WO2005110392A1 - Procedes de modulation de l'activite de flt3 - Google Patents

Procedes de modulation de l'activite de flt3 Download PDF

Info

Publication number
WO2005110392A1
WO2005110392A1 PCT/AU2005/000694 AU2005000694W WO2005110392A1 WO 2005110392 A1 WO2005110392 A1 WO 2005110392A1 AU 2005000694 W AU2005000694 W AU 2005000694W WO 2005110392 A1 WO2005110392 A1 WO 2005110392A1
Authority
WO
WIPO (PCT)
Prior art keywords
flt3
alkyl
formula
group
compound
Prior art date
Application number
PCT/AU2005/000694
Other languages
English (en)
Inventor
Bruce Kemp
Harshal Nandurkar
Richard Gilbert
Original Assignee
The University Of Melbourne
St Vincent's Institute Of Medical Research
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
Priority claimed from AU2004902608A external-priority patent/AU2004902608A0/en
Application filed by The University Of Melbourne, St Vincent's Institute Of Medical Research filed Critical The University Of Melbourne
Publication of WO2005110392A1 publication Critical patent/WO2005110392A1/fr

Links

Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • This invention relates to methods for the treatment of conditions characterised by abnormal F T3 activity, such as leukaemias.
  • FLT3 FMS-Like Tyrosine Kinase 3
  • STK-1 human stem cell kinase 1
  • F K-2 fetal liver kinase 2
  • CD135 CD135
  • FLT3 expression in the normal bone marrow appears to be restricted to early progenitor cells.
  • FLT3 ligand is expressed by cells in the bone marrow, including bone marrow fibroblasts, as well as in hematopoietic cell lines of myeloid, and B- and T-cell lineages.
  • the ligand is found in two forms, a transmembrane protein and a soluble dimer.
  • the binding of FL to FLT3 activates the receptor, causing dimerisation of the receptor which in turn leads to increased receptor tyrosine kinase activity and the activation of downstream signalling pathways. FL binding is thus able to stimulate growth of progenitor cells in the bone marrow and blood.
  • FLT3 is strongly expressed by malignant cells from a range of haematological disorders, such as acute myelogenous leukaemia (AML) , B-precursor cell acute lymphoblastic leukaemia (ALL) , a proportion of T-cell ALL, and chronic myelogenous leukaemia (CML) during the lymphoid blast crisis phase.
  • AML acute myelogenous leukaemia
  • ALL B-precursor cell acute lymphoblastic leukaemia
  • CML chronic myelogenous leukaemia
  • FLT3 expression has been demonstrated at high levels in 70-100% of AML cases and in a high percentage of ALL cases, and has been shown to be involved in the survival and proliferation of leukemic blasts. Mutations associated with FLT3 have been identified in cells from AML subjects. Internal tandem duplication (FLT3-ITD) mutations in the juxtamembrane region of FLT3 are found in 25-30% of AML patients. A further 7% of subjects exhibit point mutations in the activation loop of the kinase domain of FLT3. These point mutations may include substitution of Asp835 with Tyr, Val , His, Glu or Asn.
  • FLT3 constitutive tyrosine kinase activity by FLT3
  • leukemic subjects exhibiting these mutations have a poorer prognosis than subjects with a wild type pattern of FLT3 expression or activity.
  • the administration of FL has been demonstrated to enhance the proliferation and survival of leukemia blasts.
  • FL stimulates the proliferation of FLT3 -expressing primary AML cells and leukemic myeloid and monocytoid cell lines.
  • FL also acts in synergy with other growth factors in stimulating the proliferation of primary AML and ALL cells, and exerts an anti-apoptotic activity in primary AML cells.
  • the modulation of FLT3 tyrosine kinase activity represents a potential therapeutic target for conditions, such as haematological malignancies, which are associated with and responsive to the modulation of FLT3 activity.
  • a variety of agents targeting this molecule are in various stages of clinical development .
  • Recent animal models exhibiting the FLT3-ITD abnormality have illustrated the potential therapeutic value of FLT3 as a target for therapeutic intervention.
  • FLT3 tyrosine kinase inhibitor PKC412
  • PKC412 has subsequently been shown to decrease peripheral and bone marrow blast cell counts and FLT3 autophosphorylation in human subjects with AML.
  • a potent agonist designated CT53518, of FLT3 , platelet-derived growth factor receptor and c-Kit, was able to specifically inhibit FLT3 autophosphorylation in cells which expressed FLT3-ITD, and to induce apoptosis and inhibit autophosphorylation and cellular proliferation in AML cell lines which expressed FLT3-ITD.
  • This molecule was also reported to demonstrate therapeutic efficacy in a nude mouse model and a murine bone marrow transplant model of FLT3-ITD- induced disease.
  • Other studies have demonstrated that a tyrosine kinase inhibitor, SU11248, inhibited the phosphorylation of wild type FLT3 , FLT3-ITD and the point mutation FLT3 - Asp835 in cell lines, and that administration of this molecule in an animal model induced regression of subcutaneous FLT3-ITD tumors and increased survival in a FLT3-ITD bone marrow engraftment model.
  • a phase I/II clinical trial with the receptor tyrosine kinase inhibitor CEP-701 demonstrated that this molecule was able to reduce bone marrow and peripheral blast levels in human subjects with AML.
  • a method of modulating FLT3 activity in a subject in need thereof comprising administering to the subject a therapeutically or prophylactically effective amount of a compound of Formula I :
  • each of Rl and R2 is a hydrogen atom or a Cl-6 alkyl group ; each of R3 and R4 are each hydrogen atoms, or R3 and R4 together form a second carbon-to-carbon bond;
  • R5 is carboxylic acid; carboxylic acid ester; Cl-6 alkyl or Cl-6 alkoxy; each X is a hydroxyl group, a halogen atom, a nitro group, a Cl-6 alkyl group or a Cl-6 alkoxy group; and n is an integer of 1-3, with the proviso that when n is 2, and the two Xs are alkyl or alkoxy groups, they may be connected together to form a ring, or a salt, hydrate, pro-drug, isomer, tauto er, metabolite and/or a pharmaceutically acceptable derivative thereof.
