JP2015524405A - タンパク質高次構造の障害に関連する遺伝性筋疾患の治療のためのエピゲノム修飾化合物の使用 - Google Patents
タンパク質高次構造の障害に関連する遺伝性筋疾患の治療のためのエピゲノム修飾化合物の使用 Download PDFInfo
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- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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- 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
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
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Abstract
Description
− ジスフェリンが変異すると三好型ミオパチーの原因となる;
− アノクタミン5が変異すると三好型類似三型ミオパチー(Miyoshi-like type 3 myopathy)の原因となる;
− チチンが変異すると脛骨筋ジストロフィー(TMD)の原因となる。
− LGMD2C、γ−サルコグリカンをコードする遺伝子の変異が原因(Ben Othmane et al., 1995);
− LHMD2D、α−サルコグリカンをコードする遺伝子の変異が原因(Passos-Bueno et al., 1993);
− LHMD2E、β−サルコグリカンをコードする遺伝子の変異が原因(Lim et al., 1995);
− LHMD2F、δ−サルコグリカンをコードする遺伝子の変異が原因(Passos-Bueno et al., 1996)。
− DNAレベルにおける修飾;
− ヒストンレベルにおける修飾;
− ポリコームのような特定のタンパク質の関与;
− 非コードRNAの関与、小さなもの(マイクロRNA)及び大きなもの(長鎖非コードRNA)がある。
− ノーザンブロット又はPCR転写物の発現レベル;
− 適切な抗体によって検出されるタンパク質産生レベル(ウェスタンブロット又はELISA(enzyme linked immunosorbent assay))。
− ヌクレオシド類似体:これらは複製DNAに取り込まれる。このためDNAメチル化を阻害し、形質発現していなかった遺伝子を再活性化する。かかる分子として以下のものがある:
○ プロカイン
○ 没食子酸エピガロカテキン、エピガロカテキン 3−ガラート(EGCG);
■ APHAコンパウンド8;
■ MC1568;
■ チューバシン(原文においてTubucine);
■ 下記式で表されるヒドロキサミン酸サブエロイルアニリド(SAHA又はボリノスタット):
■ アピシジン;
■ 106
■ モセチノスタット(MGCD0103)
■ α−ケトアミド;
○ LAQ 824;
○ パノビノスタット(LBH589);
○ ジヒドロクマリン;
○ ナフトピラノン(naphthopyranone);
○ 2−ヒドロキシナフトアルデヒド(2-hydroxynaphaldehyde);
○ 10−ヒドロキシ−2−デセン酸(10HDA);
○ アベキシノスタット(Abexinostat, PCI-24781);
○ SB939;
○ レスミノスタット(Resminostat, 4SC-201);
○ ギビノスタット(Givinostat, ITF2357);
○ CUDC-101;
○ AR-42;
○ CHR-2845;
○ CHR-3996;
○ 4SC-202;
○ CG200745;
○ ACY-1215;
○ スルホラファン;
○ ケベトリン(Kevetrin);
○ アピシジン;
○ 酪酸ナトリウム;
○ (−)−デプデシン((-)-Depudecin);
○ サーチノール(Sirtinol);
○ N-ヒドロキシ-1,3-ジオキソ-1H-ベンゾ[de]イソキノリノン-2(3H)-ヘキサンアミド又はスクリプタイド(Scriptaid)
○ 酪酸のヒドロキサメート誘導体(Le derive hydroxamate de l'acide butyrique);
