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WO2025261479A1 - Conjugué utilisant du succinyle en tant que lieur, son procédé de préparation et son utilisation - Google Patents

Conjugué utilisant du succinyle en tant que lieur, son procédé de préparation et son utilisation

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Publication number
WO2025261479A1
WO2025261479A1 PCT/CN2025/102323 CN2025102323W WO2025261479A1 WO 2025261479 A1 WO2025261479 A1 WO 2025261479A1 CN 2025102323 W CN2025102323 W CN 2025102323W WO 2025261479 A1 WO2025261479 A1 WO 2025261479A1
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Prior art keywords
alkyl
succinyl
independently
formula
aryl
Prior art date
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Pending
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PCT/CN2025/102323
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English (en)
Chinese (zh)
Inventor
胡有洪
陈奕
刘佳
蒋婧升
丁健
方艳芬
张卓
沈雁雁
龙国璋
沈倩倩
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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Publication of WO2025261479A1 publication Critical patent/WO2025261479A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Definitions

  • This invention relates to conjugates, using succinyl groups as the linking chain, that link tissue-targeting recognition ligands with active substances/labeled substances related to disease treatment, diagnosis, and/or prevention, as well as their preparation methods and uses.
  • this invention relates to a class of conjugates, using succinyl groups as the linking chain, that link a ligand targeting a liver-targeting desialyl glycoprotein receptor with an active substance/labeled substance for disease treatment, as well as their preparation methods and uses.
  • Peptide-containing drug conjugates are widely used and researched in disease treatment and diagnosis. These conjugates target specific tissues, releasing the active substance or marker at the site of disease. However, various esterases in plasma can rapidly hydrolyze these conjugates, causing the active substance to be released before reaching the target tissue. This results in non-tissue specificity of the active substance or marker molecule, and the associated toxic side effects limit their use. For example, carboxylesterase 1c (Ces1c), highly expressed in plasma, can hydrolyze peptide chains, leading to premature release of the active substance.
  • Ces1c carboxylesterase 1c
  • ASGPRs desialized glycoprotein receptors
  • Gal ⁇ -D-galactose
  • GalNAc N-acetylgalactosamine residues
  • this invention uses a succinyl group as a linker to connect different ligands targeting specific tissues with a release active substance containing a peptide chain that has therapeutic, diagnostic, and/or preventative effects against diseases.
  • a succinyl group as a linker to connect different ligands targeting specific tissues with a release active substance containing a peptide chain that has therapeutic, diagnostic, and/or preventative effects against diseases.
  • conjugates with this type of linker chain improves the stability of the conjugate in human and mouse plasma and significantly enhances the distribution of the active substance in target tissues.
  • conjugates containing this linker chain significantly improve in vivo activity and reduce toxic side effects, making them suitable for the treatment, diagnosis, and/or prevention of targeted diseases.
  • the first object of the present invention is to provide conjugates of Formula I, which use succinyl groups as linking chains to connect tissue-targeting recognition ligands and ligands related to disease treatment, diagnosis and/or prevention, or pharmaceutically acceptable salts or solvates thereof; in particular, the present invention provides a class of conjugates using succinyl groups as linking chains to connect ligands of liver-targeting desialyl glycoprotein receptors with bioactive substances or markers.
  • a second object of the present invention is to provide the use of the conjugate of Formula I, which is linked by a succinyl group as a linking chain, in a pharmaceutical.
  • the present invention adopts the following technical solution:
  • the present invention provides a conjugate of Formula I with a succinyl group as the linking chain, or a pharmaceutically acceptable salt or solvate thereof.