  • the method comprising administering a therapeutically or prophylactically effective amount of a compound of Formula I to a subject in need thereof.
  • the condition associated with abnormal FLT3 activity is a haematological malignancy, such as a leukaemia.
  • a compound of Formula I for the treatment of a condition associated with abnormal FLT3 activity.
  • a pharmaceutical or veterinary agent for treating a condition associated with FLT3 activity which comprises a compound of Formula I .
  • compositions for the treatment and/or prevention of a condition associated with abnormal FLT3 activity comprising a compound of Formula I together with a pharmaceutically acceptable carrier.
  • the compound of Formula I is Tranilast.
  • Tranilast and derivatives thereof were first described in US patent 3,940,422. Since then, further derivatives have been developed and their pharmaceutical application explored. Tranilast is commercially available, and may be converted into a derivative thereof through straightforward synthetic procedures. Alternatively, any of the range of derivatives disclosed in US 3,940,442 may be synthesized using the techniques described therein. Accordingly, the entire contents of 3,940,442 are hereby incorporated into the present specification by reference. Any of the Tranilast derivatives may be used in the methods of the invention, provided that they have the ability to modulate FLT3 tyrosine kinase activity, as defined herein. Of the compounds of Formula I, those in which R 3 and R 4 together form a second carbon-to-carbon bond are preferred. Such compounds may be represented by the formula :
  • Ri, R 2 , R 5 X and n have the same meanings as those given above ; including salts, hydrates, pro-drugs, isomers, tautomers, metabolites and/or derivatives thereof.
  • R x and R 2 are hydrogen atoms.
  • R 5 is selected from carboxylic acid and carboxylic acid esters.
  • each X is a hydroxyl group, a halogen atom, a Cl-6 alkyl group or a Cl-6 alkoxy group.
  • n is 2, and each of X are alkoxy groups, more preferably methoxy.
  • alkyl used either alone or in a compound word such as "alkoxy” denotes straight chain, branched or cyclic alkyl.
  • straight chain and branched alkyl include methyl, ethyl, propyl , isopropyl, butyl, isbutyl, sec-butyl, tert-butyl, amyl , isoamyl, sec- amyl , 1 , 2-dimethylpropyl , 1 , 1-dimethylpropyl , hexyl , 4- methylpentyl, 1-methylpentyl , 2-methylpentyl , 3- methylpentyl , 1 , 1-dimethylbutyl , 2 , 2-dimethylbutyl , 3,3- dimethylbutyl, 1 , 2-dimethylbutyl , 1 , 3-dimethylbutyl , 1 , 2 , 2-trimethylpropyl , 1 , 1 , 2-trimethylprop
  • cyclic alkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • the alkyl may optionally be substituted by any non-deleterious substituent.
  • the alkyl may be Cl-6 alkyl, but is preferably Cl-4 alkyl.
  • n is 2 or more, and two Xs are alkyl or alkoxy, and together form a ring, the two Xs will be understood to form a divalent alkylene group or an alkyleneoxy group. Examples are propylene, butylene, butyleneoxy and so forth.
  • Halogen refers to chloro, fluoro, iodo and bromo.
  • alkoxy used either alone or in compound words such as denotes straight chain or branched alkoxy. Examples of alkoxy include methoxy, ethoxy, n- propyloxy, isopropyloxy and the various butyloxy isomers.
  • carboxylic acid refers to the group -
  • carboxylic acid ester refers to the group -C0 2 R 6 in which R 6 is an alkyl group, preferably a C ⁇ _ 6 alkyl group.
  • FLT3 tyrosine kinase inhibitory activity may be readily determined
  • the salts of the compound of Formula I or II are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present application, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • Examples of pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, trihalomethanesulphonic , toluenesulphonic , benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic
  • solvates are encompassed within the scope of the application.
  • pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, hydrate, or any other compound which, upon administration to the subject, is capable of providing (directly or indirectly) a compound of Formula I or an active metabolite or residue thereof .
  • pro-drug is used herein in its broadest sense to include those compounds which are converted in vivo to compounds of Formula I, for example, organic acid esters or ethers.
  • tautomer is used herein in its broadest sense to include compounds of Formula I which are capable of existing in a state of equilibrium between two isomeric forms.
  • Such compounds may differ in the bond connecting two atoms or groups and the position of these atoms or groups in the compound.
  • the term “isomer” is used herein in its broadest sense and includes structural, geometric and stereo isomers. As the compound of Formula I may have one or more chiral centres, it is capable of existing in enantiomeric forms.
  • modulating FLT3 activity refers to any one or more of inhibiting FLT3 tyrosine kinase activity, reducing FLT3 tyrosine kinase activity, reducing or inhibiting FLT3 autophosphorylation, or reducing or inhibiting one or more downstream signaling events which are dependent on FLT3 tyrosine kinase activity.
  • condition associated with abnormal FLT3 activity refers to any one or more of: conditions associated with an activating mutation of FLT3 and/or abnormally high levels of FLT3 tyrosine kinase activity or downstream signaling events which are dependant on FLT3 tyrosine kinase; for instance in conditions where FLT3 is constitutively active, such as haematological malignancies in which there is a FLT3-ITD mutation or one or more point mutations in the activation domain of FLT3 ; or conditions associated with an abnormal number or distribution of cells which express FLT3 , such as leukaemias which are characterised by the presence of circulating FLT3 -expressing leukemic blasts or elevated concentrations of blast cells in the bone marrow which express relatively high levels of FLT3 ; and including in some embodiments conditions characterized by an abnormal number or distribution of cells which express a wild-type FLT3 or a FLT3 which is dependent on ligand binding for its tyrosine kinas
