WO2025031474A1 - Méthode et médicament pour le traitement de l'endométriose - Google Patents

Méthode et médicament pour le traitement de l'endométriose Download PDF

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WO2025031474A1
WO2025031474A1 PCT/CN2024/110949 CN2024110949W WO2025031474A1 WO 2025031474 A1 WO2025031474 A1 WO 2025031474A1 CN 2024110949 W CN2024110949 W CN 2024110949W WO 2025031474 A1 WO2025031474 A1 WO 2025031474A1
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endometriosis
hematopoietic cell
cell kinase
targets
target
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Feng Ren
Aleksandrs Zavoronkovs
Wing Frank PUN
Chi Chiu Wang
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Chinese University of Hong Kong CUHK
InSilico Medicine IP Ltd
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Chinese University of Hong Kong CUHK
InSilico Medicine IP Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the field of medicine, in particular, to a method for treating endometriosis.
  • Endometriosis is a chronic inflammatory gynecological disease characterized by the presence of ectopic endometrial glands and stroma, predominantly on the pelvic peritoneum, ovaries and the rectovaginal septum. About 5 -15%of women at reproductive age are estimated to suffer from endometriosis worldwide (PMID: 27159755) , and the prevalence can reach 35 -80%in women with pelvic pain and/or infertility (PMID: 32212520, 33640070) .
  • endometriosis Despite endometriosis not being lethal, chronic pain and infertility pose significant impacts on the quality of life.
  • the economic burden of endometriosis is estimated to reach $80 billion annually in the US alone (PMID: 35620300) .
  • endometriosis is a systemic disease that disturbs cardiovascular, neurological, metabolic, and immune functions (PMID: 33640070) .
  • Patients may have increased risks of developing several chronic diseases, such as adenomyosis (PMID: 24532217) , ovarian cancer (PMID: 28240000) , and autoimmune diseases (PMID: 31260048) . These altogether urge the need to innovate effective therapeutics for the disease.
  • the purpose of the present invention is to provide a therapy or a medicament for the treatment of endometriosis.
  • One aspect of the present invention provides a method for treating endometriosis in a subject in need thereof, comprising administering to the subject an effective amount of a Hematopoietic Cell Kinase inhibitor.
  • the Hematopoietic Cell Kinase inhibitor is one or more selected from the group consisting of Bosutinib, Dasatinib, KIN-8194, RV568, Rebastinib, and a derivative thereof.
  • Another aspect of the present invention provides use of a Hematopoietic Cell Kinase inhibitor in manufacture of a medicament for treating endometriosis.
  • the Hematopoietic Cell Kinase inhibitor is one or more selected from the group consisting of Bosutinib, Dasatinib, KIN-8194, RV568, Rebastinib, and a derivative thereof.
  • Another aspect of the present invention provides a medicament for use in treatment of endometriosis, wherein the medicament comprises a Hematopoietic Cell Kinase inhibitor.
  • the S1PR1 antagonist is one or more selected from the group consisting of Bosutinib, Dasatinib, KIN-8194, RV568, Rebastinib, and a derivative thereof.
  • FIGs. 1A-1B PandaOmics identified Hematopoietic Cell Kinase as potential therapeutic targets for endometriosis.
  • FIG. 1A The pipeline of therapeutic target identification for endometriosis using PandaOmics. With the input of 11 endometriosis datasets, PandaOmics utilized a combination of Omics and text scores to prioritize targets for endometriosis (Target ID) . DEG and pathway analyses were performed using the platform. After Target ID, proposed targets were subjected to IHC validation. Only validated targets were proceeded to in vitro and in vivo validation using siRNA approach. The downstream effectors were then predicted for the validated targets via both computational and experimental methods. (FIG.
  • FIGs. 2A-2C Consistent dysregulation of Hematopoietic Cell Kinase in endometriosis.
  • FIG. 2A The expressions of Hematopoietic Cell Kinase in the eleven endometriosis-related comparisons were displayed in box plots.
  • FIG. 2B Representative image of the paraffin-embedded human endometriotic and normal endometrial stromal tissues stained with anti-Hematopoietic Cell Kinase antibodies.
