WO2024006527A1 - Méthode de traitement du cancer du sein - Google Patents

Méthode de traitement du cancer du sein Download PDF

Info

Publication number
WO2024006527A1
WO2024006527A1 PCT/US2023/026735 US2023026735W WO2024006527A1 WO 2024006527 A1 WO2024006527 A1 WO 2024006527A1 US 2023026735 W US2023026735 W US 2023026735W WO 2024006527 A1 WO2024006527 A1 WO 2024006527A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
breast cancer
tazemetostat
Prior art date
Application number
PCT/US2023/026735
Other languages
English (en)
Inventor
Ryan Willard
Original Assignee
Arvinas Operations, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Arvinas Operations, Inc. filed Critical Arvinas Operations, Inc.
Publication of WO2024006527A1 publication Critical patent/WO2024006527A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/495—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings

Definitions

  • TNBC Triple-negative breast cancer
  • ER estrogen receptor
  • PR progesterone receptor
  • Her2/neu Her2/neu.
  • TNBC accounts for 15-25% of breast cancers. It is more difficult to treat than other breast cancer subtypes because most chemotherapies target one of the three receptors.
  • TNBC has a relapse pattern that is very different from hormone-positive breast cancers. The risk of relapse is much higher for the first 3-5 years but drops sharply and substantially below that of hormone-positive breast cancers after that. This relapse pattern has been recognized for all types of triple-negative cancers for which sufficient data exists, although the absolute relapse and survival rates differ across subtypes.
  • TNBC triple-negative breast cancer
  • a combination therapy comprising an effective amount of an androgen receptor (AR) degrading proteolysis targeting chimera (PROTAC) and an enhancer of zeste homolog 2 (EZH2) degrading PROTAC to a subject in need thereof.
  • AR androgen receptor
  • PROTAC proteolysis targeting chimera
  • EZH2 enhancer of zeste homolog 2
  • TNBC triple negative breast cancer
  • TNBC triple negative breast cancer
  • the combination therapies described herein comprise an effective amount of
  • Compound 1 or a pharmaceutically acceptable salt thereof; and an effective amount of Compound 3: or a pharmaceutically acceptable salt thereof.
  • the combination therapies described herein comprise an effective amount of Compound 2: or a pharmaceutically acceptable salt thereof; and an effective amount of Compound 3:
  • the subject treated using the disclosed combination therapies is a human.
  • kits comprising: (1) Compound 1 or Compound 2: or a pharmaceutically acceptable salt thereof;
  • the kit comprises:
  • the kit comprises:
  • the kit comprises directions on how to administer at least one dose of Compound 1 or Compound 2 and at least one dose of Compound 3 to a human.
  • the kit further comprises at least one sterile container for dispensing each dose of Compound 1 or 2.
  • the kit further comprises at least one sterile container for dispensing each dose of Compound 3.
  • FIG. 1 is a bar graph measuring colony formation of BT549 cells treated with DMSO (0.1 %), enzalutamide (3 pM, enza), tazemetostat (IpM, taz), Compound 2 (0.3 pM), Compound 3 (3pM) and combinations of enzalutamide (3 pM, enza), tazemetostat (1 pM, taz), Compound 2 (0.3 pM), and Compound 3 (3 pM).
  • FIG. 2 is a bar graph measuring colony formation of BT549 cells treated with DMSO (0.1 %), enzalutamide (3 pM, enza), tazemetostat (1 pM, taz), Compound 1 (0.3 pM), Compound 3 (3 pM) and combinations of enzalutamide (3 pM, enza), tazemetostat (1 pM, taz), Compound 1 (0.3 pM), and Compound 3 (3 pM).
  • FIG. 3 is a bar graph measuring colony formation of MDA-MB-453 treated with DMSO (0.1 %), enzalutamide (3 pM, enza), tazemetostat (1 pM, taz), Compound 1 (0.3 pM), Compound 3 (3 pM) and combinations of enzalutamide (3 pM, enza), tazemetostat (1 pM, taz), Compound 1 (0.3 pM), and Compound 3 (3 pM).
  • FIG. 4 is a bar graph measuring colony formation of MCF7 cells treated with DMSO (0.1 %), enzalutamide (3 pM, enza), tazemetostat (IpM, taz), Compound 2 (0.3 pM), Compound 3 (3pM) and combinations of enzalutamide (3 pM, enza), tazemetostat (1 pM, taz), Compound 2 (0.3 pM), and Compound 3 (3 pM).
  • FIG. 5 is a bar graph measuring colony formation of T47D cells treated with DMSO (0.1 %), enzalutamide (3 pM, enza), tazemetostat (IpM, taz), Compound 2 (0.3 pM), Compound 3 (3pM) and combinations of enzalutamide (3 pM, enza), tazemetostat (1 pM, taz), Compound 2 (0.3 pM), and Compound 3 (3 pM).