○ イソブチルアミド(L'isobutyramide);
○ CBHA(m-カルボキシ桂皮酸ビスヒドロキシアミド、m-carboxycinnamic acid bishydoxyamide);
○ HC毒素(L'HC toxin);
○ M344(4-ジメチルアミノ-N-(6-ヒドロキシカルバノミル-ヘキシル)-ベンズアミド);
○ ヌルスクリプト(Nullscript)(4-(1,3-ジオキソ-1H,3H-ベンゾ[de]イソキノリノン-2-イル)-N-ヒドロキシブタンアミド);
○ 下記式で表されるPCI-34051:
PRC複合体はもともとヒストンメチル基転移酵素(histone methyltransferase, HMTase)活性を含んでおりヒストンメチル化によって発現を抑制する。
− DNAメチル化に係るもの;若しくは
− ヒストン修飾に係るもの;若しくは
− PRC複合体に係るもの;若しくは
− 非コードRNAに係るもの、好ましくはマイクロRNA及び/又は長鎖非コードRNAに係るもの。
「一以上の高次構造の障害」又は「タンパク質の高次構造の障害」とは疾患の原因となるタンパク質がそれをコードする遺伝子中の一以上の変異によりミスフォールドされており、該障害により細胞によって該タンパク質が分解されることを指す。また対象となる疾患は例えば変異タンパク質を標的とする抗体によって容易に特定できる。実際には、たとえ(転写産物レベルで確認できており)正常に発現していても、分解されているため該抗体によって検出できない。
○ γ−サルコグリカンに係る
○ α−サルコグリカンに係る
○ β−サルコグリカンに係る
○ δ−サルコグリカンに係る
○ アノクタミン5(Ano5)に係る
○ フクチン関連タンパク質(FKRP)に係る
○ フクチン(FKTN)に係る
○ プロテイン-O-マンノシルトランスフェラーゼ1(POMT1)に係る
○ プロテイン-O-マンノシルトランスフェラーゼ2(POMT2)に係る
○ プロテイン-O-関連マンノースβ 1,2-アセチルグルコサミニル-転移酵素(POMGT1)に係る
○ カベオリン3(Cav3)に係る
○ UDP-N-アセチルグルコサミン2-エピメラーゼ(GNE)に係る
○ ラミニンアルファ-2(LAMA2)に係る
○ ライク−グリコシルトランスフェラーゼ(LARGE)に係る
○ コラーゲン6A1、6A2、又は6A3に係る
○ セレンプロテイン1(SEPN1)に係る
○ インテグリンアルファ7(ITGA7)に係る
○ リアノジン受容体(RYR)に係る
○ polymerase I and transcript release factor(PTRF)に係る四型脂肪異栄養症筋ジストロフィー(la liposdystrophie congenitale de type 4 avec dystrophie musculaire)
○ ヘパラン硫酸(HSPG2)に係る軟骨形成異常型筋緊張症(la Chondrodystrophic myotonia)又はシュワルツ・ヤンペル(Schwartz Jampel)症候群
○ リソソーム膜タンパク質2(lysosomal-associated membrane protein 2, LAMP2)に係るダノン病
○ I型アクチビンA受容体(ACVR1)に係る進行性骨化性線維形成異常症(Fibrodysplasia ossificans progressiva)である。
− 正常にフォールディングされたタンパク質の割合を測定する。細胞内で正常に局在していることに基づくのが好ましい。
かかる方法は免疫学的な検出法よりも検出工程の重要性が低いため好ましい。ただし融合タンパク質(関心のあるタンパク質+標識)がタンパク質複合体の形成を妨げないことを確認することが重要である。
− タンパク質の局在の陽性対照として変異の無いタンパク質を発現する細胞でも実施し;
− 対照群として、評価を受ける化合物の非存在下で細胞を放置することで、評価を受けるタンパク質の正の効果によるものと結論される。
− 正常にフォールディングされたタンパク質の割合を測定する。
− 正常にフォールディングされたタンパク質の割合を測定する。
B/R77C変異を有するα-SGによるもの
C/R77C変異を有するα-SGによるものであって5-μMの5-aza存在下のもの。
B/R77C変異を有するα-SGによるもの
C/R77C変異を有するα-SGによるものであって1-μMのSAHA存在下のもの。
HER-911細胞を3.7%ホルムアルデヒドで室温15分間にて固定した。必要な場合は0.2%トリトンX-100で20分間、易透化処理をした。20%のウシ胎仔血清で30分間飽和させた後、適切な濃度(PBS中)の一次抗体で1時間、室温にて細胞をインキュベートした。α-SG特異的なマウスモノクローナル抗体(NCL-A-SARC)はNovocastraより入手できる。細胞をPBSで3回洗浄し、PBSで1/1,000倍に薄めた二次抗体で1時間インキュベートした。最後に細胞をPBSで洗浄し、Vectashield Mounting Medium with DAPI(Vector, H-1200)を用いてマウントし、共焦点免疫蛍光顕微鏡(Leica)で観察した。
[参考文献]
Claims (10)
- エピゲノム修飾を行う一以上の化合物を有する医薬であって、
一以上のタンパク質における高次構造の障害に関連する遺伝性筋疾患の治療において使用され、
前記障害が前記タンパク質の細胞内分解の原因となる、
医薬。 - 前記化合物が:
− DNAメチル化の活性化物質又は阻害物質;
− ヒストン修飾の活性化物質又は阻害物質;
− PRC複合体の活性化物質又は阻害物質;又は
− 非コードRNA、好ましくはマイクロRNA及び/若しくは長鎖非コードRNAの活性化物質又は阻害物質であることを特徴とする、
請求項1に記載の医薬。 - 前記化合物がSAHA又は5-アザシチジンであることを特徴とする、
請求項2に記載の医薬。 - 前記遺伝性筋疾患が進行性筋ジストロフィーであることを特徴とする、
請求項1−3のいずれかに記載の医薬。 - 前記進行性筋ジストロフィーが:サルコグリカン異常症、ジスフェリン異常症、アノクタミノパチー、及びFKRP(フクチン関連タンパク質)の異常に係るジストロフィーから成る群から選ばれることを特徴とする、
請求項4に記載の医薬。 - 投与経路が筋肉内投与、腹腔内投与、皮下投与、経口投与、又は静脈内投与であることを特徴とする、
請求項1−5のいずれかに記載の医薬。 - エピゲノム修飾を行う化合物の効果をin vitroで確認する又は評価する方法であって、
以下の工程を含む方法:
− ミスフォールドされたタンパク質であって遺伝性筋疾患の原因となるものを産生する細胞を前記化合物と接触させ、
− 正常にフォールディングされたタンパク質の割合を測定する、好ましくは細胞内での局在に基づいて測定する、
前記正常にフォールディングされたタンパク質の割合は、前記化合物のエピゲノム修飾の効率と相関する。 - 一以上のタンパク質の高次構造の障害であって細胞内で自身が分解されるものに関連する遺伝性筋疾患の治療のための化合物を特定するin vitroの方法であって、
前記化合物のエピゲノム修飾の可能性を評価することを含み、
前記化合物の前記エピゲノム修飾の可能性は、一以上のタンパク質の高次構造の障害であって細胞内で自身が分解されるものに関連する遺伝性筋疾患の治療に対する前記化合物の効率と相関する、方法。 - 一以上のタンパク質の高次構造の障害であって細胞内で自身が分解されるものに関連する遺伝性筋疾患の治療のための化合物を特定するin vitroの方法であって、以下の工程を含む方法:
− ミスフォールドされたタンパク質であって遺伝性筋疾患の原因となるものを産生する細胞を前記化合物と接触させ、
− 正常にフォールディングされたタンパク質の割合を測定する、
前記正常にフォールディングされたタンパク質の割合は、一以上のタンパク質の高次構造の障害であって細胞内で自身が分解されるものに関連する遺伝性筋疾患の治療のための前記化合物のエピゲノム修飾の効率と相関する。 - 一以上のタンパク質の高次構造の障害であって細胞内で自身が分解されるものに関連する遺伝性筋疾患を特定する方法であって、以下の工程を含む方法:
− ミスフォールドされたタンパク質であって筋の遺伝性疾患の原因となるものを産生することができる細胞を、エピゲノム修飾を行う化合物に接触させる;
− 正常にフォールディングされたタンパク質の割合を測定する、
前記正常にフォールディングされたタンパク質の割合は、一以上のタンパク質の高次構造の障害であって細胞内で自身が分解されるものに関連する遺伝性筋疾患の特定と相関する。
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