  • FIG. 2C Protein expressions of Hematopoietic Cell Kinase in IHC were assessed by H-score. Data are represented as mean ⁇ SEM. *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001. P ⁇ 0.05 is considered as statistically significant.
  • FIGs. 3A-3E Knockdown of Hematopoietic Cell Kinase inhibited proliferation and promoted apoptosis of endometriotic stromal cells.
  • Endometriotic stromal cells were transiently transfected with non-target siRNA control (Control) and siRNA targeting Hematopoietic Cell Kinase (siHCK) .
  • mRNA and protein expressions of (FIGs. 3A, 3B) Hematopoietic Cell Kinase in the transfected cells were examined by quantitative PCR and immunofluorescence staining with anti-Hematopoietic Cell Kinase antibodies, respectively. Representative images of the transfected cells stained with anti-Hematopoietic Cell Kinase were shown.
  • FIG. 3C Viability and proliferative ability of the transfected cells were assessed by (FIG. 3C) CCK8 assay and (FIG. 3D) Ki67 immunofluorescence staining, respectively.
  • FIG. 3E The transfected cells were also subjected to TUNEL assay to examine their apoptotic status. The mean percentage of apoptotic cells were shown in the bar chart. Data are represented as mean ⁇ SEM. *P ⁇ 0.05, **P ⁇ 0.01. P ⁇ 0.05 is considered as statistically significant.
  • FIGs. 4A-4L Knockdown of Hematopoietic Cell Kinase suppressed endometriosis in vivo.
  • FIG. 4A Timeline illustrating the establishment of the in vivo endometriosis models and siRNA treatment for investigating the effect of Hematopoietic Cell Kinase.
  • FIGs. 4C-4G subcutaneous
  • FIGS. 4H-4L intraperitoneal endometriosis mouse models
  • FIGs. 4C, 4H The volume and weight of the excised lesions were recorded and compared.
  • mRNA and protein expression of FIGs. 4D-4E, FIGs. 4I-4J
  • FIGs. 4I-4J Hematopoietic Cell Kinase in the murine endometriotic xenograft were analyzed by quantitative PCR and IHC. Representative images of the paraffin-embedded murine endometriotic xenografts stained with anti-Hematopoietic Cell Kinase antibodies were shown.
  • FIGs. 4F, 4K Proliferation and (FIGs.
  • 4G, 4L apoptosis status of the xenograft treated with siRNA against Hematopoietic Cell Kinase were analyzed by Ki-67 IHC staining and TUNEL assay, respectively. Representative images of each experimental group were displayed. Data are represented as mean ⁇ SEM. *P ⁇ 0.05, **P ⁇ 0.01. P ⁇ 0.05 is considered as statistically significant.
  • FIG. 5 Potentiality of Hematopoietic Cell Kinase as immune targets in endometriosis.
  • Dysregulated pathways associated with Hematopoietic Cell Kinase in endometriosis comparisons were displayed. Pathways were annotated by the Reactome database, and the degree of pathway dysregulation was determined by iPANDA algorithm. Bar colored in green and red indicates the number of comparisons with significant activation and inactivation of the corresponding pathway, respectively. Pathways labeled in blue are immune-associated.
  • FIG. 6 Expressions of Hematopoietic Cell Kinase were dysregulated in endometriosis proteomics datasets. Protein expression boxplots for Hematopoietic Cell Kinase in the endometriosis proteomics dataset PDX006553, retrieved from the ProteomeXchange Consortium.
  • the term “comprise” , “include” , “contain” and variations of these terms, such as comprising, comprises and comprised, are not intended to exclude further members, components, integers or steps. These terms also encompass the meaning of “consist of” or “consisting of” .
  • the term “consist of” or “consisting of” is a particular embodiment of the term “comprise” , wherein any other non-stated member, component, integer or step is excluded.
  • endometriosis refers to a condition in which tissue containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity or some other area of the body (most commonly the peritoneal cavity) .
  • treat refers to alleviating, inhibiting and/or reversing the progress of a disease (such as endometriosis) .
  • the term “treating” is inclusive of any indicia of success in the treatment or amelioration of the disease, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the subject; delaying or slowing in the rate of progression, etc.