  • treating is used herein to mean affecting a subject, tissue, cell or enzyme to obtain a desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or sign or symptom thereof, and/or may be therapeutic in terms of a partial or complete cure of a disease.
  • Treating covers any treatment of, or prevention of disease in a vertebrate, a mammal, particularly a human, and includes: inhibiting the disease, i.e., arresting its development; or relieving or ameliorating the effects of the disease, i.e., cause regression of the effects of the disease.
  • “Prophylaxis” or “prophylactic” or “preventative” therapy as used herein includes preventing the disease from occurring or ameliorating the subsequent progression of the disease in a subject that may be predisposed to the disease, but has not yet been diagnosed as having it.
  • the term "subject” as used herein refers to any animal having a disease or condition which requires treatment with a pharmaceutically-active agent.
  • the subject may be a mammal, preferably a human, or may be a non-human primate or non-primates such as used in animal model testing.
  • Tranilast is suitable for use in medical treatment of humans, it is also applicable to veterinary treatment, including treatment of companion animals such as dogs and cats, and domestic animals such as horses, ponies, donkeys, mules, llama, alpaca, pigs, cattle and sheep, or zoo animals such as primates, felids, canids, bovids, and ungulates .
  • Suitable mammals include members of the Orders Primates, Rodentia, Lagomorpha, Cetacea, Carnivora,
  • compositions of the present invention or usable in the methods of the present invention comprise at least a compound of Formula I or II together with one or more pharmaceutically acceptable carriers and optionally other therapeutic agents.
  • Each carrier, diluent, adjuvant and/or excipient must be pharmaceutically "acceptable" in the sense of being compatible with the other ingredients of the composition and not injurious to the subject.
  • compositions include those suitable for ocular (including tear film, anterior chamber, posterior chamber or subretinal administration) , oral, rectal, nasal, topical (including buccal and sublingual) , vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intrader al) administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound of Formula I or II with the carrier which constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association the compound with liquid carriers, diluents, adjuvants and/or excipients or finely divided solid carriers or both, and then if necessary shaping the product .
  • the compound of Formula I or II may additionally be combined with other medicaments to provide an operative combination. It is intended to include any chemically compatible combination of pharmaceutically-active agents, as long as the combination does not eliminate the activity of the compound. It will be appreciated that the compound of Formula I or II and the other medicament may be administered separately, sequentially or simultaneously.
  • Other medicaments may include, but are not limited to imatinib mesylate or other agents which are used in the treatment of AML, such as cytarabine, anthracyclines such as daunorubicin, idarubicin, etoposide, all trans-retinoic acid (ATRA) and/or arsenic trioxide.
  • a compound of Formula I or II such as Tranilast
  • MDR1 modulators such as the cyclosporine analogue PSC-833; demethylating agents such as decitabine and 5-azacytidine; histone deacetylase inhibitors such as phenylbutyrate and depsipeptide; heavy metals such as antimony; protein kinase C inhibitors such as bryostain and UCN-01; cell cycle inhibitors such as flavopiridol ; antibodies such as those directed against CD33 such as gemtuzumab, ozogamicin and anti-CD33 antibodies conjugated with a toxin (eg CMA- 676) or a radioisotope (eg Yttrium-90) ; thalidomide; and cytokines such as IL-2 and IL-12.
  • MDR1 modulators such as the cyclosporine analogue PSC-833
  • demethylating agents such as decitabine and 5-azacytidine
  • a compound of Formula I or II such as Tranilast
  • another therapeutic or prophylactic compound such as imatinib mesylate
  • imatinib mesylate is administered either simultaneously or sequentially in combination with another therapeutic or prophylactic compound, such as imatinib mesylate, to treat or prevent conditions which are not primarily activated by FLT3 , but which are characterized by the presence of cells which express FLT3.
  • an example of such combination therapy is the combined administration of imatinib mesylate and
  • Tranilast for CML, where the leukemic cells express a wild type FLT3 but are activated by ABL tyrosine kinase.
  • a compound of Formula I or II such as Tranilast might also be used in combination with inhibitors of the FLT3 downstream signaling pathway, such as inhibitors of Ras, Raf, MEK, and ERK.
  • a "pharmaceutical carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering the compound of Formula I or II to the subject.
  • the carrier may be liquid or solid and is selected with the planned manner of administration in mind. Each carrier must be pharmaceutically "acceptable” in the sense of being not biologically or otherwise undesirable i.e.
  • the carrier may be administered to a subject along with the compound of Formula I or II without causing any or a substantial adverse reaction.
  • the compound of Formula I or II may be administered orally, topically, or parenterally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • parenteral as used herein includes subcutaneous injections, aerosol for administration to lungs or nasal cavity, intravenous, intramuscular, intrathecal, intracranial , injection or infusion techniques .
  • the present application also provides suitable topical, oral, and parenteral pharmaceutical formulations for use in the methods of treatment disclosed in the present application.
