomer thereof, or a foodologically acceptable salt thereof.
  • the term “improvement” refers to any action that at least reduces the severity of a parameter associated with an abnormal condition, such as a symptom.
  • the health functional food composition can be used simultaneously or separately with a drug for treatment before or after the onset of the disease in order to prevent or improve cancer.
  • the health functional food can be prepared by encapsulating, powdering, or suspending a compound according to one aspect, a stereoisomer thereof, or a food-acceptable salt thereof, and using it as a functional food or adding it to various foods.
  • the above foods include, for example, meat, sausages, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamins. It is a combination medicine, functional food and health food.
  • the novel compound of the present invention can suppress the level of HER2 by inhibiting the protein-protein interaction of ELF3 and MED23, and thereby has a significant anticancer effect. Moreover, even in cases of resistance to trastuzumab, which is previously used clinically as a cancer treatment, treatment with the new compound of the present invention showed a remarkable level of anticancer effect. Therefore, it is expected that the new compound of the present invention can be widely used in the field of cancer treatment.
  • Figure 1a is a diagram showing the protein binding model of MED23 WT and ELF3 WT prepared using the Phyre2 server to predict the hotspot of the ELF3-MED23 complex.
  • Figure 1b is a diagram showing 3D docking of the ELF3 137-144 peptide to the MED23 protein.
  • Figure 1c is a diagram showing docking of wrenchnolol, adamanolol, gefitinib, and canertinib, which are known to have ELF3-MED23 PPI inhibitory activity.
  • Figure 1d is a diagram showing a 2D interaction diagram of gefitinib docking generated by PoseView (https://proteins.plus).
  • Figure 1e is a diagram showing hydrogen bonding and p-stacking involved in the interaction between MED23 and the above compounds.
  • Figure 2 shows a 2D diagram of canertinib, showing that canertinib can p-interact with F399 of MED23.
  • Figure 3a is a diagram showing the effect of each MED23 mutation on the binding level of gal4-ELF3 and MED23 using SEAP analysis to analyze key residues involved in the ELF3-MED23 protein-protein interaction hotspot.
  • Figure 3b is a diagram showing split luciferase analysis using a biosensor.
  • Figures 3c and 3d show the binding levels between ELF3 and the MED23 391-582 fragment in images ( Figure 3c) and quantitatively (Figure 3d).
  • Figure 3e is a diagram confirming the interaction between several full-length MED23 mutants and ELF3 by GST pull-down analysis.
  • Figure 3f shows the transcriptional activity level of HER2
  • Figure 3g shows the expression level of HER2.
  • Figure 4a is a diagram showing a small molecule design strategy for analyzing small molecules that may affect the protein-protein interaction of ELF3-MED23.
  • Figure 4b is a diagram confirming the ELF3-MED23 protein-protein interaction inhibitory effect and cell survival rate of the prepared small molecule.
  • Figure 4c is a diagram confirming the inhibitory effect and cell viability again by varying the concentration of a small molecule compound showing an ELF3-MED23 protein-protein interaction inhibitory effect of more than 65%.
  • Figure 4d is a diagram showing the docking poses of the 25 designed small molecule compounds.
  • Figure 5a shows the results of overlapping docking poses of gefitinib and candidate compounds to select small molecule compounds that significantly affect the protein-protein interaction of ELF3-MED23, showing the visualization of hydrogen bond donors and hydrogen bond acceptors. It is also a degree.
  • Figure 5b is a diagram showing a docking pose diagram of a candidate compound.
  • Figure 5c is a diagram confirming the binding between the candidate compound and MED23 wild type through hydrogen bonding through LC-MS/MS analysis.
  • Figure 5d is a diagram confirming the binding affinity of candidate compounds to various MED23 fragments through LC-MS/MS analysis.
  • Figures 5e and 5f show images and quantitative data from luciferase biosensor analysis performed using Nluc-ELF3 WT and Cluc-MED23 391-462 fragments.
