WO2018081342A1 - Inhibiteurs de lsd1 et leurs utilisations - Google Patents

Inhibiteurs de lsd1 et leurs utilisations Download PDF

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Publication number
WO2018081342A1
WO2018081342A1 PCT/US2017/058404 US2017058404W WO2018081342A1 WO 2018081342 A1 WO2018081342 A1 WO 2018081342A1 US 2017058404 W US2017058404 W US 2017058404W WO 2018081342 A1 WO2018081342 A1 WO 2018081342A1
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compound
pharmaceutically acceptable
acceptable salt
formula
composition
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PCT/US2017/058404
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English (en)
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Victor S. Gehling
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Constellation Pharmaceuticals, Inc.
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Publication of WO2018081342A1 publication Critical patent/WO2018081342A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Lysine-specific demethylase also known as lysine (K)-specific demethylase 1A (LSD1)
  • LSD1 is a protein in humans that in encoded by the KDM1A gene and specifically demethylates mono- or dimethylated histone H3 lysine4 (H3K4) and H3 lysine 9 (H3K9) via a redox process.
  • H3K4 histone H3 lysine4
  • H3K9 H3 lysine 9
  • LSD1 has been found to possess oncogenic properties in several cancers ranging from prostate (Cancer Res., 66 (2006), pp. 11341-11347) bladder (Mol. Carcinog., 50 (2011), pp.
  • neuroblastomas (Cancer Res., 69 (2009), pp. 2065-2071) lung cancers, (PLoS One, 7 (2012), p. e35065) sarcomas and hepato-carcinomas (Tumour Biol. (2012). LSD1 pharmacological inhibitors have been shown e.g., to treat leukemias (Nat. Med., 18 (2012), pp. 605-611) and also solid tumors (Tumour Biol. (2012)).
  • compositions comprising compounds of Formula I are effective inhibitors of LSD1.
  • These compounds were not only found to be effective inhibitors, but it was also surprisingly found that the replacement of ethyl for methyl led to approximately a 28- to 30-fold improvement in potency. See Table 1 in the
  • FIG. 1 depicts the X-ray crystal structure for intermediate (lR,2S)-2-((E)-l- phenylbut-l-en-2-yl)cyclopropan-l -amine (S)-2-hydroxy-2-phenylacetate.
  • Stereoisomers are compounds that differ only in the spatial arrangement of their atoms. Different spatial arrangements in a compound can result from e.g., the orientation of four different substituents around a chiral carbon atom (i.e., a chiral center), the orientation of two or more substituents around a double bond, or the orientation of two or more substituents on a cycloalkyl ring.
  • Enantiomers are one type of stereoisomer that can arise from a chiral center or chiral centers. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom or carbon atoms that acts as a chiral center(s).
  • R and S represent the absolute configuration of substituents around one or more chiral carbon atoms, where each chiral center is assigned the prefix "R” or "S” according to whether the chiral center configuration is right- (clockwise rotation) or left-handed (counter clockwise rotation). If the turn is clockwise or right-handed about a chiral carbon, the designation is "R” for rectus. If the turn is counter clockwise or left-handed about a chiral carbon, the designation is "S” for sinister.
  • Enantiomeric purity reflects the degree to which one enantiomer of a compound is predominantly present over the other enantiomer of that compound. It is determined by subtracting the percent composition of the major enantiomer with the percent composition of the minor enantiomer that is present. For example, a racemic mixture has an enantiomeric purity of 0%, while a single completely pure enantiomer has an enantiomeric purity of 100%. A composition with 70% of one enantiomer and 30% of the other has an enantiomeric purity of 40% (70% - 30%).
  • Diastereomers are stereoisomers that are not related as object and mirror image and are not enantiomers. Unlike enantiomers which are mirror images of each other and non- superimposable, diastereomers are not mirror images of each other and non-superimposable. Diastereomers have two or more chiral centers.
  • Geometric isomers arise when two or more substituents on a double bond or ring can have different spatial orientations with respect to one another due to the presence of the double bond or ring structure.
  • orientation of the substituents of a geometric isomer are on opposite sides of the double bond, those substituents are said to be “trans” to one another or denoted by the letter "E.”
  • orientation of the substituents of a geometric isomer are on the same side of the double bond, those substituents are said to be "cis" to one another or denoted by the letter "Z.”
  • stereochemical purity with respect to that double bond is at least 85%, at least 90%, at least 95%, at least 97%, at least 98% or at least 99% by weight.
  • Stereochemical purity by weight with respect to a double bond means the percent by weight of the compound in a composition having the indicated stereochemistry about the double bond.
  • compounds having the Formula I when the double bond is represented by it is to be understood that the compound has a
  • Geometric isomers can also arise based on the orientation of two or more substituents about a cyclic group.
  • the orientation of about the cyclopropyl can give rise to two different cis configurations
  • the structure includes one of the cis or trans isomers free of other cis and trans stereoisomers, or, alternatively, any mixture of cis and trans stereoisomers.
