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WO2025092703A1 - Composé conjugué photosensibilisateur, composition pharmaceutique associée et utilisation associée - Google Patents

Composé conjugué photosensibilisateur, composition pharmaceutique associée et utilisation associée Download PDF

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Publication number
WO2025092703A1
WO2025092703A1 PCT/CN2024/127987 CN2024127987W WO2025092703A1 WO 2025092703 A1 WO2025092703 A1 WO 2025092703A1 CN 2024127987 W CN2024127987 W CN 2024127987W WO 2025092703 A1 WO2025092703 A1 WO 2025092703A1
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compound
formula
compound according
cancer
ligand
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Chinese (zh)
Inventor
钱刚
王贵涛
黄保华
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Coherent Biopharma Suzhou Ltd
Coherent Biopharma Suzhou Co Ltd
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Coherent Biopharma Suzhou Ltd
Coherent Biopharma Suzhou Co Ltd
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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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/66—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
    • 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
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link

Definitions

  • the present invention belongs to the field of precision diagnosis and treatment, and relates to a photosensitizer conjugate compound, specifically to a ligand-photosensitizer conjugate (especially a dual-ligand photosensitizer conjugate), a pharmaceutical composition based on the photosensitizer conjugate compound (or a ligand-photosensitizer conjugate, a dual-ligand photosensitizer conjugate), and its application in the medical field.
  • Photodynamic therapy is a new technology that uses the photodynamic effect for disease diagnosis and treatment.
  • Photodynamic therapy consists of three major elements: light, oxygen, and photosensitizer (a compound with photosensitizing properties), which work together to achieve the desired effect (e.g., inducing tumor cell death).
  • the process of action is as follows: first, the photosensitizer selectively accumulates in the tumor tissue, and then is exposed to light of an appropriate wavelength, allowing the photosensitizer to capture light energy. Finally, in the presence of molecular oxygen, the light energy is converted into a chemical reaction, producing singlet oxygen ( 1O2 ) and other highly reactive oxygen species (ROS), and inducing cell damage through direct or indirect cytotoxicity.
  • 1O2 singlet oxygen
  • ROS highly reactive oxygen species
  • PDT Compared with traditional tumor treatment methods, PDT is a non-invasive therapy with a series of significant advantages: small side effects, low drug resistance, good selectivity; it can be used alone or in combination with other treatment methods. PDT's selectivity for target tissues and degree of damage reduces damage to normal tissues. It has the advantages of small trauma, strong applicability, auxiliary treatment, repeatable treatment, no drug resistance, elimination of tiny lesions, and preservation of important organ functions. In particular, it provides a new treatment method for cancer patients in the middle and late stages, especially those who cannot (or refuse) to use traditional treatment methods. Compared with traditional therapies, PDT can avoid the impact of multiple surgeries on patients, while also being able to exert good therapeutic effects.
  • PDT has been widely used in the treatment of malignant tumors and precancerous lesions such as skin cancer, esophageal cancer, colorectal cancer, lung cancer, cervical cancer, and bladder cancer. It is mainly used clinically for tumors in cavities, cavities, and body surfaces, as well as some abnormal proliferations.
  • APC antibody photosensitizer conjugate
  • cetuximab sarotalocan/ developed by Rakuten Medical i.e., cetuximab sarotalocan/ developed by Rakuten Medical
  • the present invention combines the advantages of ligand drug conjugates (PDC) and photodynamic therapy (PDT) to discover a series of new ligand photosensitizer conjugates (LPC), especially bi-ligand photosensitizer conjugates (BLPC) constructed based on dual targeting technology.
  • PDC ligand drug conjugates
  • PTT photodynamic therapy
  • BLPC bi-ligand photosensitizer conjugates
  • the present invention provides a coupled compound, which may comprise a photosensitizer and a targeting ligand, preferably 1 to 6 targeting ligands, more preferably 2 or 4 targeting ligands.
  • the photosensitizer in the above-mentioned coupled compound can be formed by porphyrins, phthalocyanines, cyanines or Bodipy compounds, preferably formed by phthalocyanine compounds, more preferably formed by silicon phthalocyanine or zinc phthalocyanine compounds.
  • each targeting ligand in the above-mentioned conjugate compound can independently bind to any one of the following cell surface proteins: PSMA, FOLR1 and TRPV6.
  • the above-mentioned conjugate compound when the above-mentioned conjugate compound contains 2 or 4 targeting ligands, the above-mentioned conjugate compound can bind to any one of the following cell surface protein combinations: PSMA/FOLR1, FOLR1/TRPV6 and PSMA/TRPV6, preferably PSMA/FOLR1 and FOLR1/TRPV6, and more preferably PSMA/FOLR1.
