JP2017512768A - Erg発癌遺伝子陽性癌のための新規阻害剤 - Google Patents
Erg発癌遺伝子陽性癌のための新規阻害剤 Download PDFInfo
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- C09B29/00—Monoazo dyes prepared by diazotising and coupling
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- C09B67/0071—Process features in the making of dyestuff preparations; Dehydrating agents; Dispersing agents; Dustfree compositions
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Abstract
Description
「薬学的に許容される塩(pharmaceutically acceptable salt)」は、本発明の化合物の薬学的に許容される有機または無機の酸性塩または塩基塩である。薬学的に許容される代表的な塩類としては、例えば、酢酸塩、アムソネート(amsonate)(4,4−ジアミノスチルベン−2,2−ジスルホネート)、ベンゼンスルホン酸塩、安息香酸塩、重炭酸塩、重硫酸塩、重酒石酸塩、ホウ酸塩、臭化物、酪酸塩、カルシウム、エデト酸カルシウム、カンシラート(camsylate)、炭酸塩、塩化物、クエン酸塩、クラブラン酸塩(clavulariate)、二塩酸塩、エデト酸塩、エジシル酸塩、エストレート(estolate)、エシレート(esylate)、フマル酸塩、グルセプテート(gluceptate)、グルコン酸塩、グルタミン酸塩、グリコリルアルサニレート(glycollylarsanilate)、ヘキサフルオロリン酸塩、ヘキシルレゾルシネート(hexylresorcinate)、ヒドラバミン、臭化水素酸塩、塩酸塩、ヒドロキシナフトエート(hydroxynaphthoate)、ヨウ化物、イソチオネート(isothionate)、乳酸塩、ラクトビオン酸塩、ラウリン酸塩、リンゴ酸塩、マレイン酸塩、マンデル酸塩、メシレート(mesylate)、臭化メチル、硝酸メチル、硫酸メチル、ムケート(mucate)、ナプシレート(napsylate)、硝酸塩、N−メチルグルカミンアンモニウム塩、3−ヒドロキシ−2−ナフトエート、オレイン酸塩、シュウ酸塩、パルミチン酸塩、パモ酸塩(1,1−メテン−ビス−2−ヒドロキシ−3−ナフトエート、エインボネート(einbonate))、パントテン酸塩、リン酸塩/二リン酸塩、ピクリン酸塩、ポリガラクツロン酸塩、プロピオン酸塩、p−トルエンスルホン酸塩、サリチル酸塩、ステアリン酸塩、塩基性酢酸塩、コハク酸塩、硫酸塩、スルホサリチル酸塩、スラメート(suramate)、タンニン酸塩、酒石酸塩、テオクル酸塩、トシラート(tosylate)、トリエチオジド、及び吉草酸塩などの、アルカリ金属塩類、アルカリ土類塩類、アンモニウム塩類、水溶性塩類及び水不溶性塩類が挙げられる。薬学的に許容される塩は、その構造内に複数の帯電原子を有することができる。この場合、薬学的に許容される塩は、複数の対イオンを有することができる。従って、薬学的に許容される塩は、1つ以上の帯電原子及び/または1つ以上の対イオンを有することができる。
本発明は、選択的なERG阻害剤化合物、及び患者におけるETS関連遺伝子(ETS Related Gene:ERG)、野生型ERGタンパク質または変異ERGタンパク質の過剰発現に関わる癌を治療または予防するためのかかる化合物の使用方法に関する。より具体的には、本発明のERG阻害剤は、試験された大部分のアンドロゲン受容体(androgen receptor:AR)陽性のCaP細胞系においてARシグナリングを減弱しなくても阻害しなくても良く、従って、前立腺癌を治療するための発症機序としてARシグナリングを阻害する治療薬と比較して中毒性副作用が少ない。加えて、本発明に係るERG阻害剤は、ARを発現しない腫瘍細胞系においてERGタンパク質を阻害する。