  • the compound of Formula I or II such as Tranilast, or a pharmaceutically acceptable derivative thereof may be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs.
  • the composition for oral use may contain one or more agents selected from the group of sweetening agents, flavouring agents, colouring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations.
  • Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin.
  • Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar .
  • Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, Orange or raspberry flavouring.
  • Suitable preservatives include sodium benzoate, vitamin E, alphatocopherol , ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
  • Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
  • Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
  • the tablets contain the compound of Formula I or II in admixture with non- toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents such as corn starch or alginic acid
  • binding agents such as starch, gelatin or acacia
  • lubricating agents such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as gly
  • Coating may also be performed using techniques described in the U.S. Pat. Nos . 4,256,108; 4,160,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • the compound of Formula I or II such as Tranilast
  • the compound of Formula I or II may be added or dissolved in an appropriate biologically acceptable buffer and added to a cell or tissue.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol , polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride
  • lactated Ringer's intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like.
  • Preservatives and other additives may also be present such as, for example, anti-microbials, anti-oxidants , chelating agents, growth factors and inert gases and the like.
  • the compound of Formula I or II may also be presented for use in the form of veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions include those adapted for: (a) oral administration, external application, for example drenches (e.g.
  • aqueous or non-aqueous solutions or suspensions tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;
  • parenteral administration for example by subcutaneous, intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced in the udder via the teat;
  • topical applications e.g. as a cream, ointment or spray applied to the skin; or
  • intravaginally e.g. as a pessary, cream or foam.
  • the term "therapeutically effective amount” is meant an amount of a compound of Formula I or II effective to yield a desired therapeutic response, for example, at least partial remission as measured by determining the levels of leukaemic blast cells in the peripheral circulation and/or bone marrow.
  • a “prophylactically effective amount” has a similar definition.
  • the specific “therapeutically effective amount” will, of course, vary with such factors as the particular condition being treated, the physical condition of the subject, the type of subject being treated, the duration of the treatment, the nature of concurrent therapy (if any) , and the specific compound and formulations employed.
  • Subjects may be selected for suitability for treatment according to the methods provided herein on the basis of the selection criteria used for other trials of FLT3 tyrosine kinase inhibitors (for instance Smith et al., Blood; (2004) 103: 3669-3676; and Stone, et al . , Blood; (2005) 105:54-60).
  • Subjects with an activating FLT3 mutation such subjects with AML with a FLT3-ITD mutation or a point mutation resulting in constitutive expression may be identified by clinical assessment of AML, followed by analysis of peripheral blood or bone marrow samples for the presence of FLT3 mutations as described previously (Armstrong, et al . , Blood (2004); 103 : 3544-3546) .
  • the efficacy of treatment with a compound of Formula I or II, such as Tranilast may be assessed using standard clinical measures of disease progression, such as peripheral or bone marrow blast cell levels in the case of a leukemia. Where there is a mutation of FLT3 which results in aberrant FLT3 activity, the efficacy of treatment may also be monitored by determining the level of FLT3 autophosphorylation in white blood cells from peripheral blood samples according to the method of Stone et al . , or Smith et al . (supra) .
  • This method employs the immunoprecipitation of FLT3 using a polyclonal antibody, followed by SDS-PAGE electrophoresis and western blotting with an antibody 4G10 (Upstate Biotechnology) which is directed against phosphotyrosine .
  • 4G10 Upstate Biotechnology
  • the pharmacokinetics of orally administered Tranilast have been studied in humans (for example Charng, et al . , (2002) Journal of Food and Drug Analysis 10:135- 138, which is herein incorporated by cross reference), and this information can be utilized by the skilled addressee in determining the dosage regimen of Tranilast or other compounds of Formula I or II.
  • Dosage levels of the compound, such as Tranilast, when administered for the treatment of conditions other than cancer are of the order of about 4 mg to about 13 mg per kilogram body weight per day.
  • the use of the compound in treatment of a malignancy allows a greater tolerance of side- effects, and so dosages up to 26 mg/kg/day, and possibly higher may be acceptable.
  • the amount of the compound of Formula I or II which may be combined with the carrier materials to produce a single dosage will vary, depending upon the host treated and the particular mode of administration.
  • a formulation intended for oral administration to humans may contain about 300 mg to 900mg of the compound with an appropriate and convenient amount of carrier material which may vary from about 5 to 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 100 mg to 300 mg of the compound of Formula I or II. It is envisaged that the period of administration of the compound of Formula I or II will be determined by the particular application. In the case of treatment of AML, for instance, the compound may be used to induce remission in a subject. In such a case, administration may commence following diagnosis and continue until clinical monitoring of peripheral blood counts and bone marrow aspirates demonstrate a normal cellularity of the bone marrow, morphologically normal hematopoiesis and blast levels ⁇ 5 % at evaluation of bone marrow smears.