  • Measurement of the treatment or amelioration may be based on, e.g., the results of a physical examination, a pathological test and/or a diagnostic test as known in the art.
  • Treating may also refer to reducing the incidence or onset of a disease, or a recurrence thereof (such as a lengthening in time of remission) , as compared to that which would occur in the absence of the measure taken. Clinically, such a treatment can also be called prevention.
  • active agent refers to a pharmaceutically active chemical that provides some pharmacologic effect and is used for treating or preventing a disease, such as endometriosis.
  • inhibitor and antagonist can be used interchangeably and refer to any molecule that partially or fully blocks or inhibits an activity of a target (such as the protein used as a target in the present invention) .
  • inhibitor and antagonist can also be refereed to an “active agent” .
  • derivatives of a compound refers to any pharmaceutically acceptable molecule that is derived from (i.e., structurally related to) the compound and has similar or substantially the same activity as the compound, which upon administration to a subject is capable of providing (directly or indirectly) a compound of the active agent or an active metabolite thereof.
  • the derivatives include, but are not limited to, pharmaceutically acceptable salt, hydrate, solvate, prodrug or metabolite.
  • pharmaceutically acceptable salt refers to a relatively nontoxic, inorganic or organic acid salt of a compound of the invention. These salts may be prepared in situ during the final isolation and purification of the compounds or by reacting the purified compound in its free form separately with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative acid salts include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tanna
  • solvate refers to a complex of variable stoichiometry formed by a solute (e.g., the active agent of the present invention) and a solvent.
  • a solute e.g., the active agent of the present invention
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • prodrug of a compound refers to a precursor, which when administered to a biological system, generates said compound as a result.
  • prodrugs can have the structure X-drug wherein X is an inert carrier moiety and drug is the active compound,
  • metabolite of a compound refers to a molecule which results from a modification or processing of the compound after administration to a subject.
  • the term “metabolite” may designate a modified or processed drug that retains at least part of the activity of the parent compound.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier refers to any carrier that has substantially no long term or permanent detrimental effect when administered to a subject, such as a stabilizer, diluent, additive, auxiliary, excipient and the like.
  • “Pharmaceutically acceptable carrier” should be a pharmaceutically inert material that has substantially no biological activity and constitutes a substantial part of the formulation.
  • subject refers to any organism to which the active agent of the composition of the present invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes.
  • Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates such as chimpanzees and other apes and monkey species, and humans) .
  • the subject may be a mammal, particularly a human, including a male or female, and including a neonatal, infant, juvenile, adolescent, adult or geriatric, and further is inclusive of various races and ethnicities.
  • terapéuticaally effective dose or “effective dose” , as used herein, which can be used interchangeably with "therapeutically effective amount” or “effective amount” , refers to an amount that is effective for treating a disease (such as endometriosis) as noted through clinical testing and evaluation, patient observation, and/or the like.
  • An “effective amount” can further designate an amount that causes a detectable change in biological or chemical activity. The detectable changes may be detected and/or further quantified by one skilled in the art for the relevant mechanism or process.
  • an "effective amount” can designate an amount that maintains a desired physiological state, i.e., reduces or prevents significant decline and/or promotes improvement in the condition.
  • unit dosage form refers to physically discrete units (such as capsules, tablets, or loaded syringe cylinders) suitable as unitary dosages for a subject, each unit containing a predetermined quantity of active agent calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
  • unit dose refers to a dose of a substance (such as an active agent of the present invention) in a unit dosage form.
  • HCK Hemopoietic Cell Kinase
  • the hematopoietic cell kinase is a member of the SRC family of cytoplasmic tyrosine kinases (SFKs) , and is expressed in cells of the myeloid and B-lymphocyte cell lineages.
  • SFKs cytoplasmic tyrosine kinases
  • Excessive Hematopoietic Cell Kinase activation is associated with several types of leukemia and enhances cell proliferation and survival by physical association with oncogenic fusion proteins, and with functional interactions with receptor tyrosine kinases. Elevated activity of the Hematopoietic Cell Kinase is also observed in many solid malignancies, including breast and colon cancer, and correlates with decreased patient survival rates.