  • Figure 5g is a diagram showing fluorescence polarization according to dose-dependent treatment of a candidate compound or unlabeled ELF3 protein.
  • Figure 5h is a diagram showing the IC 50 value and K i value of the candidate compound.
  • Figure 5i is a diagram showing the protein-protein interaction inhibition effect of the candidate compound by immunoprecipitation analysis.
  • Figure 5j is a diagram showing the HER2 mRNA expression level according to dose-dependent treatment of the candidate compound.
  • Figure 5k is a diagram showing the expression levels of HER2 and HER2-related downstream signaling molecules according to dose-dependent treatment of candidate compounds.
  • Figure 6a is a diagram confirming the expression levels of HER2, ELF3, and MED23 in various gastric cancer cell lines to biochemically confirm the anticancer activity of the candidate compound.
  • Figure 6b is a diagram confirming the cell survival rate after treating gastric cancer cell lines showing different HER2 levels with candidate compounds.
  • Figure 6c is a diagram confirming the cell survival rate after treating NCI-N87 cells with candidate compounds and comparison compounds.
  • Figures 7A and 7B are diagrams showing the overall survival rate (Figure 7A) and progression-free survival ( Figure 7B) of 1,065 gastric cancer patients.
  • Figure 7c is a diagram showing tumor regression observed after treatment of candidate compounds in NCI-N87 xenograft mice.
  • Figure 7d is a photograph of tumors obtained from mice in the vehicle-treated group and the candidate material-treated group.
  • Figure 7e is a diagram confirming IHC staining for HER2 and Ki75 in a tumor.
  • Figures 7f and 7g are diagrams confirming the cell cycle when treated with candidate compounds.
  • Figure 7i is a diagram confirming the apoptosis effect when treated with the candidate compound.
  • Figure 7h is a diagram confirming the levels of apoptosis-promoting markers and anti-apoptosis markers by treatment with candidate compounds.
  • Figure 8a is a diagram showing the physicochemical properties (e.g., solubility, Log P, and permeability, etc.) of the candidate compound in order to perform pharmacological evaluation of the candidate compound.
  • physicochemical properties e.g., solubility, Log P, and permeability, etc.
  • Figure 8b is a diagram showing the genotoxicity of the candidate compound.
  • Figure 8c is a diagram showing cardiac toxicity.
  • Figure 8d is a diagram showing the intravenous and oral route pharmacokinetic profiles of the candidate compound.
  • Figures 9a to 9c show the candidate compounds and trastuzumab on parental cells (BT474 and NCI-N87) and trastuzumab resistance acquired cells (BT474 TR, NCI-N87 TR and JIMT-1) to confirm the resistance-overcoming effect of the candidate compounds.
  • This is a diagram confirming the dose-dependent treatment effect of .
  • Figures 9D to 9F are diagrams showing the levels of HER2 and its main downstream signaling molecules after treating trastuzumab-sensitive and trastuzumab-resistant cells with different doses of trastuzumab and candidate compounds.
  • Figures 9G to 9I are diagrams confirming the survival and proliferation of Trastuzumab-sensitive and Trastuzumab-resistant cells while being treated with the candidate compound and Trastuzumab in a dose-dependent manner.
  • Figures 9J and 9L are diagrams showing the level of tumor cell degeneration confirmed by tumor volume, photography, volume change, etc. while treating trastuzumab-resistant cells with candidate compounds and trastuzumab in a dose-dependent manner;
  • Figures 9m and 9n are diagrams showing IHC staining of HER2 and Ki67 in tumor cells, followed by confirmation of the number of cells photographed and stained.
  • Figure 10 is a diagram confirming the change in body weight of JIMT-1 xenograft mice treated with trastuzumab or a candidate compound.