  • the compound may also be utilized in post -remission consolidation, and/or as a therapy in cases of relapse, especially in cases where the compound was not the initial primary treatment agent.
  • the compound may also be used in patients who have had an apparent cure by chemotherapy with or without bone marrow transplant to lower the risk of remission.
  • the compound of Formula I or II is administered in a divided dose schedule, such that there are at least two administrations in total in the schedule. Administrations are given preferably at least every two hours for up to four hours or longer; for example the compound may be administered every hour or every half hour.
  • the divided-dose regimen comprises a secbnd administration of the compound after an interval from the first administration sufficiently long that the level of the compound in the blood has decreased to approximately from 5-30% of the maximum plasma level reached after the first administration, so as to maintain an effective content of the compound in the blood.
  • one or more subsequent administrations may be given at a .corresponding interval from each preceding administration, preferably when the plasma level has decreased to approximately from 10-50% of the immediately preceding maximum. It is possible that during the course of treatment of leukemia, for example with Tranilast, mutations of FLT3 may arise, resulting in a population of leukemic cells which are Tranilast-resistant . In such a case, other compounds of Formula I or II may provide an alternative means of targeting FLT3.
  • Figure 1 represents the dose-response relationship between the concentration of Tranilast (horizontal axis) and its effects on the tyrosine kinase activity of FLT3 in vi tro expressed as a percent of control values (vertical axis) .
  • Figure 2 represents the results of experiments which demonstrate that Tranilast inhibits the proliferation of cells in vi tro which express FLT3-ITD.
  • MV4;11 (FLT3-ITD) cells were cultured in the presence of either 250 ⁇ M or 500 Tranilast for a range of time points: (A) 24 hours; (B) 48 hours; (C) 72 hours; and (D) 96 hours.
  • Tranilast 500 ⁇ M
  • Tranilast stopped cell proliferation at 72 hrs ' (C) while Tranilast (250 ⁇ M) showed an analogous effect at 96 hrs (D) .
  • MV4;11 (FLT3- ITD) cells were cultured in the presence of either 100 ⁇ M, 250 ⁇ M or 500 ⁇ M Tranilast for a range of time points: (A) 24 hours; (B) 48 hours; (C) 65 hours; (D) 96 hours; and (E) 122 hours. Cell viability was assessed using Trypan Blue assay. MV4;11 cells treated with 500 ⁇ M Tranilast stopped growing at 24 hours (A) and cell death followed over time (B, C, D, E) . 250 ⁇ M Tranilast slowed cell growth immediately (A) and started causing cell death at 48 hrs (B) .
  • MV4;11 cells treated with Tranilast demonstrated inhibited cell growth in a concentration and time dependent manner (F) .
  • Example 1 Cell-free kinase assay The ability of Tranilast to inhibit FLT3 tyrosine kinase activity was established in a cell-free system according to the following protocol.
  • Human FLT3 (5-10 mU) was incubated with 8 mM MOPS (3- (N-Morpholino) propanesulphonic acid) pH 7.0, 0.2 mM EDTA, 50 ⁇ M EAIYAAPFAKKK peptide, 10 mM Mg Acetate, 100 ⁇ M Tranilast (Pharm Chemical, Shanghai Lansheng Corporation, Shanghai, China) and 100 ⁇ M [ ⁇ - 33 P-ATP] in a final reaction volume of 25 ⁇ l .
  • MOPS 3- (N-Morpholino) propanesulphonic acid) pH 7.0
  • EDTA 50 ⁇ M EAIYAAPFAKKK peptide
  • 10 mM Mg Acetate 100 ⁇ M Tranilast (Pharm Chemical, Shanghai Lansheng Corporation, Shanghai, China) and 100
  • Tranilast (lOO ⁇ M) was shown to inhibit FLT3 kinase activity, as measured by the phosphorylation of FLT3 to the binding of a specific substrate, to 18% of control levels (no Tranilast) .
  • Tranilast was also found to have relatively little or no inhibitory effect on another tyrosine kinases from the same family of Class III receptor tyrosine kinases, the platelet-derived growth factor receptor, nor on a variety of other human-origin tyrosine kinases. This relative specificity may prove advantageous in minimising the undesired inhibition of other enzymes.
  • the dose-response characteristics of Tranilast on FLT3 activity was explored (Figure 1) . Tranilast concentrations of 300 ⁇ M, 100 ⁇ M, 30 ⁇ M, 10 ⁇ M, 3 ⁇ M, 1 ⁇ M,.
  • Tranilast has an IC50 of approximately 15 ⁇ M.
  • Other compounds of Formula I or II are also tested in this screening assay to determine candidate compounds for further in vi tro and in vivo testing.
  • Formula I or II to inhibit FLT3 in vi tro is assessed by measuring their effects on FLT3 phosphorylation, using a previously described method (O'Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee KW, Wong LM, Hong W, Lee LB, Town A, Smolich BD, Manning WC, Murray LJ, Heinrich MC, Cherrington JM: SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101:3597-3605, 2003), the contents of which are hereby incorporated by reference.
  • FLT3-WT wild-type FLT3
  • RS4;11 a human B-cell precursor leukemia cell line isolated from a subject with ALL (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH No. ACC 508, or ATCC CRL-1873), or cells which express FLT3 with an internal tandem duplication mutation (FLT3-ITD) such as MV4;11, a human acute monocytic leukemia cell line (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, DSMZ No. ACC 102, or ATCC CRL-9591) may be used.
  • FLT3-WT wild-type FLT3
  • RS4;11 a human B-cell precursor leukemia cell line isolated from a subject with ALL (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH No. ACC 508, or ATCC CRL-1873), or cells which express FLT3 with an internal tandem duplication mutation (FLT3-ITD)
  • MV4;11 a human acute monocytic leukemia cell line
