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WO2020207550A1 - Méthode d'inhibition du cancer par des inhibiteurs de l'alkbh5, la déméthylase ciblant les m6a de l'arn - Google Patents

Méthode d'inhibition du cancer par des inhibiteurs de l'alkbh5, la déméthylase ciblant les m6a de l'arn Download PDF

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WO2020207550A1
WO2020207550A1 PCT/EP2019/058737 EP2019058737W WO2020207550A1 WO 2020207550 A1 WO2020207550 A1 WO 2020207550A1 EP 2019058737 W EP2019058737 W EP 2019058737W WO 2020207550 A1 WO2020207550 A1 WO 2020207550A1
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compound
pharmaceutically acceptable
rna
formula
acceptable salt
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Simona SELBERG
Mati Karelson
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Chemestmed Ltd
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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
    • G16B15/30—Drug targeting using structural data; Docking or binding prediction

Definitions

  • the present invention relates generally to compositions and methods for treating cancer.
  • RNA ribonucleic acid
  • the presently disclosed subject matter generally relates to the epitrancriptomic regulation of ribonucleic acid (RNA) methylation through small-molecule inhibitors of the RNA m6A demethylase AlkBH5.
  • RNA demethylase AlkBH5 RNA demethylase AlkBH5.
  • the subject compounds and compositions are useful for the treatment of cancer, such as glioblastoma, astrocytoma, acute myeloid leukemia, acute monocytic leukemia, chronic myelogenous leukemia, T acute lymphoblastic leukemia and the like.
  • RNA stability Chemical modifications of RNA have recently been identified to have an impact on several critical cellular functions, such as proliferation, survival and differentiation, mostly through regulation of RNA stability (Helm et ah, 2017) [6]
  • the most common modification in messenger RNA is N6-methyladenosine (m6A) (Roundtree et ah, 2017) [19]. It has been shown that m6A modifications of RNA affect its splicing, intracellular distribution, translation, and cytoplasmic degradation, playing thus a crucial role in regulating cell differentiation, neuronal signaling, carcinogenesis and immune tolerance (Maity et ah, 2016) [14]
  • the m6A presence in RNA is regulated by specific enzymes, i.e. the RNA methyltransferases, RNA methyl ases and RNA reader proteins.
  • RNA methyltransferase enzyme complex METTL3/METTL14/WTAP Scholler et al, 2018 [21] consisting of the following three components: METTL3 (methyltransferase-like 3) (Bokar et.ak, 1998) [2], METTL14 (methyltransferase-like 14) (Liu et al, 2014) [9], and WTAP (Wilm's tumour- 1 -associated protein) (Horiuchi et al, 2013) [12]; RNA m6A methyltransferase Mettll6 (Pendleton et al, 2017) [18]; the RNA demethylases FTO (fat mass and obesity-associated protein) (Jia, et al, 2011) [13] and AlkBH5 (AlkB family member 5) (
  • RNA reader enzymes that recognize specific m6A methylation in RNA.
  • RNA reader enzymes include YTHDF1 (YTH N6-Methyladenosine RNA Binding Protein 1), YTHDF2 (YTH N6-Methyladenosine RNA Binding Protein 2) YTHDF3 (YTH N6- Methyladenosine RNA Binding Protein 3), YTHDC1 (YTH domain-containing protein 1) and YTHDC2 (YTH domain-containing protein 2) (Park et al., 2017) [17]. These three types of enzymes collectively coordinate the m6A RNA methylome in the eukaryotic cell.
  • the methyl group from m6A can be removed by two RNA demethylases, Fat mass and obesity associated protein (FTO) and a-ketoglutarate dependent dioxygenase homo log 5 (ALKBH5), (Jia et ah, 2011; Thalhammer et al, 2011 [13]; Zheng et ah, 2013 [29]). Both the FTO and ALKBH5 RNA demethylases belong to the AlkB subfamily of the non-heme Fe(II)/2-oxoglutarate (20G) dependent dioxygenase superfamily.
  • ALKBH5 inhibitors or activators would enable to examine more closely the physiological and pathological processes related to the m6A demethylation of RNA (Deng et al, 2018) [5] It has been shown that the ALKBH5 overexpression significantly promotes cell proliferation in human cervical cancer cell line SiHa (Wang, X. et al. 2017) [25] Furthermore, the cell motility was also increased by ALKBH5. Thus, reducing m6A level could promote cervical cancer cell proliferation, indicating that increasing m6A level might have anti-cancer effects in cervical cancer.
  • ALKBH5 is expressed at a low level in acute myeloid leukemia (AML). Consequently, ALKBH5 may exert a tumor- suppressor function in AML.
  • ALKBH5 is also inducible by hypoxia-inducible factor 1 (HIF- 1) in different cells (Thalhammer et al, 2011) [23]
  • HIF- 1 hypoxia-inducible factor 1
  • Intratumoural hypoxia is however commonly found in cancers and is an essential microenvironment for cancer progression.
  • ALKBH5 has been therefore reported to promote tumorigenesis and proliferation in glioblastoma stem- like cells (GSCs) (Zhang, S. et al.
  • the present invention is related to a method of cancer cure by of modulating the RNA methylation at 6-position of adenine (m6A) using effective amount of a compound having binding and/or inhibition of RNA m6A demethylase AlkBH5.
  • the invention includes, as an additional aspect, all embodiments of the invention narrower in scope in any way than the variations specifically mentioned above.
  • aspects of the invention may have been described by reference to a genus or a range of values for brevity, it should be understood that each member of the genus and each value or sub-range within the range is intended as an aspect of the invention.
  • various aspects and features of the invention can be combined, creating additional aspects which are intended to be within the scope of the invention.
  • FIG. 1 illustrates a dynamic and reversible m6A methylation in RNA (SAM - S-adenosyl-L- methionine; SAH - S-adenosyl-L-homocystein) described in the prior art (see Niu, et al, 2013) [16];
  • FIG. 2 illustrates the binding site of the compound (III) according to invention
  • FIG. 3 illustrates the binding site of the compound (IV) according to invention
  • FIG. 4 illustrates the inhibitory effect IE of the compound (III) on the demethylation of the probe RNA by AlkBH5;
  • FIG. 5 illustrates the inhibitory effect IE of the compound (IV) on the demethylation of the probe RNA by AlkBH5;
  • FIG. 6 illustrates the inhibitory effect INH% of the compound (III) at 100 mM concentration on the glioblastoma cell culture A- 172;
  • FIG. 7 illustrates the inhibitory effect INH% of the compound (IV) at 100 mM concentration on the glioblastoma cell culture A- 172;
  • FIG. 8 illustrates the inhibitory effect INH% of the compound (III) at 10 mM concentration on the Childhood T acute lymphoblastic leukemia cell culture CCRF-CEM;
  • FIG. 9 illustrates the inhibitory effect INH% of the compound (IV) at 100 mM concentration on the Childhood T acute lymphoblastic leukemia cell culture CCRF-CEM;
  • FIG. 10 illustrates the inhibitory effect INH% of the compound (III) at 100 mM concentration on the Childhood T acute lymphoblastic leukemia cell culture JURKAT;
  • FIG. 11 illustrates the inhibitory effect INH% of the compound (IV) at 100 mM concentration on the Childhood T acute lymphoblastic leukemia cell culture JURKAT.
  • the compound is administered in a composition that also includes one or more pharmaceutically acceptable diluents, adjuvants, or carriers.
  • RNA m6A demethylase AlkBH5 inhibitor has a structure of Formula (I),
  • R1 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl, aminoalkyl, aminoalaryl
  • R2 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, aminoalkyl, aminoalaryl; or a pharmaceutically acceptable salt thereof.
  • the RNA m6A demethylase AlkBH5 inhibitor compound has a structure of Formula (II)
  • Rl, R2 and R3 are independently selected from the group consisting of H, alkyl, aryl, alkylenearyl, acyl, alkoxycarbonyl, aryloxycarbonyl, alkylenearyloxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, and alkyleneamino; or a pharmaceutically acceptable salt thereof.
  • Rl and R2 are independently selected from the group consisting of alkyleneamino and hydrogen, where the amino group of the alkyleneamino moiety can be further substituted with one or two alkyl or alkylenearyl (e.g., a benzyl) groups.
  • the METTL3/METT14/WTAP complex activator compound has a structure of Formula (III)
  • R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, alkylenearyl, acyl, alkoxycarbonyl, aryloxycarbonyl, alkylenearyloxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, and alkyleneamino; or a pharmaceutically acceptable salt thereof
  • R1 and R2 are independently selected from the group consisting of alkyleneamino and hydrogen, where the amino group of the alkyleneamino moiety can be further substituted with one or two alkyl or alkylenearyl (e.g., a benzyl) groups.
  • R1 is methyl and R2 is hydrogen.
  • the METTL3/METT14/WTAP complex activator compound has a structure of Formula (IV)
  • R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, alkylenearyl, acyl, alkoxycarbonyl, aryloxycarbonyl, alkylenearyloxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, and alkyleneamino; or a pharmaceutically acceptable salt thereof.
  • R1 and R2 are independently selected from the group consisting of alkyleneamino and hydrogen, where the amino group of the alkyleneamino moiety can be further substituted with one or two alkyl or alkylenearyl (e.g., a benzyl) groups.
  • R1 is methyl and R2 is hydrogen.
  • alkyl refers to straight chained and branched hydrocarbon groups containing carbon atoms, typically methyl, ethyl, and straight chain and branched propyl and butyl groups. Unless otherwise indicated, the hydrocarbon group can contain up to 20 carbon atoms.
  • alkyl includes "bridged alkyl,” i.e., a C.sub.6-C.sub.l6 bicyclic or polycyclic hydrocarbon group, for example, norbomyl, adamantyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or decahydronaphthyl.
  • Alkyl groups optionally can be substituted, for example, with hydroxy (OH), halo, amino, and sulfonyl.
  • alkoxy group is an alkyl group having an oxygen substituent, e.g., -O-alkyl.
  • alkenyl refers to straight chained and branched hydrocarbon groups containing carbon atoms having at least one carbon-carbon double bond. Unless otherwise indicated, the hydrocarbon group can contain up to 20 carbon atoms. Alkenyl groups can optionally be substituted, for example, with hydroxy (OH), halo, amino, and sulfonyl.
  • alkylene refers to an alkyl group having a further defined substituent.
  • alkylenearyl refers to an alkyl group substituted with an aryl group
  • alkyleneamino refers to an alkyl groups substituted with an amino group.
  • the amino group of the alkyleneamino can be further substituted with, e.g., an alkyl group, an alkylenearyl group, an aryl group, or combinations thereof
  • alkenylene refers to an alkenyl group having a further defined substituent.
  • aryl refers to a monocyclic or polycyclic aromatic group, preferably a monocyclic or bicyclic aromatic group, e.g., phenyl or naphthyl. Unless otherwise indicated, an aryl group can be unsubstituted or substituted with one or more, and in particular one to four groups independently selected from, for example, halo, alkyl, alkenyl, OCF.sub.3, NO. sub.2, CN, NC, OH, alkoxy, amino, CO.sub.2H, CO.sub.2alkyl, aryl, and heteroaryl.
  • aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, chlorophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, nitrophenyl, 2,4-methoxychlorophenyl, and the like.
  • An "aryloxy” group is an aryl group having an oxygen substituent, e.g., -O-aryl.
  • acyl refers to a carbonyl group, e.g., C(O).
  • the acyl group is further substituted with, for example, hydrogen, an alkyl, an alkenyl, an aryl, an alkenylaryl, an alkoxy, or an amino group.
  • acyl groups include, but are not limited to, alkoxycarbonyl (e.g., C(O)— Oalkyl); aryloxycarbonyl (e.g., C(O)— Oaryl); alkylenearyloxycarbonyl (e.g., C(O)— Oalkylenearyl); carbamoyl (e.g., C(O)— NH.sub.2); alkylcarbamoyl (e.g., C(O)— NH(alkyl)) or dialkylcarbamoyl (e.g., C(O)— NH(alkyl).sub.2).
  • alkoxycarbonyl e.g., C(O)— Oalkyl
  • aryloxycarbonyl e.g., C(O)— Oaryl
  • alkylenearyloxycarbonyl e.g., C(O)— Oalkylenearyl
  • carbamoyl e.g., C(
  • amino refers to a nitrogen containing substituent, which can have zero, one, or two alkyl, alkenyl, aryl, alkylenearyl, or acyl substituents.
  • An amino group having zero substituents is—NH.sub.2.
  • halo or halogen refers to fluoride, bromide, iodide, or chloride.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid or inorganic acid.
  • nontoxic acid addition salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid lactobionic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid lactobionic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pam
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • Example 1 Computational Modeling, Pharmacophore Generation, Virtual and Functional Screening.
  • RNA m6A demethylase AlkBH5 binding compounds were carried out using the complex crystal structures.
  • the structure of the RNA m6A demethylase AlkBH5 was chosen as describing the potential target binding site for a small-molecule inhibitor.
  • the crystal structure of this complex (PDB: 4061) had been measured by X-ray diffraction with resolution 1.9 A (Xu C et al, 2014) [27]
  • the raw crystal structures were corrected and hydrogen atoms were automatically added to the protein using Schrodinger’s Protein Preparation Wizard of Maestro 10.7 (Sastry et al., 2013) [20]
  • AutoDock 4.2 (Morris et al, 2009) [15] was used for the docking studies to find out binding modes and binding energies of ligands to the receptor.