  • the chemicals and reagents used were mainly obtained from Aldrich Chemical Co., while others were obtained from companies such as TCI. Melting point was measured without correction using a Barnstead Electrothermal melting point apparatus, Manual MELTEMP (model number: 1202D). Chromatographic separation was monitored by thin-layer chromatography using commercially available pre-coated Merck Kieselgel 60 F254 plates (0.25 mm) and detected by visualization at UV 254 and 365 nm. Silica gel column chromatography was performed using Merck Kieselgel 60 (0.040-0.063 mm). All solvents used in chromatography were used as is without distillation.
  • Membranes were blocked by treatment with 5% skim milk or 5% BSA, and then incubated with primary antibodies (purchased from Thermo Fisher, Cell Signaling, Santa Cruz, Novus, or MBL) for 3 hours at room temperature or overnight at 4°C. cultured. Blots were washed three times with Tris-buffered saline-0.1% Tween20 (1X TBST) and incubated with HRP-conjugated secondary antibodies (GeneTex, USA). Protein bands were detected using ECL solution reagent (GE Healthcare, USA) and LAS-3000 (Fuji Photo Film Co., Ltd., Japan), and captured images were captured using Multi-Gauge software (Fuji Photo Film Co. Ltd.). ) was evaluated. Cell lysate preparation for the following analyzes was performed in the same manner as for Western blot analysis.
  • NCI-N87 cells a gastric cancer cell line
  • a gastric cancer cell line were seeded in a 100 mm cell culture dish and then cultured until they reached 60-70% confluence.
  • Cultured cells were transfected with p3Xflag-myc-CMV26-empty or p3Xflag-myc-CMV26-MED23 WT plasmid using Lipofectamine® 2000 (Invitrogen, USA). After transfection, 12 hours later, YK1 (5 ⁇ M) was treated and cultured for 12 hours.
  • HEK293 cells were plated in 6-well plates and then incubated with 1 ⁇ g of pNeuLite (Addgene) alone or 0.5 ⁇ g of pcDNA3.1-flag-ELF3 WT (provided by Dr. Seung Bae Rho, National Cancer Center) and p3Xflag-myc-CMV26- Transformed with MED23 mutant plasmid.
  • pNeuLite Additional Biolistics
  • pcDNA3.1-flag-ELF3 WT provided by Dr. Seung Bae Rho, National Cancer Center
  • p3Xflag-myc-CMV26- Transformed with MED23 mutant plasmid To normalize the luciferase activity of each sample, 0.5 ⁇ g of ⁇ -galactosidase expression plasmid (provided by Dr. Eun-Sook Hwang, Ewha Womens University) was added to all sample groups. All transfections were performed using Lipofectamine® 2000 Transfection Reagent (Invitrogen
  • firefly luciferase and ⁇ -galactosidase ( ⁇ -galactosidase) activities were measured using the Luciferase Assay System (Promega) and Galacto-Light Plus ⁇ -Galactosidase Reporter Gene Assay System (Invitrogen). Evaluation was performed using an Infinite M200 PRO Microplate reader (Tecan Group Ltd., Switzerland).
  • HEK293 cells were seeded in 100 mm 3 dishes and incubated until 70-80% confluency was reached.
  • Cells were transfected with p3Xflag-myc-CMV26-MED23 WT and p3Xflag-myc-CMV26-MED23 D400A/H449G plasmids for 24 hours and lysed to obtain protein extracts.
  • To isolate the candidate compound (YK1) bound to MED23 the entire lysate was incubated with YK1 for 4 hours and finally pulled down using FLAG-agarose beads (Sigma Aldrich, USA). The precipitated beads were washed three or more times to completely remove unbound compounds.
  • the sample 50 ⁇ L was extracted with 1 mL of acetonitrile and then centrifuged at 13,000 rpm at 4°C for 10 minutes. Each sample was aliquoted from the upper layer (1000 ⁇ L) into a new tube and evaporated to dryness under nitrogen gas at 37°C.
  • YK1 the residue was dissolved in 50 ⁇ L of ACN and vortexed for 10 min.