  • A is a ligand containing a connecting chain that specifically targets and recognizes tissues
  • B is an active ligand containing a peptide chain that has therapeutic and/or diagnostic effects on diseases
  • X1 is S or NR; wherein R is selected from H, C1 - C20 alkyl, C2 - C20 alkenyl, C2 - C20 alkynyl, C6 - C20 aryl, C6 -C20 arylC1- C10 alkyl, 5-20 - membered heteroaryl containing one or more (e.g., 2, 3, 4) heteroatoms selected from N, O, and S, and 5-20-membered heteroarylC1 -C10 alkyl ; preferably, X1 is S;
  • X2 is O, S, or NR; wherein R is selected from H, C1 - C20 alkyl, C2 - C20 alkenyl, C2 - C20 alkynyl, C6 - C20 aryl, C6 -C20 arylC1 -C10 alkyl , 5-20 - membered heteroaryl containing one or more (e.g., 2, 3, 4) heteroatoms selected from N, O, and S, and 5-20-membered heteroarylC1- C10 alkyl; preferably, R is H, C1 - C4 alkyl, C6 - C20 aryl, or C6 - C12 arylC1 -C4 alkyl ; preferably, X2 is O, NH, or NCH3 ;
  • P is selected from H, C1 - C20 alkyl, C2 - C20 alkenyl, C2 - C20 alkynyl, C6- C20 aryl, C6 - C20 arylC1- C10 alkyl, 5-20 -membered heteroaryl, or 5-20-membered heteroarylC1- C10 alkyl containing one or more (e.g., 2, 3, or 4) heteroatoms selected from N, O, and S; preferably, P is selected from H, C1 - C4 alkyl, C6 - C20 aryl, or C6 - C12 arylC1 -C4 alkyl ; more preferably, P is H, -CH3S , -CH2CH3S , or -benzyl ;
  • L1 is selected from -( CH2 ) k1 - Z1- ( CH2 ) k2- , -( CH2 ) k3- (O- CH2 -CH2-O)k4-( CH2 ) k5- , -( CH2 ) k6 -NH-C( O )-(CH2) k7 -Z1-(CH2) k8 - C ( O )NH-( CH2 ) k9- , and -(CH2) k10 -NH-C( O )-( CH2 ) k11-( O-CH2-CH2- O ) k12 -C(O)NH-( CH2 ) k13- , wherein k1 to k13 are each independently an integer from 0 to 10 (e.g., 0 , 1 , 2 , 3, 4, 5, 6, 7, 8, 9, 10, etc.); Z1 is independently NH, O, or S; preferably, L 1 is -(CH 2 )
  • the conjugate with succinyl group as the linking chain shown in Formula I has the structure shown in Formula II.
  • X1 is S or NH; preferably, X1 is S;
  • X2 is O, S, or NR; wherein R is H, C1 - C4 alkyl, C6 - C20 aryl, C6 - C12 aryl, or C1 - C4 alkyl; preferably, X2 is O, NH, or NCH3 ;
  • P is selected from H, C1 - C20 alkyl, C2 - C20 alkenyl, C2- C20 ynyl, C6 - C20 aryl, C6 - C20 arylC1- C10 alkyl, 5-20 -membered heteroaryl, or 5-20-membered heteroarylC1- C10 alkyl containing one or more (e.g., 2, 3, 4) heteroatoms selected from N, O, and S; preferably selected from H, C1 - C4 alkyl, C6 - C20 aryl, or C6 - C12 arylC1 -C4 alkyl ; preferably, P is H, -CH3 , -CH2CH3 , or -benzyl .
