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  • 专利说明
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    • 专利摘要:
    The present invention relates to an inhibitor of MELK and/or ROR2, preferably for use in the treatment of diffuse intrinsic pontine glioma (DIPG), wherein said DIPG is preferably characterized by overexpression of MELK and/or overexpression of ROR2. The inhibitor may be combined with a P-glycoprotein inhibitor, an Abcb1 a inhibitor, Abcb1 b inhibitor, mannitol, or an Abcg2 inhibitor.
    公开号:NL2020004A
    申请号:NL2020004
    申请日:2017-12-01
    公开日:2018-06-18
    发明作者:Ary Flohil Jacob
    申请人:Ary Flohil Jacob；
    IPC主号:
    专利说明:

    Background
    Diffuse intrinsic pontine glioma (DIPG) is a brain tumor found in a part of the brain stem called the pons. The pons controls essential bodily functions such as heartbeat, breathing, swallowing, eye movement, eyesight, and balance. DIPG affects children almost exclusively. Approximately 200-400 children in the United States are diagnosed with DIPG each year. These children are typically between the ages of 4 and 11. DIPG accounts for roughly ΙΟΙ 5% of all brain tumors in children. DIPG is an aggressive tumor that interferes with all bodily functions, depriving a child of the ability to move, to communicate, and even to eat and drink. Unfortunately, the prognosis for DIPGs is currently very poor.
    The objective of the present invention is to contribute to a better prognosis in DIPG.
    Summary of the invention
    Maternal embryonic leucine zipper kinase (MELK) is a serine/threonine kinase implicated in many cellular processes involved in embryogenesis and oncogenesis. Overexpression of MELK is a common feature of diffuse intrinsic pontine glioma (DIPG) and related to tumour grade. Inhibition of MELK by the small molecule OTS167 effectively inhibits migration, reduces proliferation and induces cell death in primary DIPG cell lines at low nanomolar concentrations. OTS167 co-inhibits neurotrophic tyrosine kinase, receptor-related 2 (ROR2), adding to a synergistic therapeutic effect in DIPG individuals that are characterized by overexpression of both targets.
    Given the integrity of the blood-brain barrier in DIPG, an important consideration of any potential drug is its capacity to reach brain concentrations high enough for a therapeutic effect. Administration of the compound yields a brain-to-plasma (B/P) ratio estimated to be about 0.02. An absolute concentration of about 10 nanomolar can be reached in the brain with pharmaceutically acceptable toxic adverse effects, and is sufficient to induce apoptosis on glioma cells and leave healthy cells unharmed. The present disclosure is directed to the compound represented by formula (1) with product name OTS167 and by a modified version of this compound represented by formula (2).
    The present inventor has endeavored to develop a cure against Diffuse Intrinsic Pontine
    Glioma and has found that a compound with product name OTS167 which inhibits target
    -2MELK (0,41 nM) and target ROR2 (50 - 100 nM), and which is represented by formula 1 or the SMILES description ora pharmaceutically acceptable compound thereof:
    SMILES: CC(=O)c1cnc2ccc(nc2c1NC3CCC(CC3)CN(C)C)c4cc(c(c(c4)CI)O)CI 1-[6-(3,5-Dichloro-4-hydroxyphenyl)-4-({4-[(dimethylamino)methyl]cyclohexyl}amino)-1,55 naphthyridin-3-yl]ethanone
    Molecular Formula C25H28CI2N4O2
    Formula 1 (OTS167); 1-[6-(3,5-Dichloro-4-hydroxyphenyl)-4-({410 [(dimethylamino)methyl]cyclohexyl}amino)-1,5-naphthyridin-3-yl]ethanone
    Cl
    Formula 1 (OTS167); 1-(6-(3,5-Dichloro-4-hydroxyphenyl)-4-({415 [(dimethylamino)methyl]cyclohexyl}amino)-1,5-naphthyridin-3-yl]ethanone
    -3MELK