  • Each sample was mixed with an internal reference material (a material similar to the candidate material but with low binding affinity for MED23, hereafter YK2) contained in ACN at a concentration of 5000 ⁇ g/mL, and then mixed with 450 ⁇ L by sonication and vortex mixing. Extracted with ACN.
  • the candidate material combined with MED23 was finally analyzed using an Agilent 6460 triple quadrupole mass spectrometer (Agilent Technologies, USA).
  • residues I139 and I140 of ELF3 are predicted to create additional hydrogen bonds with E405 and H449 of MED23, incorporating several hydrophobic interactions between residues D400, H449, E405, M396, P446, and K406 of ELF3 and MED23 ( It is expected to consolidate.
  • ELF3 137-144 and canertinib which were confirmed to have superior PPI inhibitory activity than gefitnib, were confirmed to form additional ⁇ - ⁇ interactions with F399 of MED23 (FIG. 2).
  • SEAP analysis was performed. Specifically, 293T kidney cells were seeded in a 96-well microplate (SPL, Korea) at a density of 5 x 10 3 cells/well and cultured overnight. The cells were then simultaneously transfected using 100ng of each plasmid and transfection optimized medium (Welgene, Korea).
  • the plasmid used was a SEAP reporter gene (pG5IL2SX) and a GAL4-ELF3 expression vector (pBJ GAL4-ELF3).
  • MED23 protein constructs pcDNA_MED23 WT, K397A, D400A, H449G, and D400A/H449G . Treated cells were incubated for 12 hours.
  • the candidate compounds were placed in an incubator under 5% CO 2 and 37°C conditions, and then the plate was incubated at 65°C for 3 hours to inactivate all enzymes except SEAP (Secreted Alkaline Phosphatase).
  • SPECTRAmax GEMINIEM Molecular Devices, USA
  • the biosensor used in the analysis was prepared using the In-Fusion® HD Cloning Kit with firefly (Photinus pyralis). Luciferase was split into two fragments (Nluc and Cluc). Full-length ELF3 (wild type) and MED23 mutants were cloned into Hind2 and Kpnl sites and Notl and Kpnl sites of p3Xflag -myc-CMV26, respectively.
  • the full-length cDNA of human ELF3 (accession number NM_001114309.1) was fused with the N-terminal fragment of split luciferase (Nluc), and the full-length cDNA of MED23 (accession number NM_001270521.1) was fused to the C-terminal fragment of split luciferase (Cluc). -fused with the extremities.
  • HEK293 cells were seeded in 100 mm cell culture dishes and cultured until they reached 70-80% confluence. Labeled GST-tagged ELF3 constructs were transfected using Lipofectamine® 2000 (Invitrogen, USA). 1000 ⁇ g of cell extract was incubated with 20 ⁇ L of Glutathione Sepharose beads (GE Healthcare, UK) for 1 hour at 4°C on a rotator. Beads were washed three times with 200 ⁇ L of ice-cold 1X PBS. After removing the final supernatant, the beads were eluted with elution buffer (20mM Glutathione, 100mM Tris-HCl (pH 8.0), 120mM NaCl, 10% glycerol). The precipitated proteins were loaded, separated by SDS-PAGE, and analyzed by Western blot.
  • elution buffer 20mM Glutathione, 100mM Tris-HCl (pH 8.0), 120mM NaCl, 10% gly
  • Example 4 Confirmation of the effect of small molecule compounds on key residues of ELF3-MED23 PPI and their dominant anti-proliferative effect on HER2-positive gastric cancer cell lines.
  • the 3D structure of the candidate compound YK1 was generated using the SKETCH module of the SYBYL program (Tripos Inc., St. Louis, USA). Docking of all molecules was performed using Surflex -Dock (Tripos International, 2012) linked to Sybyl -X 2.3, and the results are shown in Table 1 below.