  • Hematopoietic Cell Kinase enhances the secretion of growth factors and pro-inflammatory cytokines from myeloid cells, and promotes macrophage polarization towards a wound healing and tumor-promoting alternatively activated phenotype.
  • the active agent used to treat endometriosis can be any one selected from the group consisting of inhibitor of Hematopoietic Cell Kinase, including but not limited to Bosutinib, Dasatinib, KIN-8194, RV568, Rebastinib, and a derivative thereof.
  • the amount of each of the active agents in a unit dosage form may be 1-1000 mg, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175 , 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000mg or any range between any two of the above specific values.
  • Each of the active agent of the present invention may be administered to the subject via oral, buccal, sublingual, rectal, vaginal, parenteral, intradermal or intranasal or parenteral route.
  • the parenteral administration includes intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal, transmucosal intraarticular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional or intracranial injection or infusion.
  • the active agent (s) as used herein may be formulated for administration in a pharmaceutical composition in accordance with known techniques. See, for example, Remington, The Science and Practice of Pharmacy (9th Ed. 1995) .
  • the active agent is typically admixed with, inter alia, a pharmaceutical acceptable carrier.
  • the carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from 0.01%or 0.5%to 95%or 99%by weight of the active agent.
  • compositions of the invention may be prepared by any of the well-known techniques of pharmacy comprising admixing the components, optionally including one or more accessory ingredients and/or excipients.
  • any of the compositions, carriers, accessory ingredients excipients and/or the formulations of the invention comprise ingredients that are from either natural or non-natural sources.
  • any component of the compositions, carriers, accessory ingredients, excipients and/or the formulations of the invention may be provided in a sterile form.
  • a sterile carrier include endotoxin-free water or pyrogen-free water.
  • the pharmaceutical composition of the invention is provided as part of a sterile composition/formulation comprising an active agent of the invention and a pharmaceutically acceptable carrier and/or excipient.
  • Dosage forms suitable for the oral administration include tablet, capsule, powder, pill, granule, suspension, solution or preconcentrate of solution, emulsion or preconcentrates of emulsion.
  • Pharmaceutical acceptable carriers that can be used in an oral dosage form include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. Carriers such as starches, sugars, microcrystalline cellulose, diluents, filler, glidants, granulating agents, lubricants, binders, stabilizers, disintegrating agents and the like can be used to prepare an oral solid preparation such as powder, capsule or tablet.
  • the diluent includes, but not limited to, microcrystalline cellulose, mannitol, powdered sugar, compressible sugar, dextran, dextrin, spinose, lactose, cellulose powder, sorbitol, sucrose and Talc powder or a combination thereof.
  • the diluent may be 5%to 90%based on the total weight of the oral composition, preferably 10%to 80%, 20%-70%, 30%-60%, 40%-50%.
  • the disintegrating agent includes, but not limited to, cellulose, alginate, gum, cross-linked polymer, such as cross-linked polyvinylpyrrolidone or crospovidone, croscarmellose sodium, croscarmellose calcium, soybean polysaccharide, sodium starch glycolate, guar gum or any combination thereof.
  • the disintegrating agent may be present in an amount of about 1%to 15%, preferably 2%to 10%, based on the total weight of the oral composition.
  • the binder includes, but not limited to, starch, cellulose or derivatives thereof, such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methyl cellulose, sucrose, dextrose, corn syrup, polysaccharide, gelatin or any combination thereof.
  • the binder may be present in an amount of 0.01 to 10%, preferably 1%to 10%, based on the total weight of the composition.
  • the glidant includes, but not limited to, colloidal silicon dioxide, magnesium trisilicate, cellulose powder, talc powder or a combination thereof can be selected.
  • the glidant may be present in an amount of 0.1%to 10%, preferably 0.1%to 0.5%, based on the total weight of the composition.
  • Dosage forms can be in the form, e.g., of tablets or capsules, and the effective dose may be provided in one or more tablets, capsules or the like, and be provided once a day or throughout the day at intervals, e.g., of 4, 8 or 12 hours.
  • Tablets or capsules could contain, e.g., 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1, 000, 1, 100, or 1, 250 mg of the active agent.