  • the number of rotatable bonds of ligand was set by default by AutoDock Tools 1.5.6 (Morris et al., 2009) [15] However, if the number was greater than 6, then some of rotatable bonds were made as non-rotatable, otherwise calculations can be inaccurate.
  • the active site was surrounded with a grid-box sized 65 x 65 x 65 points with spacing of 0.375 A.
  • the AutoDock 4.2 force field was used in all molecular docking simulations.
  • the amino group of the adenosyl fragment of SAM is hydrogen bonded with Asp377 of the Mettl3 (cf. Figure 2).
  • the binding is further supported by another bond between the adenine N1 atom and an adjacent peptide bond NH group.
  • the adenine ring is sandwiched between Phe534 and Asn549, while many polar contacts help to hold the hydroxyl groups on the ribose as well as the amino and carboxyl groups of SAM.
  • the terminal amino group of SAM is acting as hydrogen bond donor to the Asp395 of the catalytic center of enzyme.
  • Example 2 Screening of computationally predicted RNA m6A demethylase AlkBH5 ligands in enzyme inhibition assay.
  • the enzymatic assay was modified from Huang et al. 2015 (Huang et ah, 2015) [31].
  • the experiments were conducted in reaction buffer (50 mM (millimolar) Tris-HCl, pH 7.5, 300 mM (micromolar) 20G, 280 mM (NH ⁇ Fe ⁇ O ⁇ and 2 mM L-ascorbic acid).
  • the reaction mixture contained 200 ng (nanogram) methylated N 6 -adenine RNA probe (5’- CUUGUCAm6ACAGCAGA-3’, Dharmacon) SEQ. 1 and lOnM (nanomolar) ALKBH5 protein. Reactions were incubated on 96-well plate for 2h at RT. After that, the amount of m6A that was measured using EpiQuik m6A RNA methylation Quantification Colorimetric Kit (Epigentek).
  • C M , C M (max) and CDMSO are the amounts of m6A at a given concentration of the inhibitor, maximum inhibition and in the case of DMSO, respectively.
  • the dependence of the IE on the inhibitor concentration for the compound (III) is shown on Fig. 4 and for the compound (IV) on Fig. 5.
  • Example 3 Inhibitory effect of RNA m6A demethylase AlkBH5 inhibitor compounds on glioblastoma cell line A-172.
  • the A-172 cell line was obtained from the Glioma Tumor Cell Panel (ATCC® TCP-1018TM).
  • the HEK-293T cells (ATCC®ACS-4500TM). Both HEK-293T and A-172 cells were grown in Dulbecco’s Modified Eagle’s medium (DMEM) supplemented with 10% heat-inactivated FBS and Pen/Strep. The cells were grown at 37 °C in the presence of 5% C02.
  • DMEM Dulbecco’s Modified Eagle’s medium
  • HEK-293T and A-172 cells were seeded in 200 pL (micro liter) on a 16-well E-plate. Cells were incubated for 48 h with added compounds at given concentrations and 0.5% DMSO was used as a vehicle control. Cells viability were measured using real-time xCELLigence machine (RTCA xCELLigence).
  • RTCA xCELLigence real-time xCELLigence machine
  • the inhibitory effect of the compounds on the proliferation of the malignant A-172 cells was estimated relative to the proliferation of the normal HEK-293T cells.
  • the cell counts n c in the HEK-293T and A-172 cell cultures at a given concentration c of the inhibitor were normalized by the cell counts n DMSO in the case of negative control (DMSO).
  • n D MSO (HEK-293T) (3) were then used for the calculation of the inhibitory effect of a compound at given concentration as follows:
  • Example 4 Inhibitory effect of RNA m6A demethylase AlkBH5 inhibitor compounds on Childhood T acute lymphoblastic leukemia cell line CCRF-CEM.
  • the CCRF-CEM cell line was obtained from the ATCC® TCP1010TM Leukemia Cell Line Panel.
  • the JURKAT cells ATCC®CRL-2899TM. Both the JURKAT and CCRF-CEM cells were grown in Roswell Park Memorial Institute medium 1640 (RPMI 1640) supplemented with 10% heat-inactivated FBS and Pen/Strep. The cells were grown at 37 °C in the presence of 5% C02.
  • lx 10 5 JURKAT and CCRF-CEM cells were seeded in 1 mL on a 24-well plate. Cells were incubated for 48 h with added compounds at given concentrations and 0.5% DMSO was used as a vehicle control. Cells viability were measured using Countess Automated Cell Counter by Thermo Fisher Scientific Invitrogen.
  • the inhibitory effect of the compounds on the proliferation of the Childhood T acute lymphoblastic leukemia cell line CCRF-CEM and cell line JURKAT cells was estimated relative to the proliferation of the normal HEK-293T cells.
  • the cell counts n c in the JURKAT and CCRF-CEM cell cultures at a given concentration c of the inhibitor were normalized by the cell counts U BMSO in the case of negative control (DMSO).
  • nDMSO (JURKAT) (6) were then used for the calculation of the inhibitory effects of a compound at given concentration as follows:
  • the time dependence of the inhibitory effect INH% of compound (III) on the malignant CCRF-CEM cells at 10 mM (micromolar) concentration is given in Fig. 8 and the time dependence of the inhibitory effect INH% of compound (IV) at 100 mM concentration in Fig. 9.
  • the time dependence of the inhibitory effect INH% of compound (III) on the malignant JURKAT cells at 10 mM concentration is given in Fig. 10 and the time dependence of the inhibitory effect INH% of compound (IV) at 100 mM concentration in Fig. 11.
  • the proliferation of the leukemia cells CCRF-CEM is suppressed as compared to the normal HEK-293T cells.
  • RNA N-6-methyladenine demethylase AFKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation, Nucl. Acid Res., 42, 4741-4754.
  • m6A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells. Cell Rep. 18, 2622-2634.
  • N6-Methyl- Adenosine (m6A) in RNA An Old Modification with A Novel Epigenetic Function. GPB. 11, 8-17.
  • ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse Fertility, Mol. Cell, 49, 18-29.
  • Xu C Liu, Ke., Tempel, W., Demetriades, M., Aik, W., Schofield, C.J., Min, J. (2014) Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single- stranded N6-methyladenosine RNA demethylation. J Biol. Chem. 289, 17299-17311.

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Abstract

La présente invention concerne, d'une manière générale, des compositions et des méthodes pour traiter le cancer. L'invention concerne des composés qui modulent spécifiquement la méthylation de l'ARN par inhibition de l'ARN déméthylase AlkBH5. De plus, les composés et compositions de l'invention sont utilisables pour le traitement de cancers, tels que le glioblastome, l'astrocytome, la leucémie aiguë myéloïde, la leucémie aiguë monoblastique, la leucémie myéloïde chronique, la leucémie aiguë lymphoblastique à précurseurs T, et analogues.
PCT/EP2019/058737 2019-04-07 2019-04-07 Méthode d'inhibition du cancer par des inhibiteurs de l'alkbh5, la déméthylase ciblant les m6a de l'arn Ceased WO2020207550A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114540481A (zh) * 2022-01-25 2022-05-27 苏州大学 一种慢性疼痛治疗靶点及其应用
GB2601520A (en) * 2020-12-02 2022-06-08 Chemestmed Ltd Method of survival and protection of neurons by inhibitors of RNA m6A demethylases FTO and ALKBH5
WO2023217109A1 (fr) * 2022-05-13 2023-11-16 中国科学院广州生物医药与健康研究院 Combinaison d'un inhibiteur d'arn méthylase m6a et d'un inhibiteur de point de contrôle immunitaire pour traiter des tumeurs
CN119490494A (zh) * 2025-01-20 2025-02-21 四川大学 芳基取代的五元氮杂环酰胺类衍生物及其用途

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GB2601520A (en) * 2020-12-02 2022-06-08 Chemestmed Ltd Method of survival and protection of neurons by inhibitors of RNA m6A demethylases FTO and ALKBH5
GB2601520B (en) * 2020-12-02 2025-10-08 Chemestmed Ltd Method of survival and protection of neurons by inhibitors of RNA m6A demethylases FTO and ALKBH5
CN114540481A (zh) * 2022-01-25 2022-05-27 苏州大学 一种慢性疼痛治疗靶点及其应用
CN114540481B (zh) * 2022-01-25 2022-12-06 苏州大学 一种慢性疼痛治疗靶点alkbh5及其应用
WO2023142230A1 (fr) * 2022-01-25 2023-08-03 苏州大学 Cible pour le traitement de la douleur chronique et son utilisation
WO2023217109A1 (fr) * 2022-05-13 2023-11-16 中国科学院广州生物医药与健康研究院 Combinaison d'un inhibiteur d'arn méthylase m6a et d'un inhibiteur de point de contrôle immunitaire pour traiter des tumeurs
CN119490494A (zh) * 2025-01-20 2025-02-21 四川大学 芳基取代的五元氮杂环酰胺类衍生物及其用途

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