  • the candidate compound showing the best PPI inhibitory activity and the best antiproliferative effect in HER2-positive gastric cancer cell lines was selected (compound No. 15, hereinafter referred to as YK1).
  • the candidate compound was confirmed to form a hydrogen bond with the oxygen in the backbone of the D400 residue, forming an additional p-interaction with F399 of MED23.
  • YK1 is predicted to form hydrophobic interactions with MED23 residues F399, E405, and P446, similar to the ELF3 137-144 peptide ( Figure 5b).
  • PCR was performed using a CFX96 TM real-time PCR detection system (Bio-Rad, USA) according to the following protocol: 95°C for 2 min, 27 cycles at 95°C for 10 s, 56°C for 10 s, and 72°C for 20 s. It was performed using . Relative amounts of mRNA were determined using the ⁇ Ct method and normalized to GAPDH or ACTIN. As a result, it was confirmed that the candidate substance directly binds to the D400 and H449 residues of MED23 through hydrogen bond formation. The candidate material could bind to FLAG-tagged wild-type MED23, but could not bind to the double mutant MED23 D400A/H449G ( Figure 5c). However, among the fragments of MED23, it specifically interacted with MED23 391-625 , a fragment containing D400 and H449 residues (FIG. 5d).
  • the candidate material can specifically bind to MED23 391-462 and thereby inhibit the PPI of ELF3-MED23 to a significant level.
  • Fluorescence Polarization Assay was performed to determine whether the candidate compound whose ELF3-MED23 PPI inhibitory effect was confirmed above could inhibit the expression of HER2. Specifically, various concentrations of (His) 6 -MED23 391-582 and fluorescein isothiocyanate (FITC) labeled ELF3 129-145 peptides (10 nM) were incubated in assay buffer (30 mM NaCl and 5 mM ⁇ -mercapto). After mixing in 20mM sodium phosphate (pH 8.0) containing ethanol ( ⁇ -mercaptoethanol), the K d value was determined. The samples were adjusted to a final volume of 50 ⁇ L and incubated for 30 minutes at room temperature.
  • assay buffer 30 mM NaCl and 5 mM ⁇ -mercapto
  • K d value was performed with Prism 6.0 (GraphPad Software, USA) using the least-squares non-linear fit method.
  • the FP signal was measured using an Infinite F200 PRO microplate reader (Tecan Group Ltd., Switzerland) with an excitation wavelength of 485 nm and an emission wavelength of 535 nm in millipolarization (mP).
  • mP millipolarization
  • graded concentrations of YK1 and unlabeled ELF3 137--144 peptides were mixed with 80 nM (His)6-MED23 391-582 and 10 nM FITC-ELF3 129-145 .
  • the candidate compound was confirmed to significantly reduce the FP signal by inducing the release of FITC-labeled ELF3 129-145 peptide from MED23 391-582 , which reconfirmed that it can directly inhibit PPI (Figure 5g) .
  • the PPI inhibitory activity (4.27 ⁇ 0.25 ⁇ M) of the candidate compound was calculated according to the above Ki value, it was confirmed to be superior to the inhibitory activity (0.78 ⁇ 0.05 ⁇ M) of the unlabeled ELF3 137-144 peptide ( Figure 5h) )
  • the candidate compound can specifically inhibit protein-protein interaction in ELF3-MED23, thereby suppressing the expression level of HER2.
  • the kinase inhibitory activity of the candidate compounds at 10 ⁇ M and 25 ⁇ M was confirmed through Eurofins kinase profiling service.
  • the inhibitory effect on c-RAF, EGFR, ErbB2, ErbB4 and PI3 kinases was analyzed according to the Kinase Profiler Service Assay protocol.
  • the candidate compound did not show significant inhibitory activity against HER family kinases (EGFR, ErbB2, and ErbB4) or AKT/MAPK pathway-related kinases (PI3 kinase and c-RAF) (Table 3 below) ).