  • L1 is selected from -( CH2 ) k1 - Z1- ( CH2 ) k2- , -( CH2 ) k3- (O- CH2 -CH2-O)k4-( CH2 ) k5- , -( CH2 ) k6 -NH-C( O )-(CH2) k7 -Z1-(CH2) k8 - C ( O )NH-(CH2) k9- , and -( CH2 )k10-NH-C(O)-( CH2 ) k11- (O- CH2 -CH2-O) k12 -C(O)NH-( CH2 ) k13- , wherein k1 to k13 are each independently an integer from 0 to 10 (e.g., 0, 1 , 2 , 3, 4, 5, 6, 7, 8, 9, 10, etc.); Z1 is independently NH, O, or S; preferably, L 1 is -(CH 2 ) k1 ,
  • G1 , G2 , and G3 are each independently an N-acetylgalactosamine group or its analogues, which can bind to the ASGPR receptor highly expressed in hepatocytes or liver cancer cells;
  • L2 , L3 , and L4 are each independently selected from -( CH2 ) n1- (O- CH2 - CH2 ) n2- (CH2)n3-, -( CH2 ) n4- (O-CH2 -CH2 ) n5 - NH- C (O) - ( CH2 ) n6- , where n1 to n6 are each independently an integer from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.); preferably, L1 , L2 , and L3 are each independently -( CH2 ) n1 , where n1 is an integer from 1 to 10, particularly selected from -( CH2 ) 6- and -( CH2 ) 4- ;
  • Y1 , Y2 , and Y3 are each independently selected from -Z2- ( CH2 ) m1- and -NHC(O)-( CH2 ) m2 - Z2- ( CH2 ) m3- , wherein m1 to m3 are each independently an integer from 0 to 10 (e.g., 1, 2, 3, etc.), and Z2 is independently NH or O; preferably, Y1 , Y2 , and Y3 are each independently selected from -O- CH2- and -NH-C(O)-( CH2 ) 2 -O- CH2- ;
  • L5 is selected from -( CH2 ) j1 -Z3 -( CH2 ) j2 -, -( CH2 ) j3 -(O- CH2 - CH2 -O) j4 -( CH2 ) j5 -, -( CH2 ) j6 -NH-C(O)-(CH2)j7 -, -( CH2 ) j8 -NH-C(O)-( CH2 ) j9 -Z3 -( CH2 ) j10 -C (O)NH-( CH2 ) j11 -, and -(CH2) j12 -NH-C( O )-( CH2 )j13 - (O -CH2-CH2-O) j14 -C( O )NH-( CH2 ) j15 -, where j1 to j15 are each independently an integer from 0 to 10 (e.g., 1 , 2, 3, 4 , 5,
  • L6 is -( CH2 ) q1 -C(O)-, where q1 is an integer from 0 to 10 (e.g., 1, 2, 3, 4, 5); preferably, L6 is -( CH2 ) 5 -C(O)-.
  • Q represents a peptide fragment that can be hydrolyzed and cleaved in target tissues of the liver to release T;
  • T refers to a small molecule, nucleic acid, polypeptide, or protein that is bioactive or labeled for the treatment, diagnosis, and/or prevention of diseases.
  • G1 , G2 , and G3 are all N-acetylgalactosamine groups.
  • L2 , L3 , and L4 are each independently selected from -( CH2 ) 6- and -( CH2 ) 4- .
  • Y1 , Y2 and Y3 are each independently selected from -O- CH2- and -NH-C(O)-( CH2 ) 2 -O- CH2- .
  • X1 in Equation II is S.
  • X2 in Formula II is -O, -NH, or -NCH3 .
  • P is -H, -CH3 , -CH2CH3 , or -benzyl .
  • Q represents a dipeptide or polypeptide fragment structure that can be cleaved by cathepsins in lysosomes; preferably, Q is a group of valine-citrulline-p-aminobenzylcarbamate (PAB) as shown in the following formula:
  • T represents a small molecule compound for treating liver diseases, such as a cytotoxin, a chemotherapeutic agent (including inhibitors or agonists targeting related disease therapeutic targets), an immunomodulator, etc.; and a labeling molecule for treating liver diseases, such as a radiolabeled, fluorescently labeled, diagnostic agent, or detectable modified enzyme that is a catalytic substrate.
  • a cytotoxin is methylaurestatin E (MMAE) or a derivative thereof.
  • MMAE methylaurestatin E
  • T is The wavy line indicates the junction of toxin molecules via amide bonds.
  • the compound represented by Formula I or Formula II may be selected from the following compounds II-1 to II-4:
  • the present invention provides a method for preparing the conjugate of Formula I with succinyl as the linking chain, the reaction route of which is as follows:
  • A, B, L1 , X1 , X2 and P are defined as before, and when X2 is 0, P is not simultaneously H;
  • step (1) is carried out under solvent conditions, wherein the solvent is an organic solvent, such as methanol; the base includes inorganic bases and organic bases, preferably selected from one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.; the reaction temperature is 0 degrees to room temperature; the reaction time is 0.5-24 hours.
  • solvent is an organic solvent, such as methanol
  • the base includes inorganic bases and organic bases, preferably selected from one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • the reaction temperature is 0 degrees to room temperature
  • the reaction time is 0.5-24 hours.