腫瘍細胞系VCaP、COLO320、KG−1、MOLT4、LNCaP及びMDA Pca2bを、American Tissue Culture Collection(ATCC、マナサス、バージニア州)から得た。供給元によって推奨されている細胞成長の促進条件下において、ATCC推奨の細胞培地内で細胞を成長させた。HUVEC(ヒト臍帯静脈内皮細胞の初代培養物)及び、ヒトパピローマウイルス18によって不死化された正常な成人前立腺上皮細胞から確立されたRWPE1細胞系などの正常細胞もATCCから得た。SV40大型T抗原によって不死化された初代上皮細胞の培養物から誘導されたBPH1細胞系は、Simon Hayward博士(Vanderbilt University Medical Center)からの贈呈物であった。LAPC4、すなわち転移性前立腺癌細胞系は、(当時UCLAの)Charles Sawyer博士からの贈呈物であった。
ERGモノクローナル抗体(CPDR ERG−MAb、9FY)は、Center for Prostate Disease Researchにおいて開発され、特徴付けられた。アンドロゲン受容体の抗体(AR、sc−816)、グリセルアルデヒドリン酸塩脱水素酵素(GAPDH、sc−25778)、及びα−チューブリン(sc−5286)を、Santa Cruz Biotechnology(サンタクルーズ、カリフォルニア州)から購入した。前立腺特異抗原の抗体(PSA、A0562012)を、DakoCytomation(カーピンテリア、カリフォルニア州)から得た。アポトーシスのための抗体(9915S)及び細胞周期調節物質(9932)サンプルキットを、Cell Signaling(ダンバース、マサチューセッツ州)から購入した。ヒツジ抗マウスIgG−HRP(NXA931)及びロバ抗ウサギIgG−HRP(NXA934V)を、GE Health Care(バッキンガムシャー、英国)から得た。小分子ライブラリを、国立癌研究所のDevelopmental Therapeutics Program(DTP)から得た。
TMPRSS2−ERG融合陽性前立腺癌細胞系、すなわちVCaP(ATCC)を用いて、ERG発現の小分子阻害剤を特定した。VCaP細胞を、適切な用量の試験化合物で48時間処理した。さらに後述するように、ERG発現の阻害を、ERG特異的なCPDR ERG−MAbを用いたIn−Cellウエスタンブロット分析(LI−COR Biosciences、リンカーン、ネブラスカ州)によって評価した。
ヒトERG遺伝子(遺伝子ID:2078、アクセッション:NM_004449)に対抗する低分子干渉RNA(Small interfering RNA:siRNA)オリゴ二本鎖(5’ CGA CAU CCU UCU CUC ACA UAU 3’、si−1、及び5’ UGA UGU UGA UAA AGC CUU A 3’:si−2)を、Dharmacon(ラファイエット、コロラド州)から購入し、ERG発現阻害スクリーンに使用される陽性対照として評価した。2つのsiRNAを、主としてオフターゲットまたは非特異的効果を除外するために選択した。双方のsiRNAが同一結果を示したため、後述されるERG発現抑制検査においてsi−1を使用した。非ターゲティング(non−targeting:NT)の二本鎖siRNAを、陰性対照(D−001206−13−20、Dharmacon、ラファイエット、コロラド州)として使用した。50nM濃度のNT siRNAまたはERG siRNAを用いたトランスフェクションの前に、細胞をそれぞれの成長培地で48時間培養した。Lipofectamine 2000(登録商標)(Invitrogen、カールスバッド、カリフォルニア州)をトランスフェクションに使用した。