  • cell lines such as 32Dcl2 (ATCC Number: CRL-11346) or Ba/F3 (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, DSMZ No. ACC 300) , which are growth-factor dependent murine cell lines, may be transduced with either wild-type FLT3 , FLT3-ITD or FLT3-D835Y by techniques such as electroporation and using lipofectamine as previously described (Grundler R, Thiede C, Montgomeryhing C, Steudel C, Peschel C, Duyster J. Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor. Blood.
  • Cells are treated with Tranilast (0.1 -300 ⁇ M) , for example, for 2 hours in medium containing 0.1% fetal bovine serum (FBS) .
  • FBS fetal bovine serum
  • Cells are then stimulated with 150 ng/mL FLT3 -ligand (FL) for 5 minutes and lysed with 1% (v/v) Triton X-100.
  • Equivalent amounts of protein from each sample are immunoprecipitated overnight at 4°C with an agarose-conjugated anti-FLT3 antibody (Santa Cruz Biotechnology, Santa Cruz, CA) .
  • Immune complexes are washed (150 mM NaCl ; 1.5 mM MgC12; 50 mM HEPES [N-2- hydroxyethylpiperazine-N' -2-ethanesulfonic acid], pH 7.5; 10% glycerol; 0.1% Triton X-100; and 1 mM EGTA (ethylene glycol tetraacetic acid) ) and, following SDS-PAGE, proteins are transferred to nitrocellulose membranes. Membranes are then probed with an anti-phosphotyrosine antibody (Upstate Biotechnology, Lake Placid, NY, or Transduction Laboratories, Lexington, KY) to indicate the state of FLT3 phosphorylation. The membranes are then stripped with Restore Western Blot Stripping Buffer (Pierce, Rockford, IL) and reprobed with an anti-FLT3 antibody (Santa Cruz Biotechnology) to identify the protein bands corresponding to FLT3.
  • Restore Western Blot Stripping Buffer Pierford, IL
  • Example 3 Proliferation and apoptosis Of leukemic cells
  • Tranilast or other compounds of Formula I or II to modulate the proliferation and/or apoptosis of human leukemia cell lines which express wild- type FLT3 (FLT3-WT) , FLT3 with internal tandem duplication mutation (FLT3-ITD) or cells expressing one or more FLT3 activation loop mutations may be examined in vi tro .
  • FLT3-WT wild- type FLT3
  • FLT3-ITD FLT3 with internal tandem duplication mutation
  • cells expressing one or more FLT3 activation loop mutations may be examined in vi tro .
  • the ability of a compound to inhibit FLT3 and influence cell proliferation and/or induce apoptosis is regarded as predictive of benefit in treating subjects with AML
  • kidney cell line HEK 293 showed no decrease in growth when treated with 250 ⁇ M Tranilast for 48 hrs, and showed a relatively small decline in cell viability when treated with 500 ⁇ M Tranilast for 48 or 96 hours when compared with the decline in viability exhibited in Tranilast- treated MV4;11 cells. Similar results were obtained with the monkey kidney cell line COS-7 (American Type Culture Collection) (data not shown) . In another experiment, MV4;11 (FLT3-ITD) cells were cultured in RPMI, 10% FBS in the presence of Tranilast at different time points to determine whether Tranilast modulated the viability of these cells.
  • MV4;11 cells treated with 500 ⁇ M Tranilast stopped growing (A) and cell death followed over time (B, C, D, E) .
  • MV4;11 cells treated with Tranilast demonstrated inhibited cell growth in a concentration and time dependent manner (F) .
  • RS4;11 and MV4;11 human leukemia cell lines are propagated as previously described (Yee KW, O'Farrell AM, Smolich BD, Cherrington JM, McMahon G, Wait CL, McGreevey LS, Griffith DJ, Heinrich MC : SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood 100:2941-2949, 2002, the contents of which are hereby incorporated by reference) .
  • mutant forms of FLT3 can also be generated in such cell lines by site-directed mutagenesis of, for example, Asp835 and/or Ile836, using techniques available in the art (see for example In Vitro Mutagenesis Protocols, 2 nd Edition, Methods in Molecular Biology, Vol 182, Braman, J. Ed, Humana Press or the ®
  • a mutated FLT3 can be transfected into CHO cells using Lipofectamine TM 2000 (Invitrogen, Düsseldorf, Germany) according to manufacturer's instructions .
  • Ba/F3 cells, a murine pro B-cell line (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH No. ACC 300) , are cultured in RPMI 1640 (GIBCO-BRL, Düsseldorf, Germany) supplemented with 10% fetal calf serum (FCS; Biochrom KG, Berlin, Germany), glutamine, and IL-3.
  • HEK 293 cells (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH No. ACC 305) were maintained in Dulbecco modified Eagle medium (DMEM; GIBCO-BRL) supplemented with 10% FCS. Ba/F3 cells are transfected by electroporation. HEK 293 cells are transfected using Lipofectamine 2000 (Invitrogen, Düsseldorf, Germany) according to the manufacturer's recommendations. Tranilast, for example, is prepared in a solution of DMSO. Cells are plated into 96-well plates (2 x 10 4 /well) , and Tranilast added at concentrations of 1 ⁇ M, 3 ⁇ M, 10 ⁇ M, 30 ⁇ M, 100 ⁇ M, 300 ⁇ M .
  • Tranilast for example, is prepared in a solution of DMSO. Cells are plated into 96-well plates (2 x 10 4 /well) , and Tranilast added at concentrations of 1 ⁇ M, 3 ⁇ M, 10 ⁇ M, 30 ⁇ M
  • cell viability and proliferation is measured using the CellTiter Proliferation Assay (Promega, Mannheim, Germany) according to the manufacturer's instructions.
  • the number and proportion of cells exhibiting apoptosis is examined at 24 hours using the Annexin V-FITC (fluorescein isothiocyanate) staining kit (PharMingen) according to the manufacturer's recommendations.
  • Annexin V-FITC fluorescein isothiocyanate
  • Example 4 In vivo testing of Tranilast on specified animal models The ability of Tranilast or other compounds of Formula I or II to inhibit growth of leukemic cells in vivo is examined in a subcutaneous nude mouse (nu/nu) model and a murine bone marrow transplant model .
  • Tranilast 200 mg/kg by gavage in 1% NaHC0 3 administered in a twice daily regimen
  • vehicle placebo, 1% NaHC0 3
