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WO2025026368A1 - Utilisation antitumorale de r406 et d'un dérivé de celle-ci en synergie avec trail - Google Patents

Utilisation antitumorale de r406 et d'un dérivé de celle-ci en synergie avec trail Download PDF

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Publication number
WO2025026368A1
WO2025026368A1 PCT/CN2024/108957 CN2024108957W WO2025026368A1 WO 2025026368 A1 WO2025026368 A1 WO 2025026368A1 CN 2024108957 W CN2024108957 W CN 2024108957W WO 2025026368 A1 WO2025026368 A1 WO 2025026368A1
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group
alkyl
trail
saturated
compound
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Chinese (zh)
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袁钧瑛
李盈
孙维敏
谭立
单恒悦
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicines, and in particular, provides the anti-tumor use of the drug R406 and its derivatives in coordination with TRAIL.
  • TRAIL-R1 and TRAIL-R2 When stimulated by TRAIL, TRAIL-R1 and TRAIL-R2 can initiate cell apoptosis by recruiting the protein FADD containing the death domain.
  • TRAIL-R3 and TRAIL-R4 are decoy receptors, which do not contain death domains in their cells, so they will not induce apoptosis when stimulated by TRAIL.
  • Different TRAIL receptors have different expressions in normal cells and tumor cells.
  • TRAIL-R1 and TRAIL-R2 are highly expressed in tumor cells, while TRAIL-R3 and TRAIL-R4 are highly expressed in normal cells. Based on the above characteristics, TRAIL can specifically induce the death of tumor cells, so the research on the anti-tumor effect of TRAIL is very popular.
  • TRAIL non-small cell lung cancer
  • NSCLC non-small cell lung cancer
  • NHS B-cell Non-Hodgkin’s Lymphoma
  • colorectal cancer TRAIL showed high tolerance and safety in clinical phase I
  • Many clinical results showed that the effect of using TRAIL alone for tumor treatment is very limited.
  • Many preclinical studies have shown that most tumor cells are not sensitive to single TRAIL treatment, so more and more studies have begun to try the combination of TRAIL and other small molecules to increase the sensitivity of tumor cells to TRAIL.
  • the research on TRAIL combined with drugs has entered the clinical stage, and clinical results have shown that TRAIL combined with drugs has a good effect on tumor inhibition. Therefore, the development of new small molecule drugs that can cooperate with TRAIL to exert better anti-tumor function can provide a good reference and hope for subsequent targeted tumor treatment.
  • R406 is a reported inhibitor of tyrosine kinase Syk, and R788, also known as Fostamatinib, is the phosphate form of R406.
  • R788 As a prodrug molecule of R406, R788 can be rapidly converted into R406 in vivo.
  • R788 has been approved by the FDA for the treatment of idiopathic thrombocytopenic purpura (ITP), but there have been no studies reported on the combination of R788 and TRAIL in the treatment of tumors. Therefore, there is no application of R406 or its phosphate R788 combined with TRAIL in the treatment of tumors in this field.
  • the object of the present invention is to provide a new use of drug R406 and its derivatives, or pharmaceutically acceptable salts, hydrates or solvates thereof in tumor treatment.
  • n 0, 1, 2, 3, 4 or 5;
  • Ring A is selected from the group consisting of a saturated or partially unsaturated C 3-8 carbocyclic group, a saturated or partially unsaturated 5-10 membered heterocyclic group, a C 6-10 aryl group, and a 5-12 membered heteroaryl group;
  • R 1 is selected from the group consisting of H, D, C 1-6 alkyl, C 2-6 acyl, C 2-6 ester, C 1-6 haloalkyl, saturated or partially unsaturated C 3-8 carbocyclic group, saturated or partially unsaturated 5-10 membered heterocyclic group, C 6-10 aryl, 5-12 membered heteroaryl;
  • R 2 and R 3 are each independently selected from the group consisting of C 1-6 alkyl, C 2-6 acyl, and C 1-6 haloalkyl;
  • X 1 is selected from the group consisting of O, NH, NR 4 , CH 2 , CHR 4 , C(R 4 ) 2 ;
  • Each R 5 is independently selected from the group consisting of hydrogen, CN, C 1-6 alkyl-C(O), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, saturated or partially unsaturated C 3-8 carbocyclyl, saturated or partially unsaturated 5-10 membered heterocyclyl, C 6-10 aryl, 5-12 membered heteroaryl;
  • R 5 is selected from the following group:
  • the compound directly binds to TAK1 and promotes the sustained activation of TAK1 kinase.