  • FIG. 5 is a bar graph measuring colony formation of T47D cells treated with DMSO (0.1 %), enzalutamide (3 pM, enza), tazemetostat (IpM, taz), Compound 2 (0.3 pM), Compound 3 (3pM) and combinations of enzalutamide (3 pM, enza), tazemetostat (1 pM, taz), Compound 2 (0.3 pM), and Compound 3 (3
  • FIG. 6 shows receptor degradation in BT549 cells treated with DMSO, enzalutamide (enza), tazemetostat (taz), Compound 2, Compound 3, and combinations of enzalutamide (enza), tazemetostat (taz), Compound 2, and Compound 3.
  • FIG. 7 shows receptor degradation in BT549 cells treated with DMSO, enzalutamide (enza), tazemetostat (taz), Compound 2, Compound 3, and combinations of enzalutamide (enza), tazemetostat (taz), Compound 2, and Compound 3.
  • FIG. 8 shows receptor degradation in BT549 cells treated with DMSO, enzalutamide (enza), tazemetostat (taz), Compound 1, Compound 3, and combinations of enzalutamide (enza), tazemetostat (taz), Compound 1, and Compound 3.
  • Breast cancer is the most common form of cancer in women. Breast cancer is a heterogeneous disease having diverse physiological characteristics and clinical responses. Breast cancer types are divided based on receptor expression.
  • estrogen receptor ER
  • progesterone receptor PR
  • human epidermal growth factor receptor 2 HER2
  • TNBC Triple-negative breast cancer
  • ER estrogen receptor
  • PR progesterone receptor
  • HER2 Her2/neu
  • Tumors that express ER and PR are treated with agents that interfere with hormone production or action.
  • Tumors that have amplified HER- 2/Neu are treated with agents that inhibit HER-2/Neu. This makes TNBC more difficult to treat because most chemotherapies target one of the three receptors.
  • Triplenegative breast cancers have a relapse pattern that is very different from hormonepositive breast cancers: the risk of relapse is much higher for the first 3-5 years but drops sharply and substantially below that of hormone-positive breast cancers after that.
  • TNBC is thus very aggressive and has the worst prognosis of all breast cancer types. This relapse pattern has been recognized for all types of triple-negative cancers for which sufficient data exists although the absolute relapse and survival rates differ across subtypes. TNBC is typically high grade (poorly differentiated) and rapidly progressive, with a higher risk of relapse and lower survival than other subtypes of breast cancer. Conventional treatments are limited by poor therapeutic response, high toxicity, and the development of resistance.
  • an object of the present disclosure is to provide a safe, tolerable, and effective method for treating a subject suffering from TNBC.
  • a combination therapy comprising an effective amount of an androgen receptor (AR) degrading PROteolysis TArgeting Chimera (PROTAC) (e.g., Compound 1 or Compound 2, or a pharmaceutically acceptable salt thereof) and an enhancer of zeste homolog 2 (EZH2) degrading PROTAC (e.g., Compound 3, or a pharmaceutically acceptable salt thereof) to a subject in need thereof.
  • AR androgen receptor
  • PROTAC PROteolysis TArgeting Chimera
  • EZH2 enhancer of zeste homolog 2
  • PROTACs androgen receptor (AR) degrading PROteolysis TArgeting Chimeras
  • PROTACs androgen receptor (AR) degrading PROteolysis TArgeting Chimeras
  • EZH2 enhancer of zeste homolog 2
  • the AR degrading PROTAC is Compound 1: or a pharmaceutically acceptable salt thereof. In embodiments, the AR degrading PROTAC is Compound 2: or a pharmaceutically acceptable salt thereof.
  • the EZH2 degrading PROTAC is Compound 3: or a pharmaceutically acceptable salt thereof.
  • administering refers to contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
  • Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
  • administering also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell.
  • treatment comprises reversing, alleviating, delaying the onset of, or inhibiting the progress of a breast cancer (e.g., triple negative breast cancer), or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a particular organism, or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.
  • a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a particular organism, or other susceptibility factors), i.e., prophylactic treatment.
  • Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.
  • the “effective amount” refers to an amount of a compound or pharmaceutically acceptable salt described herein that is sufficient to achieve the desired therapeutic effect (such as treatment of a cancer recited herein) under the conditions of administration.
  • subject is used interchangeably with “patient” and includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.
  • a mammal e.g., rat, mouse, dog, cat, and rabbit
  • cancer refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • examples of cancer include breast cancer (e.g., metastatic and/or triple negative breast cancer) and melanoma.
  • Consists essentially of and variations such as “consist essentially of’ or “consisting essentially of,” as used throughout the specification and claims, indicate the inclusion of any recited elements or group of elements, and the optional inclusion of other elements, of similar or different nature than the recited elements, that do not materially change the basic or novel properties of the specified dosage regimen, method, or composition.
  • TNBC triple negative breast cancer
  • TNBC is used herein to refer to breast cancer that is characterized by tumors with less than 10% of the cells positive for estrogen receptor and progesterone receptor and without HER2 amplification as well as patients who are not candidates for endocrine therapy (Dawood “Triple Negative Breast Cancer” Drugs 2010, Vol.70(17), p.2247-58). TNBC tends to be more aggressive than other types of breast cancer and thus, is more likely to spread beyond the breast and/or to recur after treatment.
  • breast cancer e.g., triple negative breast cancer
  • methods for treating breast cancer comprising administering a combination therapy comprising an effective amount of
  • Compound 1 or Compound 2 or a pharmaceutically acceptable salt thereof; and an effective amount of Compound 3: or a pharmaceutically acceptable salt thereof.
  • breast cancer breast cancer e.g., triple negative breast cancer
  • methods for treating breast cancer breast cancer comprising administering a combination therapy comprising an effective amount of Compound 1 : or a pharmaceutically acceptable salt thereof; and an effective amount of Compound 3: or a pharmaceutically acceptable salt thereof.
  • breast cancer breast cancer e.g., triple negative breast cancer
  • methods for treating breast cancer breast cancer comprising administering a combination therapy comprising an effective amount of Compound 2:
  • Each therapeutic agent in the disclosed combination therapies may be present either alone or as part of the same medicament (e.g., as a single pharmaceutical composition) that comprises at least each therapeutic agent and one or more pharmaceutically acceptable carriers, excipients, and diluents, according to standard pharmaceutical practice.
  • Each therapeutic agent in the described combination therapies may be administered simultaneously (z.e., in the same medicament), concurrently (z.e., in separate medicaments administered one right after the other in any order) or sequentially in any order.
  • Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms (e.g., one agent is a tablet or capsule and another agent is a sterile liquid) and/or are administered on different dosing schedules, e.g., a chemotherapeutic that is administered at least daily and a biotherapeutic that is administered less frequently, such as once weekly, once every two weeks, or once every three weeks.
  • the AR degrading PROTAC (e.g., Compound 1 or Compound 2, or a pharmaceutically acceptable salt thereof) is administered before administration of the EZH2 degrading PROTAC (e.g., Compound 3), while in other embodiments, the AR degrading PROTAC (e.g., Compound 1 or Compound 2, or pharmaceutically acceptable salt thereof) is administered after administration of the EZH2 degrading PROTAC (e.g., Compound 3, or a pharmaceutically acceptable salt thereof).
  • At least one of the therapeutic agents in the combination therapy is administered using the same dosage regimen (dose, frequency, and duration of treatment) that is typically employed when the agent is used as monotherapy.
  • the subject receives a lower total amount of at least one of the therapeutic agents in the combination therapy than when the agent is used as monotherapy, e.g., smaller doses, less frequent doses, and/or shorter treatment duration.
  • a combination therapy of the invention may be used prior to or following surgery to remove a tumor and may be used prior to, during or after radiation therapy.