  • Tumour growth was measured every three to four days using Vernier calipers. Tumour volumes were calculated as the product of length X width X height . Tranilast treated animals had slower progress to reaching a tumour volume of 200 mm 3 than the placebo treated animals . Further studies are carried out to examine the dose response effects of 200-800 mg/kg per day of Tranilast by oral gavage administered in a twice daily regimen.
  • This model may be used to define the pharmacokinetic and pharmacodynamic relationships of Tranilast or other compounds of Formula I or II with neoplastic conditions related to FLT3 expression.
  • Experiments are scheduled to evaluate the therapeutic effects of daily oral administration of Tranilast on preexisting tumours (size 300-500 mm 3 ) in all studies. Further experiments along the same lines are carried out using other FLT3 expressing cells, including leukemia cell lines such as cell lines which express point mutations in FLT3 which result in constitutive expression of FLT3 tyrosine kinase activity, or cell lines which express a wild type FLT3 which is dependent on ligand binding for FLT3 tyrosine kinase activity.
  • This model may also be used to examine the efficacy of a combination therapy involving a compound of Formula I or II, such as Tranilast, and other anti-cancer agents which target FLT3 or other molecules.
  • the bone marrow model examines the effect of Tranilast on survival in a more physiologically relevant mouse model of AML, in which tumor cells engraft in the bone marrow.
  • Severe combined immunodeficiency disease (SCID) mice or nude mice are pretreated with cyclophosphamide (Neosar, Pharmacia, Kalamazoo, MI) (150 mg/kg/d for 2 days by intraperitoneal injection) , followed by 24 hours of rest before intravenous injection of 5 X 10 6 of either of the human leukemic cell lines MV4;11 or
  • mice are anesthetized, and terminal blood collection carried out by intracardiac puncture.
  • Bone marrow cell suspensions are prepared by flushing the mouse femurs with cold, sterile PBS and total differential cell counts are prepared.
  • sections of experimental mouse tibias are prepared to investigate the morphology of the bone marrow and marrow microvasculture, and to determine levels of cellular proliferation.
  • the efficacy of the treatment is determined by examining for the continued presence of human cells in the bone marrow suspensions, and by determining and quantifying the presence of obvious human cells, abundant local mitotic figures and diffuse infiltration in the bone sections.
  • An alternative bone marrow transplant (BMT) model assay for FLT3-ITD-induced myeloproliferative disease is also used (Kelly, et al . , 2002) .
  • Athymic nude mice are injected with Ba/F3 cells expressing the FLT3-ITD mutation.
  • animals receive vehicle or Tranilast (200-800 mg/kg per day) . Differences in the cumulative survival between vehicle and Tranilast - treated groups are examined over a 60 day period.
  • Example 5 Clinical trials of Tranilast in the treatment of AML Patients with refractory AML are studied using a documented trial design for the study of such patients (Fiedler W, Mesters R, Tinnefeld H, Loges S, Staib P, Duhrsen U, Flasshove M, Ottmann OG, Jung W, Cavalli F, Kuse R, Thomalla J, Serve H, O'Farrell AM, Jacobs M, Brega NM, Scigalla P, Hossfeld DK, Berdel WE: A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukaemia. Blood 102:2763-2767, 2003, the contents of which are hereby incorporated by cross-reference) .
  • Refractory AML is defined as primary resistance against at least 2 induction chemotherapy regimens, or relapsed patients who were refractory against at least 1 re-induction protocol.
  • patients 60 years or older who are judged not medically fit to endure conventional induction chemotherapy may be entered into the protocol . All patients must be HIV-negative and free of leptomeningeal disease by clinical examination.
  • Hydroxyurea is administered to patients with high initial white blood cell count (WBC) until WBC has dropped to lower than 50xl0 9 /L (50 000 cells/ ⁇ L) , and stopped when Tranilast treatment is started. All patients receive Tranilast at a dose of 300- 1800 mg/day given in a twice daily regimen. Complete blood counts are obtained daily during the first 4 days, every 2 days for the first 2 weeks, and later twice weekly. Bone marrow and peripheral blast counts are assessed every 4 weeks to assess disease status. In case of at least a partial response (below) patients may receive additional 4 -week cycles until disease progression is observed. The primary aim of this study is the determination of objective response rate.
  • Safety assessments include the evaluation of adverse events and vital signs, hematologic tests, biochemical tests, urinalysis, and physical examination. Toxicity is graded in accordance with the Common Toxicity Criteria of the National Cancer Institute. Standard criteria are used to define a complete haematological response: decrease in marrow blasts to 5% or less, disappearance of blasts from the peripheral blood, absolute neutrophil count of more than 1 x 10 9 /L (1000 per cubic millimeter) , and a platelet count of more than 100 x 10 9 /L (100 000 per cubic millimeter) .
  • a morphological response is defined as absence of blasts from peripheral blood and 5% or less blasts of bone marrow nucleated cells without requiring recovery of neutrophil or platelet counts.
  • a partial response is defined as a decrease in marrow blast percentage and in absolute peripheral blood blast counts to at least 50% of pre-treatment value.
  • Indices of a desirable therapeutic outcome may include: a reduction in the number and proportion of bone marrow blasts; a reduction in the number and proportion of blast cells in the peripheral circulation; an improvement or normalization in the counts of peripheral neutrophils, platelets and erythrocytes; an increase in the proportion of subjects in complete remission; an increase in the proportion of subjects in partial remission; an improvement in the overall survival rate of the subject population; an improvement in the quality of life of the subject population; and an improvement in performance status of the subject population.