  • the antiproliferative effect of the candidate compound due to HER2 inhibition was confirmed.
  • cancer cells were seeded at 10 4 cells/well in a 96-well cell culture plate for 20 hours. Cells were starved in serum-free medium for 4 hours, then replaced with medium supplemented with the specified concentration of compound and cultured in an incubator at 5% CO 2 and 37°C for 72 hours. Cell viability was confirmed by applying 5 ⁇ L of EZ-cytoX to each well and then checking the absorbance at 450 nm. For measurement, an ELISA Microplate Reader (VersaMax, Molecular Devices) was used.
  • mice were prepared. NCI-N87 and JIMT-1 cells (5 x 10 6 cells) dissolved in 100 ⁇ L of 1 Korea) was injected subcutaneously into the right flank of the mouse. When tumors reached a volume of 90–100 mm 3 , mice were randomly separated into each designated group. Drug administration was repeated six times intravenously for NCI-N87 xenografts and eight times intraperitoneally for JIMT-1 xenografts, all at 3-day intervals.
  • the candidate compound (YK1) and trastuzumab (TZMB) were prepared at the same concentration of 4 mg/kg and mixed with a mixture of DMAC/Tween80/saline (5:10:85) and saline, respectively. , was injected. After drug injection, changes in tumor size were monitored until the average tumor size in the control group reached 2000-2500 mm 3 . Mice were sacrificed 28 days after the first drug injection for NCI-N87 and 46 days for JIMT-1 xenografts, then tumors were excised from each mouse and relative tumor size was determined. The length (L) and width (W) of the tumor were measured with calipers, and the tumor volume was calculated using the formula (LXW 2 ) / 2.
  • HER2 overexpression is related to cell cycle and apoptosis
  • experiments were conducted to determine the effect of candidate compounds on these. Specifically, 5 x 10 5 NCI-N87 cells were inoculated into a 60 mm dish and then cultured until reaching 70-80% confluence. The candidate compound YK1 was treated with different concentrations and then incubated for 8 hours. The cells were treated with trypsin and then washed with cold PBS (pH 7.4). For cell cycle analysis, the cells were fixed with 70% ethanol, incubated at 4°C for 30 minutes, and then stained using FxCycle TM PI/RNase staining solution (Invitrogen TM , USA). Cell cycle analysis was performed using a fluorescence-activated cell sorting (FACS) instrument (BD Biosciences, USA).
  • FACS fluorescence-activated cell sorting
  • cells for apoptosis analysis were prepared in the same manner as the cells prepared in the cell cycle analysis method. Cells were trypsinized and washed with 1X PBS, and then each sample was resuspended using FITC Annexin V Apoptosis Detection Kit I (BD Pharmingen TM ). Apoptosis was analyzed using a FACS machine.
  • the candidate compound can significantly promote apoptosis in a dose-dependent manner (Figure 7h), inducing an increase in pro-apoptotic markers c-PARP and c-caspase 7, and anti-apoptotic marker bcl- It was confirmed that a decrease in 2 was induced ( Figure 7i).
  • the candidate compound was confirmed to have a reasonable level of solubility (103.2 ⁇ 0.6 ⁇ g/ml at pH 7) and permeability (FIGS. 8A to 8C). This means that the candidate compound meets general drug-likeness criteria and, when confirmed PK profile, the candidate compound has a long half-life (T1/2 (IV), 9.74 ⁇ 2.76 h; T1/2 (PO), 10.9 ⁇ 11.00 h). It was confirmed that it had a decent level of bioavailability (Ft, 25.1%) ( Figure 8d).
  • the candidate compound has a remarkable level of anticancer effect and has physicochemical properties suitable for use as an anticancer agent.
  • the candidate compound could overcome trastuzumab resistance.