    MELK, maternal embryonic leucine zipper kinase, was previously identified as a new member of the snfl /AMPK serine-threonine kinase family that is involved in mammalian embryonic development (Heyer BS et al, Dev Dyn. 1999 Aug 21 5(4):344-51). The gene was shown to play an important role in stem cell renewal (Nakano I et al., J Ceil Biol. 2005 Aug I , 170(3):413-27), cell-cycle progression (Blot J et al., Dev Biol. 2002 Jan 15, 241(2)i327-38; Seong HA et al, Biochem J. 2002 Feb 1 , 361 (Pt 3): 597-604) and pre- mRNA splicing (Vdsieke V et a!., J Biol Chem. 2004 Mar 5, 279( i 0):8642-7. Epub 2003 Dec 29). in addition, through gene expression profile analysis using a genome-wide cDNA microarray containing 23,040 genes, MELK was recently shown to be up-regulated in breast cancer (Lin ML et al. Breast Cancer Res. 2007; 9 ( 1 ):R17, W02006/016525, W02008/023841). In fact, MELK is up-regulated in several cancer cells, for example lung, bladder, lymphoma and cervical cancer cells (See W02004/03 1413, W020077013665, and W02006/085684, the disclosures of which are incorporated by reference herein).
    In most DIPG cell lines MELK is strongly overexpressed (WEE1 Kinase Inhibition Enhances the Radiation Response of Diffuse Intrinsic Pontine Gliomas Viola Caretti et. Al. J AACR 2012).
    MELK and ROR2 targets (Ror2 as a Therapeutic Target in Cancer, Debebe at. al. Pharmacology and Therapeutics, 2015) are both primarily expressed during early embryogenesis. By Inhibiting these targets it is expected that no adverse effects or only very limited, pharmaceutical acceptable, adverse effects occur.
    US9067937 B2 and US9345709 B2 describe 1,5-naphthyridine derivatives and MELK inhibitors containing the same which may be used in the present disclosure.
    Molecular dynamic computer simulations have shown that OTS167 inhibits MELK and coinhibits to certain extend the Tyrosine-protein kinase transmembrane receptor ROR2 also known as neurotrophic tyrosine kinase, receptor-related 2, which is also overexpressed in primary DIPG cell lines (table 1). The MELK inhibitor OTS167 (IC50 is 0,41 nM) might show a synergistic effect by co-inhibiting the ROR2 (IC50 is calculated on 50 - 100 nM) target.
    -4Expression Fold normal Expression increase Pvalue
    Table 1.
    Top 20 upregulated kinases in DIPG
    Ran
    k1GeneTOP2ANameTopoisomerase(DNA) II alphaProbeset brain (log2)201292_at 1,05DIPG (log2)7,85(logz)7,45(FDR)3,30E-682MELKMaternalembryonicleucine zipperkinase204825_at 1,617,494,666,64E-623BUB1Buddinguninhibited bybenzimidazoles1 homolog209642_at 1,986,693,383,TOE-444TTKTTK proteinkinase204822_at 2,126,833,232,78E-515PBKPDZ bindingkinase219148_at 2,467,613,105,90E-616OSR1Odd-skippedrelated 1(Drosophila)228399_at 1,875,663,037,03E-227WEE1WEE1 homolog212533_at 3,608,812,452,60E-468NEK2NIMA (never inmitosis gene a)-related kinase 2204641_at 3,446,741,968,43E-249STK33Serine/threonine kinase 33228035_at 3,186,141,932,03E-195,24E-1410TEX14Testisexpressed 14221035_s_at 2,925,501,8811CHEK1CHK1checkpointhomolog (S.205394_at 2,905,371,852,57E-30
    ExpressionFoldRannormalExpressionincreasePvaiuek GeneNameProbesetbrain (log2)DIPG (log2)(iog2)(FDR)
    pombe)
    12AURKBAurora kinase B209464_at3,055,321,742,45E-2013BUB1BBuddinguninhibited bybenzimidazoles1 homolog beta(yeast)203755_at3,986,841,724,08E-3214HK2Hexokinase 2202934_at5,548,951,622,81E-3215CHEK2CHK2checkpointhomolog (S.pombe)210416_s_at3,515,431,553,41 E-1516AURKAAurora kinase A204092_s_at4,266,571,544,37E-3317ROR2Receptortyrosine kinaselike orphanreceptor 2205578_at2,413,711,543,62E-0618PLAUPlasminogenactivator,urokinase205479_s_at3,525,411,542,29E-1419DYRK3Dual-specificitytyrosine-(Y)-phosphorylationregulatedkinase 3210151_s_at4,286,321,486,32E-1520MASTLMicrotubule-associatedserine/threoninekinase-like228468_at4,216,131,463,76E-47
    -6NOTE: Top 20 upregulated kinases in DIPG tumor samples (n = 27; ref. 17) sorted on Iog2 fold increase as compared with nonmalignant brain tissues (n = 174; ref. 33) including 2 samples of normal brain stem tissue from the DIPG dataset (17). Wee1 homolog (WEE1) is identified as a highly differentially overexpressed kinase in DIPG.