Landscapes

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

Abstract

L'invention concerne des procédés de modulation de l'activité de FLT3, y compris des méthodes de traitement d'états pathologiques caractérisés par une expression anormale de FLT3, tels que la leucémie.
PCT/AU2005/000694 2004-05-14 2005-05-13 Procedes de modulation de l'activite de flt3 WO2005110392A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
AU2004902608 2004-05-14
AU2004902608A AU2004902608A0 (en) 2004-05-14 Therapeutic method
US60096704P 2004-08-12 2004-08-12
US60/600,967 2004-08-12

Publications (1)

Publication Number Publication Date
WO2005110392A1 true WO2005110392A1 (fr) 2005-11-24

Family

ID=35393977

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2005/000694 WO2005110392A1 (fr) 2004-05-14 2005-05-13 Procedes de modulation de l'activite de flt3

Country Status (1)

Country Link
WO (1) WO2005110392A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015119570A1 (fr) * 2014-02-07 2015-08-13 Agency For Science, Technology And Research Prl-3 comme biomarqueur pour le pronostic de cancer et comme cible de thérapie

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3940422A (en) * 1973-01-18 1976-02-24 Kissei Yakuhin Kogyo Kabushiki Kaisha Aromatic carboxylic amide derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3940422A (en) * 1973-01-18 1976-02-24 Kissei Yakuhin Kogyo Kabushiki Kaisha Aromatic carboxylic amide derivatives

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
SHIME ET AL: "Tranilast inhibits the proliferation of uterine leiomyoma cells in vitro through G1 arrest associated with the induction of p21(waf1) and p53", J.CLIN.ENDOCRINOL & METAB, vol. 87, no. 12, 2002, pages 5610 - 5617, XP008150267, DOI: doi:10.1210/jc.2002-020444 *
SPIEKERMANN ET AL: "The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth arrest and apoptosis in AML-derived cell lines expressing a constitutively activated FLT3.", BLOOD, vol. 101, no. 4, 2003, pages 1494 - 1504, XP002490467, DOI: doi:10.1182/blood-2002-04-1045 *
TAKAHASHI ET AL: "FLT3 mutation activates p21WAF1/CIP1 gene expression through the action of STAT5", BIOCHEM BIOPHYS RES COMMUN, vol. 316, no. 1, 2004, pages 85 - 92, XP004493145, DOI: doi:10.1016/j.bbrc.2004.02.018 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015119570A1 (fr) * 2014-02-07 2015-08-13 Agency For Science, Technology And Research Prl-3 comme biomarqueur pour le pronostic de cancer et comme cible de thérapie
JP2017511878A (ja) * 2014-02-07 2017-04-27 エージェンシー フォー サイエンス，テクノロジー アンド リサーチ 癌の予後診断のためのバイオマーカーおよび療法のためのターゲットとしてのｐｒｌ−３

Similar Documents

Publication Publication Date Title
Skoda et al. Pathogenesis of myeloproliferative neoplasms
JP2021523091A (ja) Ｂｃｌ−２阻害剤又はＢｃｌ−２／Ｂｃｌ−ｘＬ二重阻害剤及びＢＴＫ阻害剤の組合せ製品並びに疾患の予防及び／又は治療におけるその使用
AU2006247803B2 (en) Methods for treating drug resistant cancer
KR20140082591A (ko) mTOR/JAK 저해제 병용 요법
JP7434185B2 (ja) 三置換ベンゾトリアゾール誘導体の使用方法
US20190290627A1 (en) Pim kinase inhibitor combinations
JP2023504046A (ja) ジアリール大環状化合物を含む併用療法
KR20160020502A (ko) 제약 조합물
EP2043633B1 (fr) Dérivés de thiadiazolidinone pour traiter le cancer
JP2019511554A (ja) 静止細胞標的化およびｅｇｆｒ阻害剤を用いた新生物の処置のための組み合わせ
JP2022145948A (ja) 血液癌の併用療法
TW202118488A (zh) Mdm2抑制劑的藥物組合物及其在預防和/或治療疾病中的用途
JP2009537626A (ja) ９−ヒドロキシエリプチシン誘導体による悪性表現型の復帰変異
US20210069194A1 (en) Combination therapy for the treatment of cancer
KR20160090814A (ko) Jak, cdk 및 pim의 억제제를 포함하는 조합 요법
WO2005110392A1 (fr) Procedes de modulation de l'activite de flt3
CA2441016A1 (fr) Composes de taurine
FR2823975A1 (fr) Nouvelle utilisation de pyridoindolone
KR20240073112A (ko) PI3Ka 억제제와 KRAS G12D 억제제의 조합 및 관련된 치료 방법
JP2020176145A (ja) 血液癌の併用療法
EP3666266A1 (fr) Traitement et prévention du glioblastome
KR20230074533A (ko) Csf1r 키나아제 억제제 및 이의 용도

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase