JP6536911B2 - CD44遺伝子のバリアントエクソンのスキッピングを誘導し、正常型CD44mRNAの発現を増加させる核酸医薬 - Google Patents
CD44遺伝子のバリアントエクソンのスキッピングを誘導し、正常型CD44mRNAの発現を増加させる核酸医薬 Download PDFInfo
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- 239000012149 elution buffer Substances 0.000 description 1
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- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- PCIBVZXUNDZWRL-UHFFFAOYSA-N ethylene glycol monophosphate Chemical group OCCOP(O)(O)=O PCIBVZXUNDZWRL-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
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- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 150000002243 furanoses Chemical class 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 230000004077 genetic alteration Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002301 glucosamine derivatives Chemical class 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 239000004247 glycine and its sodium salt Substances 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
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- 159000000014 iron salts Chemical class 0.000 description 1
- 238000002357 laparoscopic surgery Methods 0.000 description 1
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- 229910003002 lithium salt Inorganic materials 0.000 description 1
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- 239000012139 lysis buffer Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
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- 230000009401 metastasis Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
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- 150000002772 monosaccharides Chemical class 0.000 description 1
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- 150000002823 nitrates Chemical class 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000008012 organic excipient Substances 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
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- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- NGHMEZWZOZEZOH-UHFFFAOYSA-N silicic acid;hydrate Chemical compound O.O[Si](O)(O)O NGHMEZWZOZEZOH-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229940029258 sodium glycinate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- WUWHFEHKUQVYLF-UHFFFAOYSA-M sodium;2-aminoacetate Chemical compound [Na+].NCC([O-])=O WUWHFEHKUQVYLF-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 125000002827 triflate group Chemical class FC(S(=O)(=O)O*)(F)F 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000000439 tumor marker Substances 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
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- C12N15/09—Recombinant DNA-technology
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Description
(1)CD44遺伝子のバリアントエクソンのスキッピングを誘導し、正常型CD44mRNAの発現を増加させることができるアンチセンスオリゴヌクレオチド、その医薬的に許容できる塩、溶媒和物又はプロドラッグを含む、がん治療薬。
(2)がん細胞の抗がん剤及び/又は放射線感受性を増強する(1)記載のがん治療薬。
(3)スキッピングの対象となるバリアントエクソンが、バリアント8、9及び10からなる群より選択される少なくとも1つである(1)又は(2)記載のがん治療薬。
(4)アンチセンスオリゴヌクレオチドが、CD44遺伝子のバリアントエクソン8、9又は10の塩基配列の一部又は全部に相補的な塩基配列を有するオリゴヌクレオチドである(3)記載のがん治療薬。
(5)CD44遺伝子のバリアントエクソン8、9又は10の塩基配列の一部又は全部に相補的な塩基配列を有するオリゴヌクレオチドが、配列番号1〜19のいずれかの塩基配列の全部又は一部を有し、20〜23の塩基長のオリゴヌクレオチドである(4)記載のがん治療薬。
(6)アンチセンスオリゴヌクレオチドが少なくとも1つの修飾ヌクレオチドを含む(1)〜(5)のいずれかに記載のがん治療薬。
(7)修飾ヌクレオチドを構成するD-リボフラノースが2'-O,4'-C-アルキレン化されている(6)記載のがん治療薬。
(8)配列番号1〜19のいずれかの塩基配列の全部又は一部を有する、20〜23の塩基長のオリゴヌクレオチド、その医薬的に許容できる塩、溶媒和物又はプロドラッグ。
(9)少なくとも1つの修飾ヌクレオチドを含む(8)記載のオリゴヌクレオチド、その医薬的に許容できる塩、溶媒和物又はプロドラッグ。
(10)修飾ヌクレオチドを構成するD-リボフラノースが2'-O,4'-C-アルキレン化されている(9)記載のオリゴヌクレオチド、その医薬的に許容できる塩、溶媒和物又はプロドラッグ。
(11)CD44遺伝子のバリアントエクソンを標的とするアンチセンスオリゴヌクレオチドである(8)〜(10)のいずれかに記載のオリゴヌクレオチド、その医薬的に許容できる塩、溶媒和物又はプロドラッグ。
(12)(8)〜(11)のいずれかに記載のオリゴヌクレオチド、その医薬的に許容できる塩、溶媒和物又はプロドラッグを含み、CD44遺伝子のバリアント8、9及び10からなる群より選択される少なくとも1つのバリアントエクソンのスキッピングを誘導するための薬剤。
(13)CD44遺伝子のバリアントエクソンのスキッピングを誘導し、正常型CD44mRNAの発現を増加させることができるアンチセンスオリゴヌクレオチド、その医薬的に許容できる塩、溶媒和物又はプロドラッグを医薬的に有効な量で被験者に投与することを含む、がんの治療方法。
(14)がんの治療のための、CD44遺伝子のバリアントエクソンのスキッピングを誘導し、正常型CD44mRNAの発現を増加させることができるアンチセンスオリゴヌクレオチド、その医薬的に許容できる塩、溶媒和物又はプロドラッグの使用。
(15)がんを治療する方法に使用するための、CD44遺伝子のバリアントエクソンのスキッピングを誘導し、正常型CD44mRNAの発現を増加させることができるアンチセンスオリゴヌクレオチド、その医薬的に許容できる塩、溶媒和物又はプロドラッグ。
本明細書は、本願の優先権の基礎である日本国特許出願、特願2014‐103674の明細書および/または図面に記載される内容を包含する。
〔実施例1〕アンチセンスオリゴヌクレオチド(AO)の合成
表1に示すアンチセンスオリゴヌクレオチド(AO)を合成した。CD44バリアントmRNAに相補的なAOの配列場所を図3〜5に示す。AOの配列中のC(シトシン)およびT(チミン)に修飾核酸のENA(登録商標)(2'-O,4'-C-Ethylene-bridged Nucleic Acids)(図6)を導入し、親和性と安定性を向上させた。
核酸自動合成機(日本テクノサービス社製DNA/RNA合成装置 NTS H-8)を用い、1μmolスケールで行った。各合成サイクルにおける溶媒、試薬、ホスホロアミダイトの濃度は天然オリゴヌクレオチド合成の場合と同じであり、試薬、2'-O-メチルヌクレオシドのホスホロアミダイト(アデノシン体product No. 10-3100-10、グアノシン体product No. 10-3121-10、シチジン体product No. 10-3110-10、ウリジン体product No. 10-3130-10)はグレンリサーチ社製のものを用いた。溶媒は和光純薬工業のものを用いた。非天然型のホスホロアミダイトは特開2000-297097の実施例22(5'-O-ジメトキシトリチル-2'-O,4'-C-エチレン-4-N-ベンゾイル-5-メチルシチジン-3'-O-(2-シアノエチル N,N-ジイソプロピル)ホスホロアミダイト)、実施例9(5'-O-ジメトキシトリチル-2'-O,4'-C-エチレン-5-メチルウリジン-3'-O-(2-シアノエチル N,N-ジイソプロピル)ホスホロアミダイト)の化合物を用いた。固相担体としてコントロールポアグラス(CPG)(BIOSEARCH社製product No. BG5-3400-B)を用い、表記の化合物を合成した。但し、アミダイトの縮合に要する時間は、15分とした。
実施例1の化合物と同様に目的配列を有する実施例2の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
実施例1の化合物と同様に目的配列を有する実施例3の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
実施例1の化合物と同様に目的配列を有する実施例4の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
実施例1の化合物と同様に目的配列を有する実施例5の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
実施例1の化合物と同様に目的配列を有する実施例6の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
実施例1の化合物と同様に目的配列を有する実施例7の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
実施例1の化合物と同様に目的配列を有する実施例8の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。本化合物は負イオンMALDI-TOFMSにより、同定した(計算値:6889.7、測定値:6888.40)。
実施例1の化合物と同様に目的配列を有する実施例9の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
実施例1の化合物と同様に目的配列を有する実施例10の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
実施例1の化合物と同様に目的配列を有する実施例11の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
実施例1の化合物と同様に目的配列を有する実施例12の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
実施例1の化合物と同様に目的配列を有する実施例13の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
HO-GCGTTGTCATTGAAAGAGGT -OH(AO-#14)の合成
実施例1の化合物と同様に目的配列を有する実施例14の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
実施例1の化合物と同様に目的配列を有する実施例15の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
実施例1の化合物と同様に目的配列を有する実施例16の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
実施例1の化合物と同様に目的配列を有する実施例17の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
実施例1の化合物と同様に目的配列を有する実施例18の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
実施例1の化合物と同様に目的配列を有する実施例19の化合物を合成した。脱保護後、逆相HPLC(島津製作所製LC-8A、カラム(資生堂社製CAPCELLPAK ODS type MG(20×250 mm))、A溶液:0.1M酢酸トリエチルアミン水溶液(TEAA), pH 7.0、B溶液:アセトニトリル、B%:5%→40%(30 min, linear gradient);40°C;19 mL/min;260 nm)にて精製した。酢酸を終濃度10%になるよう加えて一晩静置し、DMTr基を除去した。溶媒留去後、水1.0 mLに溶解し、NAP-10 columns(GEヘルスケア社製、product No. 17-0854-01)で精製し、凍結乾燥後目的化合物を得た。
下記の大腸がん及び胃がんのがん幹細胞をATCC(American Type Culture Collection)より購入した。これらがん幹細胞はCD44バリアントエクソンを発現(特にCD44v8-10を高発現)している。
・HT-29細胞(大腸がん)
・KATOIII細胞(胃がん)
12 well plateに播種し、一晩培養したヒト胃がん細胞KATOIIIにAO(50, 100 nM)を添加した。3時間後、FBSを加え、更に24時間培養した。その後、RNAの回収を行い、RT-PCRによりCD44mRNAを解析した。
以下のようにしてRNAの抽出を行った。
1. AOをトランスフェクションした細胞を24時間培養した後、PBSにて1回洗浄して、Lysis/binding buffer (Roche, High Pure RNA Isolation Kit) 300μL、PBS 150μLを細胞に添加した。
2. 室温で1分間放置した後、フェル内の細胞混合液をチューブに回収した。
3. High Pure RNA Isolation Kit (Roche)のプロトコールに従ってRNAを抽出した。
4. 最終的にElution buffer 36μLにてRNAを溶出させた。
以下のようにして逆転写を行った。
1. RNA 500ngにミリQ(滅菌処理済み)を加え、6μLとした。
2. 1の溶液へRandom primers (invitrogen 3μg/μLを20倍希釈したもの) 2μLと2.5mM dNTP mixture (invitrogen) 5μLを加えた。
3. 65℃で5分間加熱した。
4. 25℃で10分間放置した。
5.上記の反応液に、
M-MLV-reverse transcriptase (invitrogen 200U/μL) 1μL、RNase OUT (invitrogen 40U/μL) 1μL、0.1M DTT (M-MLV-reverse transcriptaseに添付) 1μL、5×First stand Buffer (M-MLV-reverse transcriptaseに添付) 4μL
を加えた。
6. 37℃で55分間保温し、その後70℃で15分間加熱した。
7. 反応液は-80℃で保存した。
以下のようにしてPCR反応を行った。
1. 下記の成分を混和後、94℃で3分間加熱した。
フォワードプライマー(10pmol/μL) 0.5μL
リバースプライマー(10pmol/μL) 0.5μL
dNTP(TAKARA Ex Taqに添付) 0.8μL
バッファー(TAKARA Ex Taqに添付) 1.0μL
Ex Taq 0.05μL
滅菌水 6.15μL
2. 94℃3分の処理後に94℃30秒・60℃30秒・72℃90秒の処理を25サイクル行った。
3. 72℃で3分間加熱した
なお、バリアントエクソンのスキッピングを検出するためのPCR反応に用いたフォワードプライマーとリバースプライマーの塩基配列は下記の通りである。
リバースプライマー(CD44 エクソン16) :5'-CACTGGGGTGGAATGTGTCTTGGTC-3'(配列番号24)
KATOIII細胞を12well plateに1×105 cells/wellで播種し、Lipofectamine2000 reagent (Invitrogen Life Technologies)を用いてAO-#7(50nM)又はMilli-Q(control)を添加した。37℃、5%CO2 インキュベーターにて3時間静置後、20%FBS含有IMDM(Iscove’s Modified Dulbecco’s Medium)培地 500μL/well、CDDP (最終濃度5μg/mL, 日本化薬株式会社、ランダ注 10mg/20mL)を加え、更に培養を続けた。24、48、72、96時間ごとにプレートを室温に平衡化し、調製したCell Titer-Glo Reagent (CellTiter-GloTM Luminesent Cell Viability Assay (Promega))を各ウェルに加え、マルチラベルプレートリーダー (2030 ARVO X3, PerkinElmer)にてルシフェラーゼ発光シグナルを測定した。
結果を図13に示す。図13のグラフは、コントロールの値を100%として、各値を算出してグラフ化した。CDDP(シスプラチン)添加よりも、CDDP+AO-#7の方が細胞増殖を抑制している。
KATOIII細胞を12well plateに1×105 cells/wellで播種し、Lipofectamine2000 reagent (Invitrogen Life Technologies)を用いてAO-#7(50nM)又はAO-#12(50nM)又はMilli-Q(control)を添加した。37℃、5%CO2 インキュベーターにて3時間静置後、20%FBS含有IMDM(Iscove’s Modified Dulbecco’s Medium)培地 500μL/wellを加え、更に培養を続けた。24、48、72、96時間ごとにプレートを室温に平衡化し、調製したCell Titer-Glo Reagent (CellTiter-GloTM Luminesent Cell Viability Assay (Promega))を各ウェルに加え、マルチラベルプレートリーダー (2030 ARVO X3, PerkinElmer)にてルシフェラーゼ発光シグナルを測定した。
結果を図14に示す。AO-#7は、CD44vmRNA (CD44v8-10)のスキッピング誘導が最も効果的なAO、AO-#12はCD44vmRNAのスキッピングにほとんど影響がなかったAOである。Milli-Q(水)はコントロール(比較)として使用した。AO-#7とAO-#12の比較により、AOの毒性による影響を確認した。AO-#7のみの添加でKATOIII細胞の増殖を抑制した。
本明細書で引用した全ての刊行物、特許および特許出願をそのまま参考として本明細書にとり入れるものとする。
AO-#1の塩基配列を示す。5’-actatgactggagtccatat-3’
<配列番号2>
AO-#2の塩基配列を示す。5’-ttgcagtaggctgaagcgtt-3’
<配列番号3>
AO-#3の塩基配列を示す。5’-caaacctgtgtttggatttg-3’
<配列番号4>
AO-#4の塩基配列を示す。5’-aagaggtcctgtcctgtcca-3’
<配列番号5>
AO-#5の塩基配列を示す。5’-gctctgagaattactctgct-3’
<配列番号6>
AO-#6の塩基配列を示す。5'-cttcatgtgatgtagagaag-3’
<配列番号7>
AO-#7の塩基配列を示す。5'-tcttccaagccttcatgtga-3’
<配列番号8>
AO-#8の塩基配列を示す。5'-gatggtctttatcttcttcc-3'
<配列番号9>
AO-#9の塩基配列を示す。5'-gtagaagttgttggatggtc-3’
<配列番号10>
AO-#10の塩基配列を示す。5’-tgcttgatgtcagagtagaa-3’
<配列番号11>
AO-#11の塩基配列を示す。5'-gaaggtcctgctttccttcg-3'
<配列番号12>
AO-#12の塩基配列を示す。5’-CCACCAAACCTGTGTTTGGA-3’
<配列番号13>
AO-#13の塩基配列を示す。5’-CTGTCCAAATCTTCCACCAA-3’
<配列番号14>
AO-#14の塩基配列を示す。5’-GCGTTGTCATTGAAAGAGGT-3’
<配列番号15>
AO-#15の塩基配列を示す。5'-TTCCAAGCCTTCATGTGATG-3’
<配列番号16>
AO-#16の塩基配列を示す。5'-GTCTCTTCTTCCACCTGTGA-3'
<配列番号17>
AO-#17の塩基配列を示す。5'-TTCCAGTAAAGTAGTTGAGC-3'
<配列番号18>
AO-#18の塩基配列を示す。5'-TCCAAAGGACCCAGTCTTAG-3'
<配列番号19>
AO-#19の塩基配列を示す。5'-GTTGGAATCTCCAACAGTAA-3
<配列番号20>
CD44v8 mRNAの塩基配列を示す。
atatggactccagtcatagtacaacgcttcagcctactgcaaatccaaacacaggtttggtggaagatttggacaggacaggacctctttcaatgacaacgc
<配列番号21>
CD44v9 mRNAの塩基配列を示す。
agcagagtaattctcagagcttctctacatcacatgaaggcttggaagaagataaagaccatccaacaacttctactctgacatcaagca
<配列番号22>
CD44v10 mRNAの塩基配列を示す。
ataggaatgatgtcacaggtggaagaagagacccaaatcattctgaaggctcaactactttactggaaggttatacctctcattacccacacacgaaggaaagcaggaccttcatcccagtgacctcagctaagactgggtcctttggagttactgcagttactgttggagattccaactctaatgtcaatcgttccttatcag
<配列番号23>
バリアントエクソンのスキッピングを検出するためのPCR反応に用いたフォワードプライマーの塩基配列を示す。
5'-TCCCAGACGAAGACAGTCCCTGGAT-3'
<配列番号24>
バリアントエクソンのスキッピングを検出するためのPCR反応に用いたリバースプライマーの塩基配列を示す。
5'-CACTGGGGTGGAATGTGTCTTGGTC-3'
Claims (8)
- CD44遺伝子のバリアントエクソンのスキッピングを誘導し、正常型CD44mRNAの発現を増加させることができる20〜23の塩基長のアンチセンスオリゴヌクレオチド、その医薬的に許容できる塩又は溶媒和物を含む、がん治療薬であって、
前記アンチセンスオリゴヌクレオチドの塩基配列は、CD44遺伝子のバリアントエクソン8、9又は10の塩基配列の一部に相補的な塩基配列であり、かつ配列番号7、13、15又は16の塩基配列の全部を含む前記がん治療薬。 - がん細胞の抗がん剤及び/又は放射線感受性を増強する請求項1記載のがん治療薬。
- アンチセンスオリゴヌクレオチドが少なくとも1つの修飾ヌクレオチドを含む請求項1又は2に記載のがん治療薬。
- 修飾ヌクレオチドを構成するD-リボフラノースが2'-O,4'-C-アルキレン化されている請求項3記載のがん治療薬。
- CD44遺伝子のバリアントエクソンのスキッピングを誘導し、正常型CD44mRNAの発現を増加させることができる、20〜23の塩基長のオリゴヌクレオチド、その医薬的に許容できる塩又は溶媒和物であって、
前記オリゴヌクレオチドの塩基配列は、CD44遺伝子のバリアントエクソン8、9又は10の塩基配列の一部に相補的な塩基配列であり、かつ配列番号1〜19のいずれかの塩基配列の全部を含む前記オリゴヌクレオチド、その医薬的に許容できる塩又は溶媒和物。 - 少なくとも1つの修飾ヌクレオチドを含む請求項5記載のオリゴヌクレオチド、その医薬的に許容できる塩又は溶媒和物。
- 修飾ヌクレオチドを構成するD-リボフラノースが2'-O,4'-C-アルキレン化されている請求項6記載のオリゴヌクレオチド、その医薬的に許容できる塩又は溶媒和物。
- 請求項5〜7のいずれかに記載のオリゴヌクレオチド、その医薬的に許容できる塩又は溶媒和物を含み、CD44遺伝子のバリアント8、9及び10からなる群より選択される少なくとも1つのバリアントエクソンのスキッピングを誘導するための薬剤。
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