    Herein, with the term “overexpression” is meant at least 10, 20, 30, 40, 50% increased expression as compared to expression in normal brain, preferably as depicted above.
    In most of DIPG tumour cell lines is has been shown that a concentration of 10 nM MELK inhibitor OTS167 is toxic and induces apoptosis on the primary tumour astrocytes, whereas the same doses of 10 nanomolar only slightly slows down the growth of normal astrocytes but no apoptosis occurs in non-somatic cells.
    OTS167 clinical dose and maximum tolerated dose.
    OTSP167 is an extremely potent MELK inhibitor with IC50 = 0.41 nM. To achieve a clinical effective dose of 15 micromolar solution in the blood plasma at a formula weight of 487.42 g/mol for OTS167, and an estimated 5 liters of blood plasma available in a child of age 5-12 years, the mass molarity calculation may pose a minimal dose 36,5 mg. The required minimal dose can be one order of magnitude smaller than the clinical dose or maximum tolerated dose for comparable kinase inhibiting compounds:
    ........ΗίδmtikWWid m...............................cimim111^^Βίθ80^^®!!!!88888888888888ks iV ts IS φίkWbleiBlllBliBill!MateIllil!IB11IIO8888888B!!^ι^^!!!!!8888888888888888888888ί(vb a W wvcad weS t«e s dv (iifoixxm $«$)&a toWSG λ wv(2 ms «ί ms <0kt &: wmm-m&g
    tókesm Qk w; m wy £ «te m sm I
    Table 2: Clin. Cancer Res; 22(6) March 15, 2016
    Another example of the excellent MTB outcome for OTS167 is the comparison with the clinical evaluation of the AZD1152 inhibitor on the serine/threonine kinase Aurora B, in which the MTB is, dependent on the dosing schedule, 200-450 mg.
    -7OTS167 and its passive or active transport over de blood-brain barrier
    Passive transport of OTS167 over the blood-brain barrier is possible in mouse models (wild type), brain-to-plasma (B/P) ratio = 0.02. Experiments have shown that the inhibitor can be transported actively over the blood-brain barrier preferably by co-administering a Pglycoproteinl inhibitor, or ATP-binding cassette sub-family B member 1 (Abcbla) inhibitor, increasing the concentration of OTS167 in the brain tissue by at least a factor of 4 and showing pharmaceutical acceptable adverse effects.
    Inhibition of other ABC transporters might increase the concentration of OTS167 in the brain tissue. The ABC transporters are Abcbla, Abcblb and Abcg2.
    In addition, mannitol can be used in bypassing the blood-brain barrier.
    Administering OTS167 for Diffuse Intrinsic Pontine Glioma
    OTS167 can be applied in the form of solutions, e.g., aqueous solutions, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10-3 molar and 10-9 molar concentrations. A therapeutically effective amount in vivo may range depending on the route of administration, between about 1-500 mg/kg, typically 10-100 mg/kg. When administered orally, a dose of about 200 mg/kg is suitable for the treatment of Diffuse Intrinsic Pontine Glioma.
    OTS167 and convection enhanced delivery
    OTS167 can be delivered through one to several catheters placed stereotactically directly within the pontine glioma tumour tissue. OTS167 shows a well spread distribution through convection or molecular diffusion within the tumour tissue.
    High-intensity focused ultrasound
    Stimulation in blood-brain barrier crossing of described compounds can be obtained by mediation of high-intensity focused ultrasound in the ranges 500 KHz to 1.5 MHz causing sonoporation and/or sonopermeabilization in the tight junction.
    OTS167 might be administered (as stand-alone compound) below toxic levels, comparable with typical concentrations of vitamins (approximately 20 micromoles/liter for vitamin E, or 50 micromoles/liter for vitamin C) in the blood plasma. The compound might yield at lethal levels of at least 10 nM concentration in the brain tumour tissue, by a blood plasma-driven chemical potential of 0.5 μΜ only.
    -8Modified OTS167 crosses the blood-brain barrier and binds even stronger to MELK than OTS167
    A Chemical modification of the OTS167 molecule of a specific atom N to C decreases the IC50on the MELK target to less than 0.41 nanomolar. The stronger binding occurs due to the N to C substitution and is caused by efficient expulsion of a high energetic, residing water molecule in the active site. The energy of binding from the compound to the target is increased. However, it is of paramount importance that due to increased lipophilicity at the most optimal position within the chemical structure, the compound is predicted to pass fluently through the brain barrier.
    Semi-empirical quantum chemical calculations show that the OTS167 molecule possesses an excess positive charge in solution, hindering its passage through the blood brain barrier, while the most dominant tautomer of the modified version of OTS167 is neutral in charge, yielding strongly increased lipophilicity. While the unsubstituted N atom of the OTS167 molecule does not form an energetically favourable hydrogen bridge with the Melk target, the modified OTS167 molecule yields increased desolvation energy, contributing to stronger binding energy, however the atomic substitution does not contribute to better solubility in water.
    The N to C atomic substitution of the modified OTS167, which is located in the centre of the molecule, and the centre of the targeted active site, has profound implications on bond lengths and atom angles of adjacent atoms in OTS167. In addition, the dihedral angles of all 4 atom combinations in which the N to C substitution participates, have a different dihedral potential energy profile resulting in a lower intramolecular energy. All described physical properties favour the energy of binding of the N to C substitution in the modified OTS 167 version to the MELK target.
    -9Ö
    Modified OTS167 (formula 2) or
    CC(O)=c3cnc2ccc(c1cc(CI)c(O)c(CI)c1)[nH]c2c3CC4CCC(CN(C)C)CC4 (ID: FOLDYNE-1332-A)
    Figure 1 shows the calculated Blood-brain barrier crossing of the modified OTS167 (ID: FOLDYNE-1332-A) compound: brain-to-plasma (B/P) SVM_MACCSFP BBB score = 0.025. That score is only a factor 4 smaller compared with the score of 0.1 for melatonin or ethanol which permeate perfectly through the BBB. Administering of the OTS167 compound yields a brain-to-plasma (B/P) ratio of 0.02 in mouse models. Calculated value of BBB-/BBB+ ratio as described herein concerns crossing over the tight junction in the barrier between the endothelial cells. Left image: the SVM_MACCSFP BBB score is 0.25. Right image: Threshold of BBB-/BBB+ Score is 0.02. The compound is predicted as BBB+.
    Multiple kinase binding in DIPG
    Additionally contributing to DIPG inhibiting selectivity, the modified OTS167 version has, according to molecular dynamics simulation, a strongly increased energy of binding to the following targets, present in Table 1: Top 20 upregulated kinases in DIPG and ranked at positions 3 and 12; Mitotic checkpoint serine/threonine protein kinase (gene BUB1) and Aurora kinase type B (gene AURKB).
    The modes of binding of the modified OTS167 molecule to the targets BUB1 and AURKB are similar to the binding mode in the MELK target, and involve binding to contact residues
    - 10in the kinase active site binding pockets with strongly homologous residue sequences relative to the MELK kinase.
    Increased lipophilicity of modified OTS167 and strategy of drug delivery
    The high lipophilicity and relatively low molecular weight of modified OTS167 enables the pathway strategy of intranasal administration. Generally, lipophilic drugs are strongly absorbed from the nasal cavity compared to polar drugs and the bioavailability could approach 100%, and in addition, the nasal route avoids hepatic first pass elimination associated with oral delivery. The direct connection between the brain stem and nasal mucosa through cranial nerve pathways allows direct delivery of modified OTS167. When modified OTS167 is administered in the nasal olfactory region the blood-brain barrier is optimally circumvented.
    The OTS167 molecule is calculated to yield comparable bioavailability with modified OTS167 through the described nasal pathway if formulated with multiple units of β-(1—>4)linked D-glucosamine and N-acetyl-D-glucosamine (Chitosan). The formulation might also further enhance the delivery of modified OTS167.
    权利要求:
    Claims (23)
    [1]
    Clauses
    1. Inhibitor of MILK, preferably for use in the treatment of diffuse intrinsic pontine glioma (DIPG).
    [2]
    2. Inhibitor of ROR2, preferably for use in the treatment of diffuse intrinsic pontine glioma (DIPG).
    [3]
    3. Inhibitor of MILK and ROR2, preferably for use in the treatment of diffuse intrinsic pontine glioma (DIPG).
    [4]
    4. Inhibitor according to any of the preceding clauses, wherein said DIPG is characterized by overexpression of MELK and / or overexpression of ROR2.
    [5]
    5. Inhibitor according to clause 1 or 3, wherein the inhibitor of MELK has an IC50 of <0.1 μΜ, more preferably <50 nM, even more preferably <1 nM with regard to inhibiting MELK.
    [6]
    6. Inhibitor according to clause 2 or 3, wherein the inhibitor has an IC50 of <0.1 μΜ, more preferably <50 nM, even more preferably <1 nM with regard to inhibiting ROR2.
    - 11 7. Inhibitor according to any one of the preceding clauses, wherein the inhibitor has the following structure:
    5 or a solvate or pharmaceutically acceptable salt thereof.
    8. Inhibitor according to any one of the preceding clauses, wherein the inhibitor has the following structure:
    Cl or a solvate or pharmaceutically acceptable salt thereof.
    9. Inhibitor according to any one of the preceding clauses, wherein the inhibitor has the following structure:
    , O or a solvate or pharmaceutically acceptable salt thereof.
    10. Inhibitor according to any one of the preceding clauses, wherein the inhibitor has the formula CC (O) = c3cnc2ccc (c1cc (CI) c (O) c (CI) c1) [nH] c2c3CC4CCC (CN (C) C) CC4, or a solvate or pharmaceutically acceptable salt thereof.
    11. Inhibitor according to any one of the preceding clauses, wherein the inhibitor is in combination with (2R, 3R, 4S, 5R) -2- (6-Amino-9H-purin-9-yl) -5- (hydroxymethyl) tetrahydro-3,4furandiol (adenosine), and preferably the combination is comprised in a composition.
    12. Inhibitor according to any one of the preceding clauses, wherein the inhibitor is in combination with a P-glycoprotein inhibitor, preferably 1- [6-amino-9 - [(2R, 3R, 4S, 5R) -3,4dihydroxy- 5- (hydroxymethyl) oxolan-2-yl] purin-2-yl] - N-methylpyrazole-4-carboxamide (Regadenoson), and preferably the combination is comprised in a composition.
    13. Inhibitor according to any one of the preceding clauses, wherein the inhibitor is in combination with an Abcbla inhibitor, wherein preferably the combination is comprised in a composition.