  • each targeting ligand in the above-mentioned conjugate compound can be independently formed by a polypeptide, an antibody or a small molecule.
  • the present invention also provides a coupled compound, which may include a photosensitizer, a targeting ligand and a connecting portion; the connecting portion may be used to connect the photosensitizer and the targeting ligand and/or connect a plurality of the targeting ligands.
  • the present invention also provides a coupled compound, which may include a photosensitizer, a targeting ligand, a linker and a spacer; the linker may be used to connect the photosensitizer and the targeting ligand; the spacer may be used to connect a plurality of the targeting ligands.
  • the above-mentioned coupled compound may have a structure as shown in Formula I,
  • LG indicates targeting ligand
  • S represents a spacer
  • L represents a linker
  • PS indicates photosensitizer
  • n 1 or 2;
  • the two LGs are identical to or different from each other;
  • n 2
  • two The same as or different from each other.
  • the compound of formula I may have a structure as shown in formula IA,
  • LG, S, L and PS are as defined in Formula I.
  • the compound of formula I may have a structure as shown in formula IB,
  • LG, S, L and PS are as defined in Formula I.
  • each LG in the above-mentioned compound of formula I, formula IA or formula IB can be independently combined with Any of the following cell surface proteins: PSMA, FOLR1, and TRPV6.
  • the above-mentioned compounds of Formula I, Formula I-A or Formula I-B can bind to any one of the following cell surface protein combinations: PSMA/FOLR1, FOLR1/TRPV6 and PSMA/TRPV6, preferably PSMA/FOLR1 and FOLR1/TRPV6, and more preferably PSMA/FOLR1.
  • each LG in the compound of Formula I, Formula I-A or Formula I-B can be independently formed by a polypeptide, an antibody or a small molecule.
  • each LG in the above-mentioned compound of formula I, formula IA or formula IB can be independently formed by any one of the ligand compounds of formula LG-I, LG-II and LG-III.
  • R LG1 is a hydroxyl group, Preferably, R LG1 is hydroxyl,
  • Formula LG-II is pteroic acid, folic acid or an analog thereof; preferably, the folic acid analog is selected from 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, 10-formylfolate, methotrexate, aminopterin and raltitrexed;
  • Formula LG-III comprises all or part of the amino acids in the polypeptide EGKLSSNDTEGGLCKEFLHPSKVDLPR; preferably, formula LG-III comprises 9 to 27 amino acids in the above polypeptide; more preferably, formula LG-III has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identity with the polypeptide KEFLHPSKVDLPR; further preferably, formula LG-III is the polypeptide KEFLHPSKVDLPR.
  • each LG in the above-mentioned compound of formula I, formula IA or formula IB can be independently The targeting ligand formed by the LG-I ligand compound or its optical isomer and binds to the cell surface protein PSMA; the targeting ligand formed by the LG-II ligand compound or its optical isomer and binds to the cell surface protein FORL1; or, the targeting ligand formed by the LG-III ligand compound or its optical isomer and binds to the cell surface protein TRPV6.
  • each LG in the compound of formula I, formula IA or formula IB can be independently formed by any one of the following ligand compounds or their optical isomers.
  • the LG formed by the above ligand compound can be various, and the present invention does not make any specific limitation to this.
  • it can be a monovalent group obtained by losing a hydrogen atom from a primary amino group in the structure (preferably a primary amino group located at the end of the main chain) (i.e., a secondary amino group, which can be connected to a carboxyl group of other fragments in the conjugate (e.g., S) to form an amide group), or a monovalent group obtained by losing a hydroxyl group in the structure (preferably a carboxyl group located at the end of the main chain) (i.e., a carboxyl group, which can be connected to a secondary amino group of other fragments in the conjugate to form an amide group), or a monovalent group obtained by losing a hydrogen atom from a hydroxyl group in the structure (preferably a hydroxyl group located at the end of the main chain) (e.g., an alkoxy group or an aryloxy group,
  • each ligand compound can independently form any one of the following fragments, wherein the end marked by * is connected to S in the conjugate.
  • the above-mentioned compounds of formula I-A or formula I-B are relatively preferred because the structures of these conjugates contain at least two targeting ligands, which can act in multiple ways to improve the therapeutic effect and reduce toxic side effects; at the same time, the two targeting molecules enhance the affinity of the conjugate to the target cells and reduce off-target toxicity.
  • a connecting portion e.g., a spacer
  • the spacer can be either cleavable (or degradable) or non-cleavable (or non-degradable), and the present invention has no special requirements for the specific structure of the spacer.
  • each S in the compound of formula I, formula IA or formula IB can be independently formed by any one of the following spacer compounds or optical isomers thereof.