  • stereochemistry about the cyclopropyl in the compounds of Formula I is indicated by structure only, the structure is meant to depict the relative stereochemistry at one of the chiral centers in the cyclopropyl relative to the stereochemistry at the other chiral center, and not the absolute stereochemistry at either chiral center in the cyclopropyl.
  • the stereochemical purity of the compound with respect to the depicted trans configuration about the cyclopropyl is at least 85%, at least 90%, at least 95%, at least 97%, at least 98% or at least 99% by weight, i.e., the percent by weight of the compound in the composition having the trans stereochemistry at the cyclopropyl is at least 85%, at least 90%, at least 95%, at least 97%, at least 98% or at least 99% by weight.
  • composition contains the other trans configuration as : ; or at least at least 85%, at least 90%, at least 95%, at least 97%, at least 98% or at least 99% by weight of the compound in the composition is a mixture of the two trans configurations.
  • a compound of Formula I represented by the formula: means at least 85%, at least 90%, at least 95%, at least 97%, at least 98% or at least 99% by weight, i.e., the percent by weight of the indicated stereoisomer of the compound in the composition.
  • a compound of Formula I represented by the formula: means at least 85%, at least 90%, at least 95%, at least 97%, at least 98% or at least 99% by weight, i.e., the percent by weight of the indicated stereoisomer of the compound in the composition.
  • a compound of Formula I represented by the formula: means at least 85%, at least 90%, at least 95%, at least
  • the enantiomeric purity is at least 95% (e.g., at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%).
  • the compounds described herein may be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids).
  • subject and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • companion animals e.g., dogs, cats, and the like
  • farm animals e.g., cows, pigs, horses, sheep, goats and the like
  • laboratory animals e.g., rats, mice, guinea pigs and the like.
  • mice e.g., mice, guinea pigs and the like
  • the present disclosure provides a compound of the Formula I:
  • the present disclosure provides a compound of the Formula IV:
  • the present disclosure provides a compound of the
  • the present disclosure provides a compound of the Formula IX:
  • the compound described in any one of the fifth, sixth, seventh, or eighth embodiments is a single enantiomer having an enantiomeric purity of at least 95% (e.g., at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%).
  • compositions comprising the compounds described herein, or a pharmaceutically acceptable salt thereof.
  • compositions further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in the composition is such that is effective to measurably modulate LSD1, or a mutant thereof in a biological sample or in a patient.
  • a composition described herein is formulated for administration to a patient in need of such composition. In some aspects, a composition described herein is formulated for oral administration to a patient.
  • pharmaceutically acceptable carrier, adjuvant, or vehicle refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphat
  • compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions described herein may also be prepared in injectable form.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal
  • Topically- transdermal patches may also be used.
  • compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor, such as e.g., 0.1 - 100 mg/kg body weight/day, can be
  • compositions administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of compound described herein in the composition will also depend upon the particular compound in the composition.
  • the compounds and compositions described herein are useful in treating diseases and/or disorders associated with overexpression of LSD 1 and/or expression of a mutant form of LSD1, such as those mutant forms that alter LSD1 substrate activity.
  • the compounds and compositions described herein are useful in treating diseases and/or disorders associated with cellular proliferation. In some embodiments, the compounds and compositions described herein are useful in treating diseases and/or disorders associated with misregulation of cell cycle or DNA repair. In some embodiments, the compounds and compositions described herein are useful in treating cancer. Exemplary types of cancer include breast cancer, prostate cancer, colon cancer, renal cell carcinoma, glioblastoma multiforme cancer, bladder cancer, melanoma, bronchial cancer, lymphoma and liver cancer.
  • the present disclosure provides a method of reducing the activity of LSD 1 in a subject comprising the step of administering a compound described herein, or a composition comprising any of the compounds herein. In some embodiments, the present disclosure provides a method of reducing the activity of wide-type LSD1 in a subject comprising the step of administering a compound described herein, or a composition comprising any of the foregoing. In some embodiments, the present disclosure provides a method of reducing the activity of a mutant form of LSDl in a subject comprising the step of administering a compound described herein, or a composition comprising any of the foregoing.
  • the present disclosure provides a method of treating a disease or condition related to cancer including e.g., tumors such as skin, breast, brain, cervical carcinomas, testicular carcinomas, etc.
  • cancers that may be treated by the compositions and methods described herein include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • the present disclosure provides a method of treating a disease or condition selected from one or more of the following, Cardiac: sarcoma
  • angiosarcoma fibrosarcoma, rhabdomyosarcoma, liposarcoma
  • myxoma rhabdomyoma
  • fibroma lipoma
  • teratoma teratoma
  • bronchogenic carcinoma squamous cell
  • bronchiolar carcinoma bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;
  • Gastrointestinal esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,
  • adenocarcinoma insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma
  • small bowel adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);
  • Genitourinary tract kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate ( adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocyto
  • Nervous system skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningio sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);
  • skull osteoma, hemangioma, granuloma, xanthoma, osteitis deformans
  • meninges meningioma, meningio sarcoma, gliomatosis
  • brain astrocytom
  • Gynecological uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myel
  • the present disclosure provides a method of treating a disease or condition seleted from CML, T-ALL, neuroblastoma, breast cancer, prostate cancer, herpes simplex virus reactivation, and HIV infection comprising the step of administering to a subject in need thereof a compound described herein, or a pharmaceutically acceptable salt thereof.
  • the disease or condition is selected from CML, T-ALL, and neuroblastoma.
  • the present disclosure contemplates individual compounds described herein. Where individual compounds exemplified are isolated and/or characterized as a salt, for example, as a trifluoroacetic acid salt, the present disclosure contemplates a free base of the salt, as well as other pharmaceutically acceptable salts of the free base.
  • Ethyl 2-(diethoxyphosphoryl)acetate (182.0kg, 812.5mol) was dissolved in THF (2200kg) and cooled to 0 °C.
  • Potassium ie/t-butanolate (105.0kg, 937.5mol) was added in one portion and the reaction mixture was stirred vigorously at 0 °C for 15 min.
  • (E)-2- benzylidenebutanal 130.0 kg, 812.5mol l.Oeq was added to the reaction mixture and the reaction mixture was stirred at 25 °C for 16 h.
  • the reaction mixture was quenched with H 2 0 (320.0kg) and extracted with EtOAc (360.0kg).
  • the organic layer was dried over sodium sulfate and filtered.
  • the crude oil was dissolved in petroleum ether (50 kg) .
  • the suspension was filtered through a pad of silica gel and the filter cake was washed with petroleum ether.
  • the combined filtrates were concentrated to afford the crude acyl azide.
  • the crude acyl azide was taken up in toluene (100kg) and the solution was heated to 85°C for 2 h.
  • the organic layer was concentrated to -60L.
  • Potassium trimethylsilanolate 23.0kg, 177.9mol
  • the reaction was then treated with HC1 (2N aq., 120kg) and stirred.
  • the layers were separated.
  • the organic layer was extracted twice with HC1 (2N aq., 20kg) and the aqueous extracts were combined.
  • the aqueous layer was then extracted with MTBE (150kg).
  • the organic extracts were washed with brine, dried with sodium sulfate and filtered.
  • To this MTBE solution was added HC1 (23.5kg, 12% in diethyl ether) and a white solid precipitated from solution. The solid was collected to afford (irafts)-2-((E)-l-phenylbut- l-en-2- yl)cyclopropan- 1 -amine hydrochloride (16.5kg, 73.8mol).
  • each of the aforementioned examples can be reproduced to afford the oppostite enantiomer about the cyclopropyl (i.e., 1S,2R) using the procedures described above and (lS,2R)-2-((E)-l-phenylbut-l-en-2-yl)cyclopropan-l-amine (S)-2-hydroxy-2-phenylacetate instead of (lR,2S)-2-((E)-l-phenylbut-l-en-2-yl)cyclopropan-l -amine (S)-2-hydroxy-2- phenylacetate.
  • the structures of these enantiomers are reproduced below.
  • LSD1 demethylase reactions were carried out in 50 niM HEPES pH 7.4, 100 niM NaCl, 1 niM DTT, 0.01% Tween-20, and 0.1 mg/niL BSA. All enzymatic reactions were performed for 50 minutes at room temperature in a ⁇ - ⁇ volume. Five microliters of 8 ⁇ biotinylated H3K4mel peptide solution was added to each well of a black 384 well, clear- bottom assay plate containing 80 nL compound (final concentration of 0.8% DMSO and 4 ⁇ substrate). Reactions were initiated by the addition of a mixture containing 20 nM LSD1 and 80 nM FAD (5 ⁇ ).
  • LSD1 and FAD final concentrations were 10 and 40 nM, respectively.
  • Enzyme activity was stopped by the addition of 90 ⁇ ⁇ of high salt buffer consisting of 50 mM HEPES pH 7.4, 500 mM NaCl, 1 mM DTT, 0.01% Tween-20, and 0.1 mg/mL BSA.
  • Ten microliters of the quenched reaction mixtures were transferred to a black 384 well ProxiPlate.
  • Ten microliters of detection mixture was added to the ProxiPlate, Europium-labeled antibody and Streptavidin APC were used at final concentrations of 0.3 nM and 200 nM, respectively (total assay volume of 20 ⁇ ).
  • MV4-11 cells were cultured at a density of 4 x 10 4 cells per well in a 96- well plates and treated with various doses inhibitor starting from 10 ⁇ up to 0.0005 ⁇ for 16h.
  • the LY-96 mRNA induction was quantified using the Quantigene 2.0 system (Affymetrix). The cells were lysed with Lysis Mixture containing Proteinase K. The working reagent for capturing the RNA was prepared according to the steps detailed in "Capturing Target RNA from Cultured Cell or Blood Lysates" in the Quantigene handbook. The subsequent hybridization with LY-96 probe, signal amplification and detection steps were performed as described in the manual. The chemiluminescence was read using Envision (PerkinElmer) and Abase (IDBS software) was used to plot the dose response curves and calculate IC 50 . Results are shown in Table 1.
  • the disclosed compounds are not only effective LSD1 inhibitors, but they displayed a 28- 30-fold improvement in potency when compared to the methyl analogue comparator compound.

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Abstract

L'invention concerne de nouveaux composés de formule (I) et leurs sels pharmaceutiquement acceptables, qui sont utiles pour le traitement de divers troubles, maladies ou états pathologiques, associés à LSDl. L'invention concerne également des compositions pharmaceutiques comprenant les nouveaux composés de formule (I), leurs sels pharmaceutiquement acceptables, et leurs procédés d'utilisation dans le traitement d'un ou de plusieurs troubles, maladies ou états pathologiques, associés à LSDl.
PCT/US2017/058404 2016-10-26 2017-10-26 Inhibiteurs de lsd1 et leurs utilisations WO2018081342A1 (fr)

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Cited By (8)

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Publication number Priority date Publication date Assignee Title
WO2019025588A1 (fr) 2017-08-03 2019-02-07 Oryzon Genomics, S.A. Méthodes de traitement des altérations du comportement
WO2020188090A1 (fr) 2019-03-20 2020-09-24 Oryzon Genomics, S.A. Procédés de traitement d'un trouble de la personnalité borderline
WO2020188089A1 (fr) 2019-03-20 2020-09-24 Oryzon Genomics, S.A. Procédés de traitement d'un trouble d'hyperactivité avec déficit de l'attention au moyen d'inhibiteurs de kdm1a tels que le composé vafidemstat
WO2021004610A1 (fr) 2019-07-05 2021-01-14 Oryzon Genomics, S.A. Biomarqueurs et procédés pour le traitement personnalisé d'un cancer du poumon à petites cellules au moyen d'inhibiteurs de kdm1a
WO2022214303A1 (fr) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 pour le traitement de cancers myéloïdes
WO2023217784A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement de tumeurs mutantes nf1 à l'aide d'inhibiteurs de lsd1
WO2023217758A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement d'une tumeur maligne des gaines des nerfs périphériques (tmgnp) à l'aide d'inhibiteurs de lsd1
WO2024110649A1 (fr) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 et d'inhibiteurs de ménine pour le traitement du cancer

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019025588A1 (fr) 2017-08-03 2019-02-07 Oryzon Genomics, S.A. Méthodes de traitement des altérations du comportement
WO2020188090A1 (fr) 2019-03-20 2020-09-24 Oryzon Genomics, S.A. Procédés de traitement d'un trouble de la personnalité borderline
WO2020188089A1 (fr) 2019-03-20 2020-09-24 Oryzon Genomics, S.A. Procédés de traitement d'un trouble d'hyperactivité avec déficit de l'attention au moyen d'inhibiteurs de kdm1a tels que le composé vafidemstat
WO2021004610A1 (fr) 2019-07-05 2021-01-14 Oryzon Genomics, S.A. Biomarqueurs et procédés pour le traitement personnalisé d'un cancer du poumon à petites cellules au moyen d'inhibiteurs de kdm1a
WO2022214303A1 (fr) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 pour le traitement de cancers myéloïdes
WO2023217784A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement de tumeurs mutantes nf1 à l'aide d'inhibiteurs de lsd1
WO2023217758A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement d'une tumeur maligne des gaines des nerfs périphériques (tmgnp) à l'aide d'inhibiteurs de lsd1
WO2024110649A1 (fr) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 et d'inhibiteurs de ménine pour le traitement du cancer

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