  • an in vitro non-diagnostic non-therapeutic method for inhibiting tumor cells comprising the steps of:
  • FIG2 shows the purity of hTAK1-TAB1 purified by sf9 expression analyzed by AUC.
  • FIG5 shows that R406 promotes TAK1 hyperactivation in an in vitro kinase reaction.
  • FIG. 8 shows that R406/R788 can promote TNF ⁇ -induced RIPK1-dependent programmed cell necrosis in FADD-deficient Jurkat cells.
  • FIG. 10 shows that R406 can promote TNF ⁇ -induced RIPK1-dependent programmed cell necrosis in NCI-H1975 cells.
  • FIG. 12 shows that R406 can promote TRAIL-induced apoptosis in E0771 cells.
  • Figure 13 shows that the sensitivity of the modified ZsGreen-LUC-expressing E0771 cells to the compounds remains unchanged.
  • FIG. 14 shows that R406 can promote TRAIL-induced apoptosis in LLC cells.
  • Figure 16 shows the bioluminescence imaging changes of ZsGreen-LUC-expressing E0771 in C57BL/6 mice.
  • Figure 17 shows that R788 combined with TRAIL significantly inhibited tumor growth in the ZsGreen-LUC-expressing E0771 breast cancer model in C57BL/6 mice.
  • Figure 18 shows the immunohistochemical staining of Cleaved Caspase-3 in ZsGreen-LUC-expressing E0771 tumor tissue sections.
  • Figure 20 shows immunohistochemical staining of CD31 in ZsGreen-LUC-expressing E0771 tumor tissue sections.
  • FIG. 21 shows in vitro visualization images of LLC tumor tissues in C57BL/6 mice.
  • FIG. 22 shows the effects of R788 combined with TRAIL on tumor volume and tumor weight in LLC tumor-bearing mice.
  • Figure 23 shows the effects of R788 combined with TRAIL on HE staining of tumor tissue sections, immunohistochemistry of Ki-67, Cleaved caspase-3, and CD31 in LLC tumor-bearing mice.
  • FIG. 24 shows the effects of R788 combined with TRAIL on PARP1 cleavage and RIPK1 activation in tumor tissues of LLC tumor-bearing mice.
  • the inventors unexpectedly discovered that the small molecule R406 and its phosphate R788 can promote TRAIL-induced tumor cell death through large-scale screening of a known active compound library.
  • R406 and its phosphate R788 can promote TRAIL-induced tumor cell death through large-scale screening of a known active compound library.
  • R788 has been approved by the FDA for the treatment of idiopathic thrombocytopenic purpura, indicating that it has good safety and tolerability in the human body. On this basis, the present invention was completed.
  • halogen refers to F, Cl, Br or I.
  • C 1-6 alkyl refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, such as methyl,
  • C 1-4 alkyl and C 1-3 alkyl have similar meanings.
  • C2-6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl, etc.
  • C2-4 alkenyl has a similar meaning.
  • C 2-6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl, etc.
  • C 2-4 alkynyl has a similar meaning.
  • C 3-8 cycloalkyl refers to a cyclic alkyl group having 3-8 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
  • C 3-6 cycloalkyl has a similar meaning.
  • C 1-6 alkoxy refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is a C 1-4 alkoxy group, and more preferably, it is a C 1-3 alkoxy group.
  • heterocyclyl or “heterocycloalkyl” refers to a 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O, S, including (but not limited to) the following groups:
  • aromatic ring or "aryl group” has the same meaning, preferably “C 6-10 aryl group”.
  • C 6-10 aryl group refers to an aromatic ring group having 6 to 10 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc.