  • each spacer compound can independently form any one of the following fragments, wherein the end marked by * is connected to one LG in the conjugate; the end marked by ** is connected to another LG in the conjugate; the group marked by *** can react with the corresponding group in the linker compound (for example, the cycloaddition reaction of the alkynyl group and the azide group, or the double bond addition reaction of the alkenyl group in the maleimide ring and the thiol group), thereby completing the connection between S and L.
  • the linker compound for example, the cycloaddition reaction of the alkynyl group and the azide group, or the double bond addition reaction of the alkenyl group in the maleimide ring and the thiol group
  • each S in the above-mentioned compound of formula I, formula I-A or formula I-B can be independently formed by any one of S-1, S-2, S-3 and S-4 spacer compounds or their optical isomers and additional amino acids or amino acid combinations or their optical isomers, wherein the additional amino acids or amino acid combinations can be selected from Lys, Cys, Glu, Lys-Cys, Cys-Cys, Lys-Cys-Lys, Arg-Arg, Ala-Ser-Asn, Ala-Ala-Ala, Ser-Ser-Arg, Pro-Arg, Asp-Asp-Lys-Cys and Pro-Leu-Gly, and the additional amino acids or amino acid combinations can be optionally amidated (for example, Lys is amidated to L-2,6-diaminohexanamide).
  • a double ligand compound can be formed by the spacer compound and the two ligand compounds, and the latter also falls within the protection scope of the present invention.
  • each BLG can independently be any one of the following compounds, wherein the alkynyl group or thiol group can react with the corresponding group in the linker compound (for example, the azido group or the olefinic group in the maleimide ring) to complete the connection between the biligand fragment and the linker fragment.
  • the linker compound for example, the azido group or the olefinic group in the maleimide ring
  • each BLG can be independently any one of the following compounds or their optical isomers.
  • a connecting part e.g., a linker
  • PS photosensitizer
  • BLG biligand
  • the linker can be either cleavable (or degradable) or non-cleavable (or non-degradable), and the present invention has no special requirements for the specific structure of the linker.
  • each L in the above-mentioned compound of formula I, formula IA or formula IB can be independently formed by any one of the linker compounds of formula LI and L-II,
  • s is any integer from 1 to 8, preferably any integer from 3 to 5, more preferably 4 or 5;
  • R L1 is amino, carboxyl or Where W is and the two ends are connected to other fragments through amide bonds; t is 0 or 1; u is any integer from 1 to 4, preferably 2 or 3, more preferably 3; v is any integer from 1 to 4, preferably 1 or 2, more preferably 2; preferably, RL1 is amino, carboxyl,
  • p is any integer from 1 to 4, preferably any integer from 1 to 3, more preferably 2 or 3;
  • q is any integer from 0 to 3, preferably any integer from 0 to 2, more preferably 0 or 1;
  • r is 0 or 1;
  • each L in the compound of formula I, formula IA or formula IB can be independently formed by any one of the following linker compounds or optical isomers thereof.
  • each linker compound can independently form any one of the following fragments, wherein the end marked by * is connected to PS in the conjugate; the group marked by *** can react with the corresponding group in the spacer compound (for example, the cycloaddition reaction of the alkynyl group and the azide group, or the double bond addition reaction of the alkenyl group in the maleimide ring and the thiol group), thereby completing the connection between L and S.
  • L in the above-mentioned compounds of formula I, formula I-A or formula I-B, when S can be formed by any one of the spacer compounds S-3 and S-4, L can be formed by any one of the linker compounds L-1A, L-1B, L-1C, L-1D, L-1E and L-1F, and the two are connected to each other through a double bond addition reaction of the alkenyl group in the maleimide ring and the thiol group (for example, thiol-Michael reaction).
  • the photosensitizer (PS) contained in the coupled compound of the present invention can undergo a photochemical reaction after absorbing light, thereby generating reactive oxygen species that induce cancer cell death, thereby achieving a therapeutic effect.
  • the above-mentioned photosensitizer can be formed by porphyrins, phthalocyanines (for example, silicon phthalocyanine or zinc phthalocyanine), cyanines or Bodipy compounds, preferably formed by phthalocyanine compounds, more preferably formed by silicon phthalocyanine or zinc phthalocyanine compounds.
  • phthalocyanines for example, silicon phthalocyanine or zinc phthalocyanine
  • Bodipy compounds preferably formed by phthalocyanine compounds, more preferably formed by silicon phthalocyanine or zinc phthalocyanine compounds.
  • PS in the above-mentioned compound of formula I, formula IA or formula IB can be substituted by any one of the following photosensitizers: compounds or their optical isomers.
  • the photosensitizer compound may form any of the following fragments, wherein the end marked by * is connected to L in the conjugate.
  • PS when PS can be formed by any one of the photosensitizer compounds PS-1 and PS-3, L can be formed by any one of the linker compounds L-1A and L-2B, and the two are connected to each other through an amidation reaction of a carboxyl group and a primary amino group.