    14. Inhibitor according to any one of the preceding clauses, wherein the inhibitor is in combination with an Abcblb inhibitor, preferably N- [3- (4-Morpholinyl) propyl] -5,7-13-diphenylpyrazolo [1,5-a] pyrimidine -3-carboxamide (Reversan), and wherein preferably the combination is comprised in a composition.
    15. Inhibitor according to any one of the preceding clauses, wherein the inhibitor is in combination with mannitol, and wherein preferably the combination is comprised in a composition.
    16. Inhibitor according to any one of the preceding clauses, wherein the inhibitor is in combination with an Abcg2 inhibitor, preferably N- [4- [2- (3,4-Dihydro-6,7-dimethoxy-2 (1H) isoquinolinyl) ethyl] phenyl] -9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (Elacridar), and preferably the combination is comprised in a composition.
    17. Inhibitor according to any one of the preceding clauses, wherein convection enhanced delivery is used and / or wherein at least 1 catheter is applied for delivery in the tumor tissue.
    18. Inhibitor according to any one of the preceding clauses, wherein ultrasound is used to disrupt the blood-brain barrier, preferably by localized exposure to high-intensity focused ultrasound disrupting the local blood-brain barrier of the tumor tissue with a frequency range 500 kHz - 1.5 MHz.
    19. Inhibitor according to any one of the preceding clauses, wherein delivery across the blood-brain barrier is performed by encapsulation in a liposome, preferably wherein the liposome has molecules on its surface which are actively transported over the blood-brain barrier, wherein said molecules are preferably molecules that bind a endothelial cell receptor, preferably the endothelial cell receptor for transferrin or insulin.
    20. Inhibitor according to any one of the preceding clauses, for use in the treatment of a brain tumor, preferably a glioma, more preferably a brainstem glioma or glioblastoma multiforme, most preferably diffuse intrinsic pontine glioma.
    21. Inhibitor according to clause 20, wherein the brain tumor is a brain metastasis, astrocytoma (including glioblastoma), oligodendroglioma, ependymomas, optic nerve glioma or a mixed glioma.
    22. Inhibitor according to any one of the preceding clauses, wherein the administration is oral or intravenously.
    - 1423. Inhibitor according to any one of the preceding clauses, wherein the amount of the inhibitor to be administered to the subject is between 0.001 mg / kg per day and 50 mg / kg per day.
    5 24. Inhibitor accordion thing to any one of The preceding clauses, Wherein the amount of the inhibitor to be Administered to the subject is between 10 mg / m 2 per day and 2000 mg / m 2 per day.
    - 15 CONCLUSIONS
    An inhibitor of MILK, preferably for use in the treatment of diffuse intrinsic punch glioma (DIPG).
    2. Inhibitor of ROR2, preferably for use in the treatment of diffuse intrinsic punch glioma (DIPG).
    3. Inhibitor of MILK and ROR2, preferably for use in the treatment of diffuse intrinsic punch glioma (DIPG).
    Inhibitor according to any of the preceding claims, wherein the DIPG is characterized by overexpression of MILK and / or overexpression of ROR2.
    The inhibitor according to claim 1 or 3, wherein the inhibitor of MELK has an IC50 of <0.1 µM, more preferably <50 nM, even more preferably <1 nM with respect to the inhibition of MILK.
    The inhibitor according to claim 2 or 3, wherein the inhibitor has an IC50 of <0.1 µM, more preferably <50 nM, even more preferably <1 nM, with respect to inhibiting ROR2.
    [7]
    Inhibitor according to any of the preceding claims, wherein the inhibitor has the following structure:
    h 3 c
    16 or a solvate or pharmaceutically acceptable salt thereof.
    [8]
    Inhibitor according to any of the preceding claims, wherein the inhibitor has the following structure:
    Cl or a solvate or pharmaceutically acceptable salt thereof.
    [9]
    Inhibitor according to any of the preceding claims, wherein the inhibitor has the following structure:
    ί • You or a solvate or pharmaceutically acceptable salt thereof.
    [10]
    Inhibitor according to any of the preceding claims, wherein the inhibitor has the formula CC (O) = c3cnc2ccc (cIC (Cl) c (O) c (Cl) cl) [nH] c2c3CC4CCC (CN (C) C). CC4,
    17 or a solvate or pharmaceutically acceptable salt thereof.
    [11]
    Inhibitor according to any of the preceding claims, wherein the inhibitor is in combination with (2R, 3R, 4S, 5R) -2- (6-amino-9H-purin-9-yl) -5- (hydroxymethyl) tetrahydro- 3,4-furandiol (adenosine), and wherein preferably the combination is included in a composition.
    [12]
    Inhibitor according to any of the preceding claims, wherein the inhibitor is in combination with a P-glycoprotein inhibitor, preferably 1- [6-amino-9 - [(2R, 3R, 4S, 5R) -3,4dihydroxy- 5- (hydroxymethyl) oxolan-2-yl] purin-2-yl] -N-methylpyrazole-4-carboxamide (Regadenoson), and wherein the combination is preferably included in a composition.
    [13]
    Inhibitor according to any of the preceding claims, wherein the inhibitor is in combination with an Abcbla inhibitor, the combination preferably being contained in a composition.
    [14]
    Inhibitor according to any of the preceding claims, wherein the inhibitor is in combination with an Abcblb inhibitor, preferably N- [3- (4-morpholinyl) propyl] -5,7-diphenylpyrazolo [1,5-a] pyrimidine -3-carboxamide (Reversan), and wherein the combination is preferably included in a composition.
    [15]
    Inhibitor according to any of the preceding claims, wherein the inhibitor is in combination with mannitol and wherein the combination is preferably included in a composition.
    [16]
    Inhibitor according to any of the preceding claims, wherein the inhibitor is in combination with an Abcg2 inhibitor, preferably N- [4- [2- (3,4-dihydro-6,7-dimethoxy-2 (1H) isoquinolinyl) ) ethyl] phenyl] -9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (Elacridar), and wherein the combination is preferably included in a composition.
    [17]
    Inhibitor according to any of the preceding claims, wherein convection enhanced release is used and / or at least one catheter is used for delivery into the tumor tissue.
    [18]
    Inhibitor according to any one of the preceding claims, wherein ultrasound is used to disrupt the blood-brain barrier, preferably by localized exposure to focused high-intensity ultrasound that disrupts the local blood-brain barrier of the tumor tissue at a frequency range of 500 kHz -1 .5 MHz.
    Inhibitor according to any of the preceding claims, wherein delivery across the blood brain barrier is performed by encapsulation in a liposome, preferably wherein the liposome has molecules on its surface which are actively transported across the blood brain barrier, molecules preferably being molecules which bind to one
    Endothelial cell receptor, preferably the endothelial cell receptor for transferrin or insulin.
    [19]
    Inhibitor according to any of the preceding claims, for use in the treatment of a brain tumor, preferably a glioma, more preferably a brain stem glioma or glioblastoma multiforme, most preferably diffuse intrinsic punch glioma.
    [20]
    The inhibitor of claim 20, wherein the brain tumor is a brain metastasis, astrocytoma (including glioblastoma), oligodendroglioma, ependymomas, optic nerve glioma or a mixed glioma.
    15
    [21]
    Inhibitor according to any of the preceding claims, wherein the administration is oral or intravenous.
    [22]
    Inhibitor according to any of the preceding claims, wherein the amount of the inhibitor to be administered to the patient is between 0.001 mg / kg per day and
    20 50 mg / kg per day.
    [23]
    Inhibitor according to any of the preceding claims, wherein the amount of the inhibitor to be administered to the patient is between 10 mg / m 2 per day and 2000 mg / m 2 per day.
    1/1
    Figure 1
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    同族专利:
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    NL2017972|2016-12-09|
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