  • aromatic heterocycle or “heteroaryl” has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms.
  • C 3-10 heteroaryl refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen and 3 to 10 carbon atoms.
  • Non-limiting examples include: furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.
  • the heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • halo means substituted with halogen
  • deuterated means substituted with deuterium.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituent is the substituent described above or the substituent appearing in the embodiments.
  • a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those that are stable or chemically feasible.
  • the substituents include, for example (but not limited to): halogen, hydroxyl, carboxyl (-COOH), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 8 cycloalkyl, 3 to 12 membered heterocyclic group, aryl, heteroaryl , C 1-8 aldehyde group, C 2-10 acyl group, C 2-10 ester group, amino group, C 1-6 alkoxy group, C 1-10 sulfonyl group and the like.
  • the term 1-6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms independently have similar meanings.
  • the term “plurality” refers to 2-6, such as 2, 3, 4, 5 or 6.
  • the present invention provides a compound that can be used in combination with TRAIL to enhance its inhibitory effect on tumor cells, and a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • the compound structure is shown in formula (I):
  • the term "pharmaceutically acceptable salt” refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts is a salt formed by a compound of the present invention and an acid.
  • Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid
  • Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.
  • an alkali metal salt e.g., sodium salt or potassium salt
  • an alkaline earth metal salt e.g., magnesium salt or calcium salt
  • an ammonium salt e.g.
  • the present invention's various embodiments specifically describe the preparation methods of the compounds of formula I of the present invention, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • the raw materials and reagents used in the preparation process of the compounds of the present invention can be obtained from commercial Purchase through business channels.
  • compositions and methods of administration are provided.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compounds.
  • the compounds of the present invention have excellent anti-tumor activity
  • the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.
  • the pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.
  • safe and effective amount means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • the pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.
  • compositions of the present invention include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings and other materials known in the art. They may contain opacifying agents and the active compound or active ingredients in such compositions may be present in the form of a granule. The release of the compound can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottons
  • composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).
  • the treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.
  • the present invention found that compounds that activate TAK1 kinase activity can promote TRAIL-induced tumor cell apoptosis and necrosis.
  • the TAK1 kinase activator and TRAIL combination composition of the present invention can significantly inhibit the growth of tumor cells.
  • 6-Bromo-2-nitropyridine-3-ol (1.5 g, 6.85 mmol), potassium hydroxide (1.5 g, 27 mmol) and DMSO (20 mL) were added to a round-bottom flask. The reaction was pre-stirred for 5 min at room temperature, and iodomethane (850 ⁇ L, 13.7 mmol) was added and stirred for 30 min. After the reaction was complete, the mixture was diluted with water and extracted with DCM. The organic phase was washed with potassium hydroxide aqueous solution and saturated brine in turn, concentrated, and purified by silica gel column chromatography. Elution with PE/EA (2:1) gave the target compound with a yield of 63%. MS-ESI: m/z calculated for C 6 H 5 BrN 2 O 3 , Exact Mass 231.95, found 233.0[M+H] + .
  • reaction solution is diluted with water, extracted with DCM, and the organic phase is washed with water and saturated brine in turn, concentrated, and purified by silica gel column chromatography, eluted with PE/EA (2:1) to obtain a crude product of 2,4-dimethoxybenzylamine substituted bromine. Dissolve the crude product in DCM (1 mL), add 200 ⁇ L trifluoroacetic acid, and stir overnight at room temperature. After the reaction was complete, the reaction solution was concentrated and purified by silica gel column chromatography, eluted with DCM/MeOH (2M NH 3 ) (4:1), to obtain 50 mg of solid with a yield of 70%. MS-ESI: m/z calculated for C 8 H 13 N 3 O, Exact Mass 167.11, found 168.2 [M+H] + .
  • R406 and its phosphate R788 were purchased from Selleck, dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mM storage solution and stored at -20°C.
  • DMEM medium and fetal bovine serum were purchased from Gibco (Life Technologies, Grand Island, NY, USA).