  • L when PS can be formed by a PS-2 photosensitizer compound, L can be formed by an L-2A linker compound, and the two are connected to each other through an etherification reaction of two hydroxyl groups.
  • PS when PS can be formed by any one of the photosensitizer compounds PS-4, PS-7 and PS-8, L can be formed by any one of the linker compounds L-1B, L-1F and L-2C, and the two are connected to each other through an esterification reaction of a hydroxyl group and a carboxyl group.
  • PS when PS can be formed by any one of the photosensitizer compounds PS-5 and PS-6, L can be formed by any one of the linker compounds L-1C, L-1D and L-1E, and the two are interconnected through a nucleophilic substitution reaction between a silanol group and a silyl ether group.
  • the coupled compound intermediate (CM) formed by the linker compound and the photosensitizer compound also falls within the protection scope of the present invention.
  • each CM can be independently any one of the following compounds, wherein the alkenyl group in the azide group or maleimide ring can react with the corresponding group (e.g., alkynyl group or thiol group) in the spacer compound to complete the connection between the coupled compound intermediate and the spacer fragment.
  • the alkenyl group in the azide group or maleimide ring can react with the corresponding group (e.g., alkynyl group or thiol group) in the spacer compound to complete the connection between the coupled compound intermediate and the spacer fragment.
  • each CM may be independently any one of the following compounds or their optical isomers.
  • the amide group when different fragments used to construct the coupled compound are connected in series via an amide group, the amide group can be formed by a condensation reaction of a primary amino group (e.g., an amino group in a compound forming L, S or LG) and a carboxyl group (e.g., a carboxyl group in a compound forming PS).
  • a primary amino group e.g., an amino group in a compound forming L, S or LG
  • a carboxyl group e.g., a carboxyl group in a compound forming PS
  • the above condensation reaction can be carried out in the presence of a coupling agent to activate the carboxylic acid to a preferred electrophilic
  • the coupling reagents can be used to promote the forward reaction.
  • Exemplary coupling reagents include, but are not limited to, EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide), DCC (dicyclohexylcarbodiimide), HOBt (1-hydroxybenzotriazole), HATU (O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), etc.
  • the formation of amide bonds can also be achieved by activating carboxylic acids with N-hydroxysuccinimide (NHS) to form succinimide esters, which can be further reacted with amines without any other coupling reagents.
  • NHS N-hydroxysuccinimide
  • the present invention provides the following specific presentation forms of the conjugate compound.
  • the present invention provides the following specific presentation forms of the coupled compound or optical isomers thereof.
  • the present invention provides a pharmaceutical composition comprising the conjugate compound described in ⁇ the first aspect> or ⁇ the second aspect>.
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.
  • the present invention provides use of the conjugate compound described in ⁇ the first aspect> or ⁇ the second aspect> or the pharmaceutical composition described in ⁇ the third aspect> in the preparation of a drug for diagnosing, preventing and/or treating a disease or condition.
  • the present invention provides the conjugate compound described in ⁇ the first aspect> or ⁇ the second aspect> or the pharmaceutical composition described in ⁇ the third aspect>, which is used for diagnosing, preventing and/or treating a disease or condition.
  • the present invention provides a method for diagnosing, preventing and/or treating a disease or condition, comprising: administering a diagnostically, preventively and/or therapeutically effective amount of the conjugate compound described in the first aspect or the second aspect or the pharmaceutical composition described in the third aspect to the patient. For use by individuals who need it.
  • the disease or condition is cancer or a precancerous lesion; preferably, the cancer or precancerous lesion occurs in a cavity, a lumen or a body surface; more preferably, the cancer is selected from skin cancer, esophageal cancer, colorectal cancer, lung cancer, cervical cancer and bladder cancer.
  • the conjugate compound of the present invention (or its pharmaceutically acceptable derivative form, such as an addition salt) combines the advantages of ligand-drug conjugates and photodynamic technology.
  • a photosensitizer to a ligand with a targeting effect
  • the advantages of the photosensitizer drug itself such as small side effects and low drug resistance
  • the targeting of the photosensitizer is improved, thereby providing a possible drug-making method for the photosensitizer drug.
  • FIG1 is the MS spectrum of intermediate 1 in Example 3.
  • Figure 2 is the MS spectrum of compound CM-5' in Example 3.
  • Figure 3 is the MS spectrum of compound 9' in Example 3.
  • Figure 4 is the MS spectrum of compound 10' in Example 4.
  • Figure 5 is the MS spectrum of compound CM-4' in Example 5.
  • Figure 6 is the MS spectrum of compound 7' in Example 5.
  • Figure 7 is the MS spectrum of compound 8' in Example 6.
  • Figure 8 is the MS spectrum of compound BLG-2' (compound NC) in Example 7.
  • Figure 9 is the MS spectrum of compound 11' in Example 7.
  • Figure 10 shows the effect of compound 8' on the body weight of mice in each group of SKOV-3 model (mean ⁇ standard error).
  • Figure 11 shows the effect of compound 8' on the body weight changes of mice in each group of the SKOV-3 model (mean ⁇ standard error).
  • Figure 12 shows the effect of compound 8' on the tumor volume of each group of mice in the SKOV-3 model (mean ⁇ standard error).
  • Figure 13 shows the effect of compound 8' on the changes in tumor volume in each group of mice in the SKOV-3 model (mean ⁇ standard error).
  • target or “drug target” refers to the binding site between drugs and biological macromolecules of the body, mainly involving receptors, enzymes, ion channels, transporters, immune system, genes, etc.
  • drugs target receptors which become the main and most important targets
  • drugs target enzymes especially enzyme inhibitors, which have a special status in clinical applications
  • about 6% of drugs target ion channels 3% of drugs target nucleic acids
  • the targets of 20% of drugs are still to be further studied.
  • conjugate compound refers to a pharmaceutically acceptable compound formed by connecting fragments of different functions through optional connecting fragments and capable of exerting corresponding activities, such as antibody-drug conjugates (ADC), polypeptide-drug conjugates (PDC), small molecule-drug conjugates (SMDC), radionuclide-drug conjugates (RDC), ligand-photosensitizer conjugates (LPC), etc.
  • ADC antibody-drug conjugates
  • PDC polypeptide-drug conjugates
  • SMDC small molecule-drug conjugates
  • RDC radionuclide-drug conjugates
  • LPC ligand-photosensitizer conjugates
  • photosensitizer refers to a drug that can trigger a photodynamic reaction to destroy cell structures.
  • ligand-photosensitizer conjugate or “ligand-coupled photosensitizer” refers to a pharmaceutically acceptable conjugate formed by connecting fragments such as a photosensitizer and a targeting ligand for at least one target through a linker and a spacer, wherein the photosensitizer portion can exert a photodynamic effect, the targeting ligand portion is used to exert targeted positioning for one or more specific targets (such as receptors), and the linker portion and the spacer portion are used to connect the photosensitizer portion and the targeting ligand portion to each other to form the complete structure of the ligand-photosensitizer conjugate.
  • targeting ligand refers to any molecule or part that can be targeted to a target site, target tissue, target organ, target cell, or target cell intracellular region.
  • the targeting ligand allows the portion connected to the targeting ligand to be distributed more in the target site, target tissue, target organ, target cell or target cell intraregional area, for example, at least 10%, 20%, 50%, 80%, 100%, 150%, 200%, 300%, 400%, 500% or higher.
  • the conjugate compound or agent with a targeting ligand is distributed more in the target site, target tissue, target organ, target cell or target cell intraregional area, for example, at least 10%, 20%, 50%, 80%, 100%, 150%, 200%, 300%, 400%, 500% or higher.
  • the targeting ligand can trigger or promote the specific binding of the conjugate compound containing such a targeting ligand to the target molecule, trigger or promote the endocytosis of the conjugate compound by the target cell, trigger or promote the enrichment of the conjugate compound around the target cell and/or enter the target cell.
  • ligand may include a variety of chemical molecules or polypeptides, which have specific binding affinity for the selected target, and the selected target may be a cell surface protein (e.g., a cell surface receptor or a cell surface antigen), a specific protein, a cell, a tissue, an organ, etc.
  • the ligand may specifically bind to a cell surface receptor.
  • the ligand may specifically bind to a cell surface antigen.
  • the ligand may specifically bind to a specific protein, which may be a disease-causing protein.
  • overexpression of the specific protein may cause a disease or the specific protein may be a mutant protein that causes a disease.
  • the ligand of the present application binds to the target with an affinity of 10-6 to 10-11 M ( Kd value). In some embodiments, the ligand of the present application binds to the target with an affinity of at least 10-6 , at least 10-7 , at least 10-8 , or at least 10-9 M ( Kd value).
  • the ligand of the present application binds to the target with a certain affinity
  • the certain affinity means that the affinity of the ligand for the target is at least two times, three times, four times, five times, six times, eight times, ten times, twenty times, fifty times, one hundred times or more higher than the affinity of the non-target (e.g., other cell surface receptors, cell surface antigens or specific proteins, etc.).
  • the expression of the cell surface receptors, cell surface antigens, and specific proteins of the present application on the surface of target cells (e.g., cancer cells or cells with abnormal physiological functions) or in target cells is significantly higher than that in normal cells.
  • the term "significant" used in the present application refers to a statistically significant difference, or a significant difference that can be recognized by a person skilled in the art.
  • FOLR1 refers to folate receptor 1, a glycosylphosphatidylinositol (GPI)-anchored glycoprotein that binds folate with nanomolar affinity, thereby promoting receptor-mediated endocytosis.
  • GPI glycosylphosphatidylinositol
  • TRPV6 refers to transient receptor potential cation channel subfamily V member 6, which is a highly selective calcium ion transmembrane transport channel that mediates the active transport of calcium ions from the extracellular to the intracellular.
  • TRPV6 is expressed in normal human kidneys, gastrointestinal tract, pancreas, breast, salivary glands, etc., but is mainly expressed in intestinal epithelial cells, where it participates in the transport of calcium ions into cells. Therefore, when the number or function of TRPV6 channels changes, changes in calcium ion regulation may occur, further leading to structural or functional abnormalities in related tissues and organs.
  • TRPV6 expression is significantly increased in malignant tumors such as breast cancer, bile duct cancer, ovarian cancer, squamous cell lung cancer, and prostate cancer, and its abnormal expression may be related to the formation and progression of tumors.
  • PSMA prostate-specific membrane antigen
  • prostate-specific membrane antigen refers to a type II transmembrane glycoprotein present in the membrane of prostate epithelial cells, consisting of 750 amino acids, which have 19 intracellular amino acids, 24 transmembrane amino acids and 707 extracellular amino acids.
  • Prostate-specific membrane antigen is expressed in normal prostate epithelial cells, but its expression level in prostate cancer cells is much higher.
  • prostate-specific membrane antigen is a more sensitive and specific prostate cancer tumor marker, especially in hormone-refractory prostate cancer and prostate cancer metastasis, which are highly expressed, and has high sensitivity and specificity in distinguishing prostate cancer from other types of malignant tumors.
  • prostate-specific membrane antigen is also highly specifically expressed on tumor vascular endothelial cells.
  • pharmaceutical composition refers to a composition for pharmaceutical use, which contains a small molecule drug, a polypeptide, an antibody (or an antibody-like ligand) or a conjugate thereof as an active pharmaceutical ingredient (API), and other components (e.g., pharmaceutically acceptable excipients).
  • the pharmaceutical composition can be prepared using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding and/or lyophilizing processes.
  • pharmaceutically acceptable excipients refer to auxiliary materials widely used in the field of drug production.
  • the main purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in nature and/or has specific functionality, and also to provide a method so that after the drug is administered to the subject, the active ingredient can be dissolved at a desired rate, or to promote the active ingredient to dissolve at the desired rate after receiving the drug.
  • the drug is effectively absorbed in the body of the subject.
  • a pharmaceutically acceptable excipient may be an inert filler or an effective ingredient that provides a certain function to the pharmaceutical composition (e.g., stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient in the composition).
  • “pharmaceutically acceptable excipients” include, but are not limited to, binders, suspending agents, emulsifiers, diluents (or fillers), granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, photosensitizers, preservatives, colorants, flavoring agents, sweeteners, etc.
  • the starting materials used in the present invention can be synthesized by methods known in the art, or purchased by conventional commercial means.
  • the separation and purification of the compounds of the present invention can be achieved by methods well known to those skilled in the art, including but not limited to column chromatography (CC), high performance liquid chromatography (HPLC), ultra-high performance liquid chromatography (UPLC), etc.
  • the structural identification of the compounds of the present invention can be achieved by methods well known to those skilled in the art, including but not limited to nuclear magnetic resonance (NMR), mass spectrometry (MS), etc.
  • BLG-1', BLG-2' and BLG-3' were obtained by steps similar to the above method.
  • CM-3 (9.8 mg, 6.09 mmol) was added to DMF (0.8 ml), and purified water (0.17 ml) was added and stirred at 25 ° C.
  • BLG-1' (19.2 mg) was weighed and added to the reaction solution.
  • the pH value of the reaction system was adjusted to about 8 with DIPEA, and cuprous bromide (2.7 mg) was added.
  • intermediate 1 (2.7 g, 3.357 mmol) and 6-maleimidocaproic acid (1.4 g, 6.71 mmol) were dissolved in DMF (50 ml), HATU (3.8 g, 10.07 mmol) was added, and then DIPEA (2.6 g, 20.14 mmol) was added dropwise, and the mixture was reacted at room temperature for 1.5 h. Water (150 ml) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 ml*3).
  • intermediate 1 (4.90 g, 6.09 mmol) and 6-maleimidocaproic acid (3.08 g, 14.61 mmol) were dissolved in DMF (100 mL), HATU (6.94 g, 18.28 mmol) was added, and then DIPEA (4.73 g, 36.56 mmol) was added dropwise, and the mixture was reacted at room temperature for 1.5 h.