  • administration to a human subject of the active agent of the present invention may comprise a daily dosage in the range of 100-1, 250, 150-1, 000, 200-800, or 250-750 mg, which daily dosage can be administered either once a day in its entirety or fractions of which are administered throughout the day in intervals.
  • Liquid formulations can also be prepared so that any dosage may readily and conveniently be dispensed.
  • Parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a subject.
  • Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable carrier for injection, suspensions ready for injection, and emulsions.
  • Suitable carriers that can be used to provide parenteral dosage forms provided herein include, but are not limited to: water for injection; aqueous vehicles such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection; water-miscible carriers such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous carriers such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection
  • water-miscible carriers such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol
  • non-aqueous carriers such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil,
  • cyclodextrin and its derivatives can be used to increase the solubility of an active agent of the present invention.
  • a therapeutically effective dose may be determined by a physician, according to such as the type, stage and/or severity of the disease, the condition, age, body weight, sex and response of the subject to be treated, as well as the route of administration.
  • a therapeutically effective amount is an amount such that when administered to a subject is sufficient to achieve a plasma concentration of from about 0.01 ⁇ g/ml to about 100 ⁇ g/ml, from about 0.1 ⁇ g/ml to about 10 ⁇ g/ml, from about 1 ⁇ g/ml to about 5 ⁇ g/ml.
  • the therapeutically effective amount of each of the active agents generally may be in the range of about 0.5 to about 250 mg/kg, about 1 to about 250 mg/kg, about 2 to about 200 mg/kg, about 3 to about 120 mg/kg, about 5 to about 250 mg/kg, about 10 to about 200 mg/kg, or about 20 to about 120 mg/kg for each active agent of the present invention.
  • the therapeutically effective amount may be 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 8 mg/kg, 10 mg/kg, 20 mg/kg, 25 mg/kg, 40 mg/kg, 50 mg /kg, 60 mg/kg, 75 mg/kg, 100 mg/kg, 120 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 225 mg/kg, 250 mg/kg or 300 mg/kg.
  • Each of the active agents of the present invention may be administered once or twice one day; or once every 2, 3, 4, 5, 6, 7, 8, 9 or 10 days or once every 1, 2 or 3 weeks.
  • each of the active agents of the present invention may be administered in a five times weekly scheme. In the five times weekly scheme, the administration may be done on five consecutive days (once daily) followed by two consecutive days off.
  • kit refers to a package and, as a rule, instruction for use.
  • An active agent or a pharmaceutical composition in a kit can be in any of a variety of forms suitable for distribution in a kit. Such forms can include a liquid, powder, tablet, suspension and the like. Two or more active agents may be provided in separate containers suitable for administration separately, or alternatively may be provided in a composition in a single container in the package.
  • the kit may contain an amount sufficient for one or more dosages of agents according to the treatment methods.
  • the instruction for use generally comprises a literal statement of how to treat a disease (such as ALS) with the agents in the kit.
  • combination or pharmaceutical composition of the present invention may include other therapeutic agents or therapies, such as biological therapeutic agents and/or chemotherapeutic agents in addition to the active agents of the present invention.
  • the method may include administration of other therapeutic agents or therapies, such as biological therapeutic agents and/or chemotherapeutic agents in addition to administration of the active agents of the present invention.
  • Other therapeutic agents or therapies may be administered simultaneously, separately or sequentially with the therapeutic agents of the present invention.
  • PandaOmics was a cloud-based target discovery platform with multiple deep learning models and AI algorithms incorporated in the target prioritization process. Twenty-three target prioritization models covering Omics, Text-based, Financial, and Key Opinion Leader (KOL) data were developed to predict the association between the target genes and a particular indication. Scores of each of the models are given in a normalized scale from zero to one, with higher scores corresponding to better target-disease association as predicted by the model. These models were validated using a Time Machine approach to confirm their abilities in target identification. Adjustable filters for druggability, tissue specificity, target family, and developmental status were also available to refine the target list.
  • KOL Key Opinion Leader
  • the targets were subjected to immunohistochemistry (IHC) analysis in the human paraffin-embedded ovarian endometrial stromal (EMS) , peritoneal EMS and normal EMS tissue to confirm their protein expressions using anti-Hematopoietic Cell Kinase antibody.