  • the antibodies used are as follows: p-S321 RIPK1, RIPK1, p-TAK1, TAK1, p-IKK ⁇ / ⁇ , IKK ⁇ , FADD, His were all purchased from Cell signaling technology, ⁇ -actin was purchased from TransGen Biotech, GST was purchased from Santa Cruz, and mouse anti-Tubulin was purchased from Sigma-Aldrich.
  • Transfer Semi-dry transfer, transfer current is 0.2-0.4V, adjust the time according to the size of the protein.
  • Blocking Block with TBST containing 5% skim milk at room temperature on a decolorizing shaker for 1 hour.
  • Binding to primary antibody dilute the antibody at 1:2000-1:10000 in TBST containing 5% BSA, place on a decolorizing shaker at room temperature for 1 hour, and incubate at 4°C overnight. Wash three times with TBST, 10 minutes each time.
  • Binding secondary antibody dilute the antibody in TBST containing 5% BSA at 1:5000-1:10000, place on a decolorizing shaker at room temperature for 1 hour, and wash three times with TBST, 10 minutes each time.
  • Cells in the logarithmic growth phase were inoculated in a 384-well culture plate at an appropriate density, with 40 ⁇ L per well. After overnight culture, different concentrations of drugs were added for different time points, with triplicate wells for each concentration. After the end of the treatment, 15 ⁇ L/well of ATP was added to each well for 15 minutes, and the chemiluminescence value was detected with an enzyme-labeled instrument.
  • PTSM Protein Thermal Shift Microsoft
  • the photoaffinity probe and its control compound were incubated with the protein for 2 h, the concentration of the compound was 10 ⁇ M, the concentration of the protein was 2 mg/ml, and a total of 300 ⁇ l of the system solution;
  • the samples are sent to the mass spectrometry platform for analysis.
  • insect cells are used to express the recombinant protein of TAK1 kinase domain. Since TAK1 has kinase activity only after fusion with TAB1, the insect cell expression system is used to express TAK1-TAB1, as shown in Figure 2, and used to study the binding effect of R406, R788 and TAK1-TAB1.
  • the thermal stability of proteins can be used to study the stability changes of proteins and small molecules or other proteins. When small molecules bind to proteins, they can stabilize the globular structure of proteins and change the Tm value of proteins in thermal stability experiments, so the change of Tm can reflect the binding situation with proteins.
  • R406 and R788 were incubated with hTAK1-TAB1 protein for 60 minutes respectively, and then the thermal stability experiment was started. The results are shown in Figure 3. From the Tm value and thermal stability fluorescence change spectrum of TAK1, it can be seen that R406 and R788 can increase the Tm value of the thermal stability of the hTAK1-TAB1 reaction by 4-6°C, which has a significant effect on thermal stability, indicating that R406 can directly bind to TAK1.
  • Plasmids of Flag-RIPK1 and Flag-IKK ⁇ K44A were overexpressed in HEK293T cells, respectively. To minimize the background of RIPK1 autophosphorylation, 10 ⁇ M Nec-1s was added during overexpression. After 24 h, RIPK1 and IKK ⁇ were immunoprecipitated with Flag beads, respectively. Then, in vitro kinase reactions were performed with recombinant His-tagged TAK1-TAB1 proteins. At the same time, 20 ⁇ M R406 and 1 ⁇ M 5Z7 were added, respectively. After reacting at 30°C for 60 min, the samples were boiled for Western detection, as shown in Figure 4.
  • T-5-27 was a photo-crosslinking probe derived from S-8-56.
  • the cells were treated with small molecules, or the small molecules and proteins were co-incubated, as shown in Figure 6. After photo-crosslinking and click chemistry reactions, the biotin-avidin system could be used to co-precipitate the biotin-labeled target protein and detect the target protein.
  • the diaziridine group of T-5-27 can undergo a photochemical reaction under ultraviolet light of a certain wavelength, so that this part of the group can be covalently cross-linked to the vicinity of the target protein binding site, and the alkynyl group on the left can undergo a click reaction with the azide group of the biotin probe to enrich the protein labeled with the photocross-linking probe.