  • CM-4' (20 mg, 0.0168 mmol) was dissolved in DMF (3 mL), and an aqueous solution (1.2 ml) of BLG-4' (84.31 mg, 0.0403 mmol) was added dropwise.
  • the pH value was adjusted to 6-7 with PBS solution, and the mixture was reacted at room temperature for 1 h. After dissolution with PBS solution, the mixture was purified to obtain compound 7' (33.6 mg, 0.0063 mmol, yield: 37.5%); MS (ESI-): m/z 1342.3 [M-4H] 4- (as shown in FIG6 shown).
  • Fmoc-Cys(Trt)-OH was immobilized on an amino resin by Fmoc chemical solid phase synthesis, and then the Fmoc protecting group was removed with a 20% piperidine DMF solution, and the mixture was washed with DMF to remove impurities.
  • a DMF solution of Fmoc-Glu-OtBu was added, and HATU and DIPEA were added for condensation reaction. Ninhydrin developed a light yellow color, and the mixture was washed with DMF to remove impurities.
  • the Fmoc removal and condensation steps were repeated to obtain a crude resin.
  • the product was cleaved from the resin with trifluoroacetic acid and the protecting group was removed at the same time to obtain a crude raw material 3, which was purified by preparative chromatography to obtain raw material 3.
  • Table 1 The results in Table 1 showed that 293T cells did not express FOLR1, PSMA and TRPV6; 293T-FOLR1/PSMA cells highly expressed FOLR1 and PSMA, but did not express TRPV6; SK-OV-3 cells highly expressed FOLR1, but lowly expressed PSMA and TRPV6; HT29 cells expressed FOLR1, and lowly expressed PSMA and TRPV6.
  • the sample was gradiently diluted with culture medium (initial concentration 10 ⁇ M, 5-fold gradient dilution), and a total of 9 concentration gradients were set; the culture medium in the well plate was discarded, and the drug solution was added to a 96-well plate at a volume of 100 ⁇ l per well, with 3 replicates, and a negative control, a blank control and a non-illuminated group were set up, and placed in a 37°C, 5% CO2 incubator for 24 hours; the well plate was irradiated with 16 J/ cm2 of light energy, and then placed in a 37°C, 5% CO2 incubator for another 24 hours.
  • GraphPad Prism 8.0.2 was used to perform four-parameter curve fitting and obtain IC50 values.
  • the ligand-photosensitizer conjugate of the present invention requires light conditions to exert its efficacy, so the compound NC that does not contain a photosensitizer (PS) does not show an inhibitory effect on cells;
  • PS photosensitizer
  • the efficacy of the drug is correlated to a certain extent with the cell expression.
  • the killing effect is higher (293T-FOLR1/PSMA)
  • the killing effect is lower/no killing (293T, HT29). This is also in line with the concept of targeted precision diagnosis and treatment.
  • the two-arm dual-ligand conjugate (e.g., compound 8') shows a higher killing effect than the one-arm dual-ligand conjugate (e.g., compound 10') or the two-arm single-ligand conjugate (e.g., compound PC), whether for 293T-FOLR1/PSMA or SK-OV-3, indicating that the two-arm dual-ligand structure can further enhance the affinity of the conjugate to the target cells and improve the efficacy; moreover, when achieving equivalent efficacy, the actual dosage of the two-arm dual-ligand conjugate can also be reduced, further improving the safety of the drug.
  • SK-OV-3 cells were cultured in vitro in a McCoy's 5A medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin in a 37°C, 5% CO 2 incubator. Routine treatment and subculture were performed twice a week. When the number reaches 80%-90%, the cells are collected, counted and inoculated.
  • mice 10*10 6 cells (inoculation volume 0.1 mL) were subcutaneously inoculated into the right dorsal flank of each mouse, and the mice were randomly divided into groups when the average tumor volume reached 150 mm 3. The day of grouping was set as D0, and the day of first administration was set as D1.
  • the animal body weight and tumor size were measured on the day of grouping. According to the size of the animal tumor, 33 animals were randomly divided into 11 groups using Grouping, namely, the blank control group; the high, medium and low dose groups of compound 8' (45 mg/kg, 15 mg/kg and 5 mg/kg, respectively), each large group was set up with 4, 6 and 8h light exposure groups after administration (administered once every two weeks, three times in total) and the 5 mg/kg dose group of compound 8', with 4h light exposure after administration (administered once a week, five times in total). No operation was given to the blank control group. Animal grouping and lighting conditions are shown in Table 3.
  • the medication is as follows:
  • Dosing frequency once every two weeks and once a week.
  • the tumor volume and tumor volume changes of the experimental mice at different time points are shown in Figures 12 and 13.