  • IHC immunohistochemistry
  • EMS cells were transfected with 10nM of non-target control siRNA or siRNA targeting Hematopoietic Cell Kinase, and expression of Hematopoietic Cell Kinase was confirmed by quantitative PCR (qPCR) and immunofluorescence (IF) staining with anti-Hematopoietic Cell Kinase antibody.
  • qPCR quantitative PCR
  • IF immunofluorescence
  • Three functional assays were performed subsequently, including CCK8 assay for cell viability, IF staining against anti-Ki-67 antibody for cell proliferation, and TUNEL assays for apoptosis assay. Both CCK8 and TUNEL assays were conducted according to the manufacturer’s instructions.
  • Endometriosis mimic mouse models were established by the subcutaneous and intraperitoneal transplantation of the endometrial tissue dissected from the uterus horns of a healthy female mouse in another healthy female mouse, respectively. 2 weeks following the transplantation, the mice were divided into two groups, and subjected to either of the treatments: intraperitoneal administration of siRNA of Hematopoietic Cell Kinase or non-target siRNA control, for a week. Body weight of the mice was monitored daily. At day 7, mice were sacrificed and the peritoneal lesions were excised. Lesion volume and weight were recorded. The xenografts underwent expression validation of Hematopoietic Cell Kinase by qPCR and IHC, followed by Ki-67 IHC staining and TUNEL assay.
  • Endometriosis meta-analysis with 11 subtype and cycle nonspecific comparisons was utilized for target identification (Table 1) .
  • 141 unique genes with three levels of novelties were screened based on the ranking calculated by PandaOmics, the consistency of dysregulated expression across comparisons included in the meta-analysis, statistical significance of the dysregulation, as well as literature support in driving endometriosis or with potential roles in the underlying mechanisms promoting endometriosis.
  • Hematopoietic Cell Kinase was identified as potential therapeutic candidates for endometriosis. It ranked as the top-50 targets under novel settings in the meta-analysis, and had 6 Omics score models having 6 models scored 0.8 or above (FIG. 1B) .
  • Immunohistochemistry (IHC) staining was performed to evaluate the protein expression dysregulation of the targets in the paraffin-embedded ovarian and peritoneal EMS tissue samples, and revealed Hematopoietic Cell Kinase was significantly overexpressed in the ovarian EMS tissues in contrast to the normal endometrial stroma (FIG. 2B and 2C) .
  • consistent upregulations of Hematopoietic Cell Kinase were observed in mRNA and protein levels in endometriosis samples, supporting its potential in driving endometriosis.
  • siHCK treatment decreased Ki-67 IHC staining intensity in the endometriotic cells (FIG. 4F) .
  • Inhibition of Hematopoietic Cell Kinase also significantly promoted cell apoptosis (FIG. 4G) .
  • intraperitoneal treatment of HCK significantly reduced ectopic lesion growth (FIG. 4H) .
  • Target knockdown was confirmed for siHCK (FIG. 4I) .
  • siHCK tended to decrease the proliferative ability of the endometriotic cells (FIG. 4K) and significantly induced apoptosis in the ectopic lesions (FIG. 4L) .
  • dysregulated pathway analysis was performed to address the mechanistic explanation of the effect of Hematopoietic Cell Kinase on endometriosis.
  • the number of comparisons having significant dysregulation of each pathway was indicated by the length of the bar, by which green and red represent activation and inhibition, respectively.
  • the majority of the altered pathways associated with Hematopoietic Cell Kinase was linked to immune and infection (lower panel) .
  • Four out of eight Hematopoietic Cell Kinase-associated immune pathways (labeled in blue) were activated. These spotted the potential for developing Hematopoietic Cell Kinase as immune targets.

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Abstract

L'invention concerne une méthode et un médicament pour le traitement de l'endométriose chez un sujet qui le nécessite, comprenant l'administration d'une quantité efficace d'un inhibiteur de la kinase des cellules hématopoïétiques chez ledit sujet.
PCT/CN2024/110949 2023-08-10 2024-08-09 Méthode et médicament pour le traitement de l'endométriose Pending WO2025031474A1 (fr)

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