  • the condensing agent used in the condensation reaction is selected from one or more of benzotriazole-N,N,N′,N′-tetramethylurea hexafluorophosphate (HBTU), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 1-hydroxybenzotriazole (HOBt), 1,8-diazabicycloundec-7-ene (DBU), N,N-diisopropylethylamine, triethylamine, and pyridine.
  • HBTU benzotriazole-N,N,N′,N′-tetramethylurea hexafluorophosphate
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDCI 1-(3-dimethylamino
  • the condensing agent used is a combination of benzotriazole-N,N,N′,N′-tetramethylurea hexafluorophosphate (HBTU) and N,N-diisopropylethylamine.
  • HBTU benzotriazole-N,N,N′,N′-tetramethylurea hexafluorophosphate
  • step (2) is carried out under solvent conditions, wherein the solvent is an organic solvent, such as dichloromethane or dimethylformamide; the reaction temperature is 0°C to 60°C; and the reaction time is 0.5 to 24 hours.
  • solvent is an organic solvent, such as dichloromethane or dimethylformamide
  • the reaction temperature is 0°C to 60°C
  • the reaction time is 0.5 to 24 hours.
  • compound III can be obtained by conventional methods in the art, or similarly by methods described in Chinese patent application No. 202310079838.3.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the succinyl-linked conjugate or a pharmaceutically acceptable salt or solvate thereof as described in the first aspect, and optionally a pharmaceutically acceptable excipient.
  • the present invention also provides the use of the conjugate of the first aspect with succinyl as the linking chain or a pharmaceutically acceptable salt or solvate thereof, and the use of the pharmaceutical composition of the third aspect in the preparation of a medicament for treating liver diseases.
  • the liver disease is liver cancer.
  • alkyl refers to a fully saturated straight-chain or branched monovalent hydrocarbon group. Alkyl groups preferably contain 1-20 carbon atoms, more preferably 1-16 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms, or 1-3 carbon atoms. The number preceding the alkyl group indicates the number of carbon atoms. For example, “ C1 - C6 alkyl” indicates an alkyl group having 1-6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc.
  • alkenyl refers to a straight-chain or branched monovalent hydrocarbon group containing at least one double bond. Alkenyl groups preferably contain 2-20 carbon atoms, more preferably 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Representative examples of alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, heptenyl, octenyl, etc.
  • alkynyl refers to a straight-chain or branched monovalent hydrocarbon group containing at least one triple bond.
  • the alkynyl group preferably contains 2-20 carbon atoms, more preferably 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms.
  • Representative examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentyynyl, isopentenynyl, hexynyl, heptyynyl, and octyynyl.
  • aryl refers to an aryl group consisting of 6-20, preferably 6-14, more preferably 6-12, and most preferably 6-10 rings formed by the fusion of one or more rings.
  • An aryl group having 6-10 ring carbon atoms includes: a monocyclic aryl group (e.g., phenyl); or a fused bicyclic system, wherein one ring is an aromatic ring and the other ring is an aromatic ring (e.g., in naphthalene, biphenyl) or a non-aromatic ring (e.g., in dihydroindene, tetrahydronaphthalene).
  • Non-limiting examples of aryl groups include phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indene, dihydroindene, or anthracene, etc.
  • heteroaryl refers to a 5-20 membered, preferably 5-10 membered, more preferably 5-7 membered or 5-6 membered aromatic ring system containing 1-4, preferably 1-3, cyclic heteroatoms selected from N, O or S, including monocyclic, bicyclic or fused polycyclic rings, with the remaining ring atoms being carbon atoms.
  • heteroaryl groups include, but are not limited to: pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, oxazinyl, oxadiazinyl, quinolinyl, isoquinolinyl, borazinyl, quinazolinyl, quinoxalinyl, benzoxazinyl, 2H-chromene, benzopyranyl, benzothiophene, indole, inzolyl, benzene Pyrazole, benzimidazolyl, imidazopyridyl, benzoxazolyl, benzothiazolyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl,
  • the conjugate of the present invention using succinyl as the linking chain significantly improves plasma stability and enhances the liver tissue targeting of the released active or labeled substances, making it more suitable for the treatment and diagnosis of liver diseases.