  • a combination therapy of the invention is administered to a patient who has not been previously treated with a biotherapeutic or chemotherapeutic agent, i.e., is treatment-naive.
  • the combination therapy is administered to a patient who failed to achieve a sustained response after prior therapy with a biotherapeutic or chemotherapeutic agent, i.e., is treatment-experienced.
  • the described compounds, or their pharmaceutically acceptable salts, of the methods described herein can be administered alone or as part of a pharmaceutical composition that includes an effective amount for a patient, typically a human, in need of such treatment in a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may contain the described compound or pharmaceutically acceptable salt as the only active agent, or, in an alternative embodiment, the described compound or pharmaceutically acceptable salt and at least one additional active agent for treating breast cancer (e.g., triple negative breast cancer).
  • the pharmaceutical compositions may be administered in a therapeutically effective amount by any desired mode of administration, but typically is administered as an intravenous injection or infusion.
  • the described compounds or pharmaceutically acceptable salts are delivered in an effective amount with a pharmaceutically acceptable carrier for oral delivery.
  • the pharmaceutical composition may be suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, transdermal, pulmonary, vaginal, or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous, and intravenous), injections, inhalation, or spray, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, or by other means of administration containing conventional pharmaceutically acceptable carriers.
  • Suitable dosage ranges depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound used, the route and form of administration, and the preferences and experience of the medical practitioner involved.
  • One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compositions of the disclosure for a given disease.
  • a pharmaceutical composition is in a dosage form comprising from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 750 mg, from about 1 mg to about 500 mg, or from about 5 mg, 10 mg, 15 mg, or 20 mg to about 250 mg of a described compound or a pharmaceutically acceptable salt thereof.
  • dosage forms are those delivering at least 0.01 mg, 0.05 mg, 0.1 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 750 mg of active compound, or its salt.
  • the weight can refer to either the compound alone or the compound in combination with its pharmaceutically acceptable salt.
  • an effective amount of a described compound or a pharmaceutically acceptable salt thereof may be administered based on the weight, size, or age of the patient.
  • an effective amount may for example be in the range of about 0.01 mg/kg to about 250 mg/kg body weight, or about 0.1 mg/kg to about 10 mg/kg, in at least one dose.
  • the patient can be administered as many doses as are required to reduce and/or alleviate and/or cure the disorder in question.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • the effective amount ranges from about 0.01 mg/kg to about 100 mg/kg of subject’s body weight, for example, about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, or about 100 mg/kg.
  • compositions may be in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of a described compound or pharmaceutically acceptable salt thereof.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packed tablets, capsules, and powders in a sterile container (e.g., vial, ampoule, blister pack, bottle, sachet, syringe, etc.).
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge, or it can be the appropriate number of any of these in a sterile container.
  • Non-limiting examples of pharmaceutically acceptable salts include: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palm
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
  • compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrup, suspensions, creams, ointments, lotions, paste, gel, spray, aerosol, foam, or oil, injection or infusion solution, a transdermal patch, a subcutaneous patch, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution, or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
  • Carriers include excipients and diluents and should be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