  • the prepared compounds Nos. 1 to 22 were used for JIMT-1 (ER-/PR-/HER2+ subtype, congenital TZMB resistance) and TZMB-refractory BT474 (BT-TR, ER+/PR+/HER2+ subtype, acquired resistance). and TZMB-refractory NCI-N87 (NCI-N87 TR; HER2+ subtype, acquired resistance) group, and then the effect was confirmed.
  • clonal analysis was performed. Specifically, cells were seeded in 6-well culture plates at a density of 2000 cells/well and then incubated for 14 days with or without TZMB (10 or 20 ⁇ g/mL) and YK1 (0.5 or 1 ⁇ M). The incubated cells were fixed with 100% methanol for 1 hour and then stained with 200 ⁇ L of crystal violet solution per well. Cells were washed with tap water, then images were taken with a ChemiDoc bio-image analyzer (Bio-Rad) and quantified with Image J software (NIH, Bethesda, MD, USA). After fixation, all above steps were performed at room temperature.
  • TZMB 10 or 20 ⁇ g/mL
  • YK1 0.5 or 1 ⁇ M
  • Example 7-1 As a result, as confirmed in Example 7-1, the candidate compound was effective in TZMB resistance, but it was confirmed that TZMB did not have this effect (FIGS. 9g to 9i).
  • JIMT-1 xenograft mice were treated with 4 mg/kg of the candidate compound and TZMB, respectively, and the resistance evasion effect was confirmed in vivo.
  • the level of HER2 was significantly reduced, and the growth and volume of the tumor were significantly reduced (FIGS. 9J to 9M).
  • Ki67 a proliferation marker, was also confirmed to be significantly reduced in the candidate compound treatment group compared to the TZMB treatment group (FIG. 9n). Meanwhile, the body weights of mice were generally similar throughout the experiment ( Figure 10).

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Abstract

La présente invention concerne un nouveau composé et une composition pour la prévention ou le traitement du cancer HER2-positif, le comprenant. Le nouveau composé selon la présente invention peut supprimer le niveau de HER2 par inhibition de l'interaction protéine-protéine entre ELF3 et MED23, et présente ainsi un effet anticancéreux significatif. De plus, même dans des cas de résistance au trastuzumab, qui est classiquement utilisé sur le plan clinique en tant que traitement anticancéreux, le traitement avec le nouveau composé selon la présente invention a montré un niveau remarquable d'efficacité anticancéreuse. Par conséquent, il est attendu que le nouveau composé selon la présente invention peut être largement utilisé dans le domaine du traitement du cancer.
PCT/KR2023/011697 2022-08-08 2023-08-08 Nouveau composé et composition pour prévenir ou traiter le cancer her2-positif le comprenant WO2024035085A1 (fr)

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Citations (2)

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KR20150025601A (ko) * 2013-08-29 2015-03-11 건국대학교 산학협력단 신규한 칼콘 유도체 및 그 유도체를 포함하는 항암 조성물
KR101655697B1 (ko) * 2015-09-15 2016-09-08 이화여자대학교 산학협력단 신규한 피라졸린 유도체 및 이의 용도

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KR20150025601A (ko) * 2013-08-29 2015-03-11 건국대학교 산학협력단 신규한 칼콘 유도체 및 그 유도체를 포함하는 항암 조성물
KR101655697B1 (ko) * 2015-09-15 2016-09-08 이화여자대학교 산학협력단 신규한 피라졸린 유도체 및 이의 용도

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JIMI M. ALEX; SANDEEP SINGH; RAJ KUMAR: "1‐Acetyl‐3,5‐diaryl‐4,5‐dihydro(1H)pyrazoles: Exhibiting Anticancer Activity through Intracellular ROS Scavenging and the Mitochondria‐Dependent Death Pathway", ARCHIV DER PHARMAZIE, WILEY VERLAG, WEINHEIM, vol. 347, no. 10, 19 August 2014 (2014-08-19), Weinheim , pages 717 - 727, XP071648140, ISSN: 0365-6233, DOI: 10.1002/ardp.201400199 *
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