  • Figure 1 shows the hydrolysis efficiency of compounds II-0 to II-4 under the action of cathepsin B.
  • Figure 2 shows the tissue distribution of MMAE (bottom) and MMAE released by hydrolysis of compounds II-0 (middle) and II-1 (top) in a mouse orthotopic liver cancer model.
  • Figure 3 shows the inhibitory effects of MMAE and compound II-1 on the growth of human hepatocellular carcinoma PLC/PRF/5-Luciferase in nude mice.
  • Figure A shows the luminescence intensity of mouse liver tumors under different doses of II-1
  • Figure B shows the changes in mouse body weight under different doses of II-1
  • Figure C shows the imaging photographs taken by a small animal in vivo imaging system on days 0, 7, 14, 21, and 28 of the dosing cycle.
  • Compound II-0 can be synthesized according to the method of II-3 in Example II-3 of Chinese Patent Application No. 202310079838.3, the relevant content of which is incorporated herein by reference.
  • Pharmacological test example 1 Stability test of compounds II-0 to II-4 in human and mouse plasma
  • the specific steps are as follows: The experiment was conducted in 96-well plates, with a final incubation volume of 320 ⁇ L per well. Each well contained 156 ⁇ L of plasma, 8 ⁇ L (40 ⁇ M) of the test compound, and 156 ⁇ L of PBS (pH 7.4). 50 ⁇ L of culture medium was collected at 0, 0.5, 1, 2, and 5 h of incubation and prepared into 96-well plates containing 200 ⁇ L of acetonitrile. After the reaction, the plates were centrifuged, and the supernatant was analyzed by LC-MS/MS. The half-life (T ⁇ sub>1/2 ⁇ /sub>) of each compound in plasma was calculated, and the results are shown in Table 1.
  • Pharmacological test example 2 Hydrolysis efficiency test of compounds II-0 to II-4 in cathepsin B (CTSB)
  • Cathepsin B was purchased from Merk (Merk, C0150, derived from human placenta).
  • a stock solution of CTSB (Merk, C0150, derived from human placenta) was prepared in an activation buffer containing 352 mM KH2PO4 , 48 mM Na2HPO4 , 4 mM EDTA, and 8 mM L-cysteine HCl ( pH 5.0).
  • the CTSB stock solution was then diluted with the activation buffer to obtain a final concentration of 3 ⁇ M/mL.
  • the test compound was added to a final concentration of 1 ⁇ M, and DMSO (for solubilization) was added to a final concentration of 0.002%.
  • the mixture was incubated at 37°C.
  • a control group was prepared in a buffer without CTSB. Samples were collected at different time points and analyzed by UPLC-MS/MS. The results are shown in Figure 1.
  • mice Five-week-old male BALB/cA nude mice (purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd.) were used for this experiment. Under aseptic conditions, PLC-PRF5-Luciferase cells were orally inoculated into the livers of male nude mice.
  • the psPAX2 plasmid, pMD2.G plasmid, and pLX304Luciferase-V5 blast plasmid (Addgene plasmids #12259, #12260, and #98580) were transfected into logarithmically growing HEK-293T cells using Lipofectamine 3000.
  • the virus was harvested 48 h post-transfection, filtered through a 0.45 ⁇ m filter, and stored at 4°C for later use.
  • PLC/PRF5 cells were infected with lentivirus by simultaneously incubating with 8 ⁇ g/mL polybrene. After 72 h of transfection, 2.5 ⁇ g/mL cymoxanil was added for selection.
  • the bioluminescent signal of the PLC/PRF5-Luciferase cell line was detected using a glow-type firefly luciferase reporter gene assay kit (Yeasen, #11404ES60).
  • the cell seeding density was 2.5 ⁇ 106. /mouse (day d0).
  • mice were intraperitoneally injected with 50 mg/kg of Shutai 50 (telatamine hydrochloride for injection, 5ml: 250 mg, batch number: BN 93LWA). After anesthesia, the mouse peritoneum was opened, and the cell suspension (20uL) was directly inoculated into the nude mouse liver in situ, followed by suturing with aseptic sutures. On day 35, all surgical mice were injected with 150 mg/kg of substrate D-luciferin (Cas: 115144-35-9, Lot.: N1102D) according to body weight.