  • the carrier can be inert, or it can possess pharmaceutical benefits of its own.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Classes of carriers include, but are not limited to adjuvants, binders, buffering agents, coloring agents, diluents, disintegrants, excipients, emulsifiers, flavorants, gels, glidents, lubricants, preservatives, stabilizers, surfactants, solubilizer, tableting agents, wetting agents, or solidifying material.
  • Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others.
  • Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers and vegetable oils.
  • Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of a described compound of pharmaceutically acceptable salt thereof.
  • excipients include, but are not limited, to liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like.
  • the compound can be provided, for example, in the form of a solid, a liquid, spray dried material, a microparticle, nanoparticle, controlled release system, etc., as desired according to the goal of the therapy.
  • Suitable excipients for non-liquid formulations are also known to those of skill in the art. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington’s Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).
  • a biological buffer can be any solution which is pharmacologically acceptable, and which provides the formulation with the desired pH, a pH in the physiologically acceptable range.
  • buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’ s buffered saline, and the like.
  • conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, and the like, an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like.
  • permeation enhancer excipients including polymers such as: poly cations (chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosanthiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).
  • polymers such as: poly cations (chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosanthiobutylamidine, chito
  • the excipient is selected from butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (com), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xyl,
  • compositions containing the described compounds or pharmaceutically acceptable salts are formulated for oral administration.
  • the composition may take the form of a tablet, capsule, a softgel capsule or can be an aqueous or nonaqueous solution, suspension, or syrup. Tablets and capsules are typical oral administration forms. Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added.
  • compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and the like.
  • an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and the like.
  • suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • suitable binders include starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • a described compound or pharmaceutically acceptable salt thereof may be combined with any oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents can be added as well.
  • Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.
  • Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions.
  • sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing, or wetting agents and suspending agents.
  • the sterile injectable formulation can also be a sterile injectable solution or a suspension in a acceptably nontoxic parenterally acceptable diluent or solvent.
  • acceptable vehicles and solvents that can be employed are water, Ringer’ s solution, and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters, or polyols are conventionally employed as solvents, or suspending media.
  • parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
  • Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacterio stats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • aqueous and non-aqueous, isotonic sterile injection solutions which can contain antioxidants, buffers, bacterio stats, and solutes that render the formulation isotonic with the blood of the intended recipient
  • aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • Administration via certain parenteral routes can involve introducing the formulations of the disclosure into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as a continuous infusion system.
  • a formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.
  • BT549 triple negative breast cancer, AR+, M subtype cells were treated with DMSO (0.1%), enzalutamide (3 pM), tazemetostat (1 pM), Compound 2 (0.3 pM), Compound 3 (3 pM), enzalutamide (3 pM) and tazemetostat (1 pM), Compound 2 (0.3 pM) and tazemetostat (1 pM), enzalutamide (3 pM) and Compound 3 (3 pM), and Compound 2 (0.3 pM) and Compound 3 (3 pM).
  • Cells were retreated every 3-4 days. Colony formation was measured by Cell Titer Gio Assay (Promega, Catalog # G7573) after 14 days.
  • BT549 triple negative breast cancer, AR+, M subtype cells were treated with DMSO (0.1%), enzalutamide (3 pM), tazemetostat (1 pM), Compound 1 (0.3 pM), Compound 3 (3 pM), enzalutamide (3 pM) and tazemetostat (1 pM), Compound 1 (0.3 pM) and tazemetostat (1 pM), enzalutamide (3 pM) and Compound 3 (3 pM), and Compound 1 (0.3 pM) and Compound 3 (3 pM).
  • Cells were retreated every 3 - 4 days. Colony formation was measured by Cell Titer Gio Assay (Promega, Catalog # G7573) after 14 days.
  • MDA-MB-453 (HER2+ BCa, LAR) cells were treated with DMSO (0.1%), enzalutamide (3 pM), tazemetostat (1 pM), Compound 1 (0.3 pM), Compound 3 (3 pM), enzalutamide (3 pM) and tazemetostat (1 pM), Compound 1 (0.3 pM) and tazemetostat (1 pM), enzalutamide (3 pM) and Compound 3 (3 pM), and Compound 1 (0.3 pM) and Compound 3 (3 pM).
  • Cells were retreated every 3-4 days. Colony formation was measured by Cell Titer Gio Assay (Promega, Catalog # G7573) after 14 days.
  • Compound 3 was equally effective in inhibiting colony formation as tazemetostat. However, Compound 1 was more effective than enzalutamide in inhibiting colony formation. Dual treatment with Compound 1 and Compound 3 effectively inhibited colony formation and was more effective than Compound 1 or 3 alone (FIG. 3).
  • MCF7 (ER+ BCa, Luminal A, AR+) cells were treated with DMSO (0.1%), enzalutamide (3 pM), tazemetostat (1 pM), Compound 2 (0.3 pM), Compound 3 (3 pM), enzalutamide (3 pM) and tazemetostat (1 pM), Compound 2 (0.3 pM) and tazemetostat (1 pM), enzalutamide (3 pM) and Compound 3 (3 pM), and Compound 2 (0.3 pM) and Compound 3 (3 pM).
  • Cells were retreated every 3-4 days. Colony formation was measured by Cell Titer Gio Assay (Promega, Catalog # G7573) after 14 days.
  • monotreatment with Compound 3 is more effective than tazemetostat and is substantially the same as to dual treatment with enzalutamide and tazemetostat.
  • dual treatment with Compounds 2 and 3 was the most effective in inhibiting colony formation. Indeed, dual treatment with Compounds 2 and 3 were overall more effective than small molecule inhibitors (z.e., enzalutamide and tazemetostat), either as a monotherapy or a combination therapy with either of Compounds 2 or 3 or with each other (z.e., enzalutamide and tazemetostat, Compound 2 and tazemetostat, or enzalutamide and Compound 3).
  • T47D (ER+ BCa, Luminal A, AR+) cells were treated with DMSO (0.1%), enzalutamide (3 pM), tazemetostat (1 pM), Compound 2 (0.3 pM), Compound 3 (3 pM), enzalutamide (3 pM) and tazemetostat (1 pM), Compound 2 (0.3 pM) and tazemetostat (1 pM), enzalutamide (3 pM) and Compound 3 (3 pM), and Compound 2 (0.3 pM) and Compound 3 (3 pM).
  • Cells were retreated every 3-4 days. Colony formation was measured by Cell Titer Gio Assay (Promega, Catalog # G7573)after 14 days.
  • BT549 triple negative breast cancer, AR+, M subtype cells were treated with DMSO, enzalutamide, tazemetostat, Compound 1 or Compound 2, Compound 3, enzalutamide and tazemetostat, Compound 1 or Compound 2 and tazemetostat, enzalutamide and Compound 3, and Compound 1 or Compound 2 and Compound 3. Treatments were carried out in 6-well plates for 72-hours. Plates were frozen at 80 °C.
  • the cells were harvested, and lysed in RIPA buffer (50 mM Tris pH8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% Sodium Deoxycholate) supplemented with protease and phosphatase inhibitors. Lysates were clarified at 16,000 g for 10 minutes, and supernatants were separated by SDS-PAGE. Immunoblotting was performed using standard protocols.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des méthodes de traitement du cancer du sein (par exemple, un cancer du sein triple négatif) comprenant l'administration d'une polythérapie comprenant une quantité efficace d'une chimère ciblant la protéolyse de dégradation du récepteur des androgènes (AR) (par exemple, le composé 1 ou le composé 2) et un activateur de la chimère ciblant la protéolyse de dégradation de l'homologue 2 de Zeste (EZH2) (par exemple, le composé 3) à un sujet en ayant besoin.
PCT/US2023/026735 2022-07-01 2023-06-30 Méthode de traitement du cancer du sein WO2024006527A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263357848P 2022-07-01 2022-07-01
US63/357,848 2022-07-01