  • the enriched protein can be subjected to mass spectrometry analysis after trypsin digestion, attempting to find the approximate binding site of T-5-27 on TAK1 by increasing the molecular weight peptide information shown in the figure.
  • the photosensitive affinity probe T-5-27 can indeed enrich and separate TAK1 from cell lysate, while S-8-56, a derivative of the light-stable control small molecule R406 of T-5-27, cannot co-precipitate TAK1.
  • S-8-56 a derivative of the light-stable control small molecule R406 of T-5-27
  • the cross-linking effect of the probe will be weakened, which proves the effectiveness of the photo-cross-linking probe.
  • the probe and TAK1 protein were photocrosslinked in vitro.
  • the probe was linked to Biotin through click chemistry reaction, and then the TAK1 protein crosslinked with the probe was precipitated with streptavidin agarose beads. Then, the TAK1 protein was digested with trypsin.
  • the peptides with probes and biotin were washed and analyzed by protein spectrum in order to identify the interaction sites between R406 or its derivatives and TAK1. As shown in Figure 7, if the peptide is connected to the probe and biotin, the peptide will increase the mass migration of 1000.4865Da.
  • the amino acids in the peptide that are connected to the probe and biotin can be identified by the secondary mass spectrometry spectrum.
  • R406 and its phosphate R788 were purchased from Selleck, dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mM storage solution and stored at -20°C.
  • Recombinant human TRAIL protein was purchased from R&D.
  • DMEM, RMI1640, McCoy’s 5A medium and fetal bovine serum were purchased from Gibco (Life Technologies, Grand Island, NY, USA).
  • the antibodies used in the study are as follows: rabbit anti-PARP, p-S166 RIPK1, RIPK1, p-S227 RIPK3, RIPK3, p-S358 MLKL, Cleaved caspase-3, caspase 3, TAK1, p-IKK ⁇ / ⁇ , IKK ⁇ / ⁇ , FADD were all purchased from Cell signaling technology, and mouse anti-Tubulin was purchased from Sigma-Aldrich.
  • the above cell lines were all cultured in a cell culture incubator at 37°C containing .5% CO 2 , and the experiments were performed when the cells were in the logarithmic growth phase.
  • the number of SYTOX Green positive cells is the number of dead cells, and the ratio is the final result.
  • R406 and R788 can significantly promote cell necrosis induced by TNF ⁇ , and this promotion can be protected by Nec-1s.
  • R406 and R788 significantly enhance the phosphorylation of RIPK1 and MLKL, and this phosphorylation can be protected by Nec-1s. This shows that R406 can promote TNF ⁇ -induced RIPK1-dependent programmed necrosis.
  • Human colon cancer cells HT-29 and human lung adenocarcinoma cells NCI-H1975 were pretreated with R406 (3 ⁇ M) and Nec-1s (10 ⁇ M) for 30 minutes, and then TNF ⁇ (20 ng/ml) and caspase inhibitor zVAD.fmk (20 ⁇ M) were added to induce cell necrosis.
  • the SYTOX Green level of the cells was measured every 7 h to evaluate the cell death.
  • R406 can significantly promote cell necrosis induced by TNF ⁇ /zVAD.fmk, and this promotion can be protected by Nec-1s.
  • R406 significantly enhances the phosphorylation of RIPK1 and MLKL, and this phosphorylation can be protected by Nec-1s. This indicates that R406 can promote TNF ⁇ -induced RIPK1-dependent programmed necrosis.
  • human lung cancer cells NCI-H1299 were pretreated with R406 (3 ⁇ M) and Nec-1s (10 ⁇ M) for 30 minutes, and then TNF ⁇ (20 ng/ml) was added. Similarly, the cell SYTOX Green level was measured every 7 h to evaluate cell death.
  • R406 can significantly promote cell death induced by TNF ⁇ , and this promotion can be protected by Nec-1s.
  • R406 significantly enhances the phosphorylation of RIPK1 and the cleavage of PARP1, and this phosphorylation and cleavage can be protected by Nec-1s. This shows that R406 can promote TNF ⁇ -induced RIPK1-dependent cell apoptosis.