  • Tissue distribution results in a mouse orthotopic liver cancer model showed that, after intravenous administration, the content of active molecules released by compounds II-0 and II-1 in liver-related tissues was higher than that of the unconjugated active molecule MMAE, indicating that the conjugates of the present invention have stronger liver-targeting ability, and the tissue distribution of MMAE released by the hydrolysis of compound II-1 of the present invention is significantly better than that of II-0.
  • mice were intraperitoneally injected with 50 mg/kg of telatamine hydrochloride (5 ml: 250 mg, batch number: BN 93LWA). After anesthesia, the peritoneal cavity of the mice was opened, and the cell suspension (20 ⁇ L) was directly inoculated into the livers of the nude mice, followed by suturing with aseptic sutures.
  • mice On day 7 post-inoculation (d0), all surgical mice were injected with 150 mg/kg of substrate D-fluorescein (Cas: 115144-35-9, Lot.: N1 102D) according to body weight. Within 10-15 minutes of injection, the mice were anesthetized using an XGI-8qitimazuixitong gas anesthesia machine (anesthetic: Isoflurane, batch number: 2023110302). Imaging was then performed using a small animal in vivo imaging system (IVIS Lumina II) (imaging parameters: Exposure Time: 5s; Binning: 8; F/Stop: 1.2).
  • IVIS Lumina II imaging system
  • mice with in situ tumor growth were selected and randomly divided into a solvent control group and different drug administration groups, with 9 mice in each group, taking into account tumor size.
  • Groups II (15 mg/kg, 2.5 mg/kg, and 1 mg/kg) received the drug via tail vein injection once a week for 4 weeks; the MMAE 0.3 mg/kg group received the drug via tail vein injection every four days for 4 weeks (a total of 7 administrations).
  • the solvent control group received an equal volume of physiological saline.
  • mice were anesthetized weekly, and in vivo imaging was performed using a small animal in vivo imaging system (Exposure Time: 5s; Binning: 8; F/Stop: 1.2), while mouse weight was measured. The results are shown in Figure 3.
  • the MMAE 0.3 mg/kg group had no inhibitory effect on the growth of human hepatocellular carcinoma PLC/PRF5-Luciferase xenografts implanted in situ in the liver of mice.
  • the conjugate of this invention exhibits a significant dose-dependent inhibitory effect on tumor growth; the high-dose group (5 mg/kg) showed a significant tumor-inhibiting effect and complete tumor regression, without significant weight loss in mice. Therefore, the compound of this invention is superior to direct administration of the active molecule, achieving targeted and effective treatment of diseases, reducing the toxic side effects caused by the tissue distribution of the active molecule, and improving the safety of this type of linker conjugate.

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Abstract

La présente invention concerne un conjugué utilisant du succinyle en tant que lieur, son procédé de préparation et son utilisation. Plus particulièrement, le conjugué utilisant du succinyle en tant que lieur selon la présente invention est tel que représenté par la formule (I), le succinyle étant utilisé en tant que lieur, qui est lié en position α à un ligand avec un lieur pour une reconnaissance spécifique de tissu spécifique, et est lié par l'intermédiaire d'une liaison amide à un ligand actif contenant une chaîne peptidique qui a des effets thérapeutiques et/ou diagnostiques sur une maladie. L'utilisation du lieur succinyle peut améliorer la stabilité au plasma et la propriété de ciblage du conjugué, et le conjugué contenant le lieur peut être utilisé pour traiter, diagnostiquer et/ou prévenir une maladie ciblée.
PCT/CN2025/102323 2024-06-21 2025-06-20 Conjugué utilisant du succinyle en tant que lieur, son procédé de préparation et son utilisation Pending WO2025261479A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202410816172.XA CN121181640A (zh) 2024-06-21 2024-06-21 以丁二酰基为连接链的偶联物及其制备方法和用途
CN202410816172.X 2024-06-21

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WO2025261479A1 true WO2025261479A1 (fr) 2025-12-26

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