Publications (1)

Publication Number Publication Date
WO2024006527A1 true WO2024006527A1 (fr) 2024-01-04

Family

ID=87474093

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/026735 WO2024006527A1 (fr) 2022-07-01 2023-06-30 Méthode de traitement du cancer du sein

Country Status (1)

Country Link
WO (1) WO2024006527A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018119357A1 (fr) * 2016-12-24 2018-06-28 Arvinas, Inc. Composés et méthodes pour la dégradation ciblée d'activateur du polypeptide homologue 2 de zeste
WO2022031642A2 (fr) * 2020-08-04 2022-02-10 Oric Pharmaceuticals, Inc. Utilisations d'associations d'antagoniste du récepteur des glucocorticoïdes (gr) et d'agent de dégradation du récepteur des androgènes (ar)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018119357A1 (fr) * 2016-12-24 2018-06-28 Arvinas, Inc. Composés et méthodes pour la dégradation ciblée d'activateur du polypeptide homologue 2 de zeste
WO2022031642A2 (fr) * 2020-08-04 2022-02-10 Oric Pharmaceuticals, Inc. Utilisations d'associations d'antagoniste du récepteur des glucocorticoïdes (gr) et d'agent de dégradation du récepteur des androgènes (ar)

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY
DAWOOD: "Triple Negative Breast Cancer", DRUGS, vol. 70, no. 17, 2010, pages 2247 - 58
HAN XIN ET AL: "Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer", JOURNAL OF MEDICINAL CHEMISTRY, vol. 64, no. 17, 25 August 2021 (2021-08-25), US, pages 12831 - 12854, XP093059787, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.1c00882 *
LV MOYANG ET AL: "Proteolysis-targeting chimeras: A promising technique in cancer therapy for gaining insights into tumor development", CANCER LETTERS, NEW YORK, NY, US, vol. 539, 30 April 2022 (2022-04-30), XP087056291, ISSN: 0304-3835, [retrieved on 20220430], DOI: 10.1016/J.CANLET.2022.215716 *
WANG CHENG ET AL: "Discovery of precision targeting EZH2 degraders for triple-negative breast cancer", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 238, 20 May 2022 (2022-05-20), XP087102922, ISSN: 0223-5234, [retrieved on 20220520], DOI: 10.1016/J.EJMECH.2022.114462 *

Similar Documents

Publication Publication Date Title
US10722512B2 (en) Combinations of histone deacetylase inhibitors and either HER2 inhibitors or PI3K inhibitors
AU2014299699B2 (en) Use of eribulin and lenvatinib as combination therapy for treatment of cancer
RU2543348C2 (ru) Способ лечения путем применения комбинированной терапии
JP6182510B2 (ja) カバジタキセルの新規の抗腫瘍的使用
US10463654B2 (en) Combination therapies for treating cancer
BR112016015763B1 (pt) Preparação farmacêutica incluindo composto de ácido piridilaminoacético, e, uso da mesma
ES2405323T3 (es) Tratamiento de melanoma
EP3324968B1 (fr) Combinaisons thérapeutiques de paclitaxel et d'un inhibiteur de p-gp à usage oral pour le traitement du cancer
US20230046317A1 (en) Inhibitors of Glutathione S-Transferases (GSTS) and NAD(P)H:Quinone Oxidoreductase 1 (NQO1), Pharmaceutical Compositions, and Uses in Managing Cancer
EP2538935B1 (fr) Suppression du développement du cancer et des métastases en utilisant des dérivés d'acide nordihydroguaïarétique avec de la 7-hydroxystaurosporine
WO2024006527A1 (fr) Méthode de traitement du cancer du sein
US20160120871A1 (en) Pharmaceutical combinations of a pi3k inhibitor and a microtubule destabilizing agent
TW202128151A (zh) 癌症治療方法
US20190046513A1 (en) Combination therapies of hdac inhibitors and tubulin inhibitors
JP2006089455A (ja) 動脈瘤予防および／または治療剤
US20220409611A1 (en) Methods of treating, ameliorating, and/or preventing cancer using pyrvinium compositions
US20230165811A1 (en) Method for treating symptoms of viral infections
US8273721B2 (en) Combination treatment for bladder cancer
US10064798B1 (en) Method for modulating pigmentation by targeting BET bromodomain proteins
JP2024520567A (ja) 肺線維症の予防または治療用の薬学製剤
KR20210091713A (ko) 테세탁셀로 cns 종양을 치료하는 방법
RU2242229C2 (ru) Применение эпотилонов для лечения рака
KR20060120204A (ko) 삼출성 중이염의 예방 및/또는 치료제

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23745699

Country of ref document: EP

Kind code of ref document: A1