  • E0771 cells were treated with different concentrations of TRAIL to induce apoptosis, and 1 ⁇ M, 3 ⁇ M and 5 ⁇ M R406 were used, respectively.
  • the cellular ATP level was detected after 24 h, and the cell survival rate was evaluated by CellTiter-Glo assay.
  • the experimental results showed that the cells with the strongest luciferase activity of the modified ZsGreen-LUC-expressing E0771 were not sensitive to the compound compared to the E0771-BLANK cells.
  • the compound alone or TRAIL alone could promote 20%-30% cell death (12h).
  • the compound and TRAIL were used in combination, they could promote 70%-80% cell death (12h) in both cells. This promotion effect was significantly different.
  • the cell death promoted by compound R788 under TRAIL-induced conditions could be inhibited by Nec-1s, but the cell death promoted by TRAIL itself could not be inhibited by Nec-1s.
  • LLC LLC cells were treated with different concentrations of TRAIL to induce apoptosis, and 1 ⁇ M, 3 ⁇ M and 5 ⁇ M R406 were used, respectively.
  • the cellular ATP level was detected after 24 h, and the cell survival rate was evaluated by CellTiter-Glo assay.
  • R406 can promote TRAIL-induced PARP1 cleavage and RIPK1-S166 phosphorylation, thereby promoting RIPK1 activation.
  • R406/R788 can promote TRAIL-induced apoptosis in E0771 and LLC cells.
  • mTRAIL Purified endotoxin-free mTRAIL was prepared in endotoxin-free PBS at a concentration of 10 mg/kg.
  • the superposition of the bright field and dark field background images can intuitively display the location and intensity of specific photons in the animal body, completing the imaging operation.
  • the tumor tissue was embedded in paraffin, sliced into 4 ⁇ m thick sections, spread in 42°C water and placed in a 37°C oven. The dried tissue sections were dewaxed the next day using xylene for 5-10 minutes.
  • the resuspended LLC cells were subcutaneously injected into the armpit of male mice, with the cell concentration ranging from 1.0*10 6 to 1.5*10 6 ;
  • mice When the tumors of the mice were visible to the naked eye (the tumor volume was about 60 mm3 ), the mice were divided into groups, and the mice that were not successfully vaccinated were eliminated. The successfully vaccinated mice were evenly divided into 4 groups, namely the control group, the R788 group, the TRAIL group, and the TRAIL+R788 group;
  • mice were gavaged with R788 (200 ⁇ l R788 dissolved in CMC-Na solution) every day according to the treatment group, and mTRAIL was injected intraperitoneally once a day;
  • mice were injected orthotopically with D-Luciferin (150 mg/kg), and the changes in light intensity were detected by a small animal in vivo imaging device to monitor the drug effect;
  • ZsGreen-LUC-expressing E0771 tumors were inoculated for 16 days and drug treatment lasted for 11 days.
  • the constructed ZsGreen-LUC-expressing E0771 tumor cells were implanted into C57BL/6 female mice. On the 11th and 15th days, the mice were injected with D-Luciferin (150 mg/kg) in situ. The light intensity changes were detected by small animal in vivo imaging to monitor the effect of the drug.
  • the tumor size of the mouse tumors in the R788 alone treatment group and the TRAIL alone treatment group were reduced compared to the control group.
  • the mouse tumors were not only significantly reduced compared to the control group, but also significantly reduced compared to the mouse tumors in the R788 alone and TRAIL alone groups.
  • the growth curve and tumor size of the tumor were statistically analyzed, as shown in Figure 16.
  • a total of 32 6-8 week old C57BL/6 female mice successfully inoculated with ZsGreen-LUC-expressing E0771 tumor cells were used for the experiment. Eight mice were used in each experiment, and there were 4 experimental groups in total. Starting from the first day of the treatment, the volume of the mouse tumor and the weight of the mouse were recorded every day. After 11 days of treatment, the tumor of the mouse was weighed in vitro, and the statistical results were compared and analyzed.
  • the growth rate of tumors in the two groups of mice treated with R788 alone and TRAIL alone was slowed down.
  • the tumor volume was about 1500mm3
  • the tumor volume of the control group was about 2300mm3 .