  • the animal data of the groups exposed to light at intervals of 4h after administration (Groups 1, 4, 7 and 11) were relatively impressive and dose-related, among which 45mg/kg exposed to light once every two weeks (Group 7) had a good tumor inhibition effect.
  • 5mg/kg exposed to light once a week (Group 11) and 15mg/kg exposed to light once every two weeks (Group 4) showed similar tumor inhibition effects. No obvious tumor inhibition effect was observed at 5mg/kg exposed to light once every two weeks (Group 1).

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Abstract

L'invention concerne un conjugué ligand-photosensibilisateur, en particulier un conjugué bi-ligand-photosensibilisateur représenté par la formule I, une composition pharmaceutique à base du composé conjugué photosensibilisateur, et son utilisation dans le domaine de la médecine. Le composé conjugué photosensibilisateur de la présente invention combine les avantages du conjugué ligand-médicament et de la technologie photodynamique, et améliore la propriété de ciblage du photosensibilisateur au moyen de la conjugaison du photosensibilisateur au ligand avec l'effet de ciblage tout en utilisant les avantages de faibles effets secondaires et de faible pharmaco-résistance inhérents au médicament photosensibilisateur.
PCT/CN2024/127987 2023-10-30 2024-10-29 Composé conjugué photosensibilisateur, composition pharmaceutique associée et utilisation associée Pending WO2025092703A1 (fr)

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US20170145035A1 (en) * 2015-09-09 2017-05-25 On Target Laboratories, LLC Synthesis and composition of photodynamic therapeutic agents for the targeted treatment of cancer
WO2017197104A1 (fr) * 2016-05-11 2017-11-16 The Jackson Laboratory Inhibiteurs de la yap1 et méthodes associées
US10207005B2 (en) * 2013-02-15 2019-02-19 Case Western Reserve University Photodynamic therapy composition
US20190365897A1 (en) * 2017-02-23 2019-12-05 Rakuten Medical, Inc. Therapeutic compositions and related methods for photoimmunotherapy
WO2020156513A1 (fr) * 2019-01-30 2020-08-06 同宜医药（苏州）有限公司 Conjugué médicament-ligand et utilisation de celui-ci
US20210060170A1 (en) * 2013-02-15 2021-03-04 Case Western Reserve University Photodynamic therapy composition
US20220001011A1 (en) * 2020-07-03 2022-01-06 Case Western Reserve University Photodynamic therapy composition
US20230135597A1 (en) * 2013-02-15 2023-05-04 Case Western Reserve University Photodynamic therapy composition
CN116059392A (zh) * 2021-09-03 2023-05-05 同宜医药（苏州）有限公司 配体偶联物及其应用
WO2023202654A1 (fr) * 2022-04-20 2023-10-26 同宜医药（苏州）有限公司 Composé et son utilisation
WO2024216150A1 (fr) * 2023-04-14 2024-10-17 Nira Biosciences, Inc. Analogues de benzoporphyrine, conjugués et leurs procédés d'utilisation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008039994A2 (fr) * 2006-09-28 2008-04-03 The Trustees Of The University Of Pennsylvania Agent thérapeutique photodynamique ciblé
US20210060170A1 (en) * 2013-02-15 2021-03-04 Case Western Reserve University Photodynamic therapy composition
US10207005B2 (en) * 2013-02-15 2019-02-19 Case Western Reserve University Photodynamic therapy composition
US20230135597A1 (en) * 2013-02-15 2023-05-04 Case Western Reserve University Photodynamic therapy composition
CN106573054A (zh) * 2014-06-02 2017-04-19 利康公司 酞菁探针及其用途
US20170145035A1 (en) * 2015-09-09 2017-05-25 On Target Laboratories, LLC Synthesis and composition of photodynamic therapeutic agents for the targeted treatment of cancer
WO2017197104A1 (fr) * 2016-05-11 2017-11-16 The Jackson Laboratory Inhibiteurs de la yap1 et méthodes associées
US20190365897A1 (en) * 2017-02-23 2019-12-05 Rakuten Medical, Inc. Therapeutic compositions and related methods for photoimmunotherapy
WO2020156513A1 (fr) * 2019-01-30 2020-08-06 同宜医药（苏州）有限公司 Conjugué médicament-ligand et utilisation de celui-ci
US20220001011A1 (en) * 2020-07-03 2022-01-06 Case Western Reserve University Photodynamic therapy composition
CN116059392A (zh) * 2021-09-03 2023-05-05 同宜医药（苏州）有限公司 配体偶联物及其应用
WO2023202654A1 (fr) * 2022-04-20 2023-10-26 同宜医药（苏州）有限公司 Composé et son utilisation
WO2024216150A1 (fr) * 2023-04-14 2024-10-17 Nira Biosciences, Inc. Analogues de benzoporphyrine, conjugués et leurs procédés d'utilisation

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