  • the tumor volume of the group of mice treated with R788 and TRAIL combined was significantly slowed down compared with the control group and the groups treated with R788 and TRAIL alone.
  • the tumor volume of the mice treated with the combination drug was about 700mm3 .
  • the cleavage of Caspase-3 represents the occurrence of cell apoptosis.
  • the immunohistochemical staining area of cleaved Caspase-3 in the mouse ZsGreen-LUC-expressing E0771 tumor tissue sections was the largest, indicating that cell apoptosis was most obvious at this time.
  • R788 has an anti-tumor effect by promoting TRAIL-induced cell apoptosis, thereby slowing down the growth rate of tumors.
  • Ki-67 is a marker of cell proliferation. The darker the Ki-67, the more vigorous the cell proliferation. As shown in Figure 19, Vehicle has the darkest color and the ZsGreen-LUC-expressing E0771 tumor cells proliferate the most vigorously. Compared with the control group, Ki-67 was weaker in TRAIL alone and R788 alone, and the tumor cell proliferation ability decreased. The contrast was more obvious in the TRAIL+R788 group. Compared with the control group, Ki-67 showed a significant change and became significantly weaker, and the tumor cell proliferation ability was the worst.
  • CD31 is a marker for endothelial cells.
  • Vehicle had the darkest immunohistochemical staining and the fastest endothelial cell proliferation rate, while CD31 was weaker in R788 alone and TRAIL alone compared to the control group, and the endothelial cell proliferation ability decreased. The contrast was more obvious in the TRAIL+R788 group. Compared with the control group, CD31 had a significant change and became significantly weaker. The endothelial cell proliferation ability was the worst, the blood vessels were the least, the nutrition supplied to the tumor cells was the poorest, and the tumor cells grew the slowest.
  • mice were used in a group of experiments, with a total of 4 experimental groups. Starting from the first day of the drug treatment, the volume of the mouse tumor and the weight of the mouse were recorded every day. After 14 days of drug treatment, the tumor of the mouse was weighed in vitro, and the statistical results were compared and analyzed.
  • the tumor tissue sections of mice treated with R788 alone showed little damage and necrosis compared with the control group. Some areas of damage and necrosis were clearly found in the tissue sections of mice after intraperitoneal injection of TRAIL, but the area of cell death was small. After the combination of R788 and TRAIL, the areas of tissue damage and cell necrosis were significantly enlarged, accompanied by large areas of bleeding spots. It is speculated that R788 can promote TRAIL-induced cell death in LLC tumor tissues of mice.
  • 1/2/3 represent the numbers of mice treated with drugs in each group. There are 6 mice in each group, and tumor tissue samples of 3 mice were randomly selected for Western Blot detection. The results showed that neither R788 alone nor the control group could activate RIPK1 and caspase; while the phosphorylation of RIPK1-S166 site in tumor tissue of mice injected intraperitoneally with TRAIL alone was slightly activated, and caspase-3 and PARP1 cleavage occurred at the same time; however, when R788 and TRAIL were used in combination, the phosphorylation of RIPK1-S166 site was significantly enhanced, and the cleavage of caspase-3 and PARP1 was also more obvious.
  • R788 can be well absorbed in vivo and can promote TRAIL-induced activation of RIPK1 and caspase in LLC and E0771 tumor tissues.

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Abstract

L'invention concerne une série de composés ayant la formule générale telle que représentée dans la formule (I), des sels, hydrates ou solvates pharmaceutiquement acceptables de ceux-ci, et une utilisation des composés en combinaison avec TRAIL dans le traitement de tumeurs ou l'inhibition de cellules tumorales. La composition pharmaceutique est utilisée pour résister à des tumeurs, présente les caractéristiques d'une bonne sécurité, d'une forte tolérance, d'une sensibilité élevée, etc., et est appropriée pour le développement de médicaments antitumoraux.
PCT/CN2024/108957 2023-07-31 2024-07-31 Utilisation antitumorale de r406 et d'un dérivé de celle-ci en synergie avec trail Pending WO2025026368A1 (fr)

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