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培養細胞を、試験ERG阻害剤のそれぞれを用いて特定用量で処理した。処理済み細胞を指定時間インキュベートした後、プロテアーゼ阻害剤カクテル及びホスファターゼ阻害剤カクテルI&III(Sigma、セントルイス、ミズーリ州)を含むMammalian Protein Extraction Reagent(M−PER、Pierce、ロックフォード、イリノイ州)を用いて細胞を溶解させた。50μgの総タンパク質を含む細胞溶解物を4〜12%のBis−Tris Gel(Invitrogen、カールスバッド、カリフォルニア州)を通じて電気泳動にかけ、細胞タンパク質をPVDF膜(Invitrogen、カールスバッド、カリフォルニア州)に転写した。AR、PSA、GAPDH、α−チューブリン、アポトーシス標識及び細胞周期調節物質の一次抗体と共に膜を4℃で12時間インキュベートした。一次抗体に暴露した後、当該膜をバッファで洗浄し(室温で3回、各5分)、その後、24℃で1時間、関連二次抗体と共にインキュベートした。最後に、当該膜をバッファで洗浄し、ECLウエスタンブロット検出試薬(GE Health Care、バッキンガムシャー、英国)を用いて培養させた。
適切なERG陽性癌細胞、対照ERG陰性細胞またはERG陽性正常細胞を、ベンダーによって提案された適切な成長培地を用いて組織培養皿内で粘着性単層または懸濁液として成長させた。細胞の播種後48時間、適切な試験化合物を所定濃度で組織培養皿の各ウェルに添加する。細胞成長阻害分析の指定期間中、同一の試験化合物を同一濃度で含む新たな成長培地を用いて24時間毎に培地を補充した。組織培養皿の各試験ウェル内の細胞密度を推定するための血球計数器、ならびに各試験ウェル内の生菌の割合を推定するためのトリパンブルー染料除外顕微鏡法及び写真撮影術を用いて細胞成長阻害率を算出した。
TMPRSS2−ERG融合陽性前立腺癌細胞系、すなわちVCaPをATCCから購入した。ベンダーによって規定された条件を用いて細胞を培地で成長させた。対数増殖中のVCaP細胞を、1ウェル当たり細胞20,000個の細胞密度で組織培養皿に播種した。播種後の細胞を終夜回収した後、小分子ライブラリ(Developmental Therapeutics Program、Approved Oncology Drugs Set II、Diversity Set II、Mechanistic Set、及びNatural Products Set、国立癌研究所(National Cancer Institute:NCI))に存在する各化合物及び商業ベンダーのSpectrum Collectionから選択された化合物の1μMの単一用量に当該細胞を48時間暴露した。
一次スクリーンによって特定されたERG阻害剤を定量的RT−PCR分析に使用して、ERG mRNA発現を阻害する能力を評価した。簡単に言えば、VCaP細胞を、10個の各化合物を用いて1μMの濃度で24時間処理した。試験化合物とのインキュベーション後、細胞を溶解し、全RNAを単離させた。200ngの全RNAを、分析用のtERGのコード配列に特異的な一対のERGプライマーを用いたqRT−PCRによってERG転写を分析するのに使用した。このスクリーンは、以下の3種類の試験化合物、NSC139021(ERGi−USU)、NSC72292及びNSC99629をERG−mRNA発現の阻害剤として特定した。
(上記の)VCaP細胞を用いたERGタンパク質阻害検査は、ERGi−USUが、この癌細胞系においてERGに加えてAR及びPSAタンパク質も阻害することを示している。VCaP前立腺癌細胞におけるERGの発現はARによって調節されているため、AR陽性/ERG陰性のLNCaP細胞、MDA PCa2b細胞及びLAPC4細胞を用いたさらなる検査に着手して、VCaP細胞において観察されたERG発現の阻害がERGi−USUによるAR特異的な阻害の結果によるものではないことを確認した。
上記のタンパク質阻害検査は、ERGi−USUがERG発現の選択的阻害剤であることを示している。ERGi−USUがERG陰性癌細胞の成長を阻止せずにERG陽性癌細胞の成長を選択的に阻止したかどうかを調べるために、細胞成長阻害検査を、次の癌細胞系及び正常細胞系、すなわち、ERG陽性癌細胞(VCaP、COLO320、MOLT−4及びKG−1)癌細胞、ERG陰性癌細胞(LNCaP、MDA PCa2b及びLAPC4)癌細胞、正常前立腺RWPE−1細胞及びBPH−1細胞、ならびに正常内皮HUVEC細胞を用いて実施した。各細胞系を培養して対数増殖中の細胞を得て、次いで、これらの細胞を、1ウェル当たり細胞2×106個の細胞密度で組織培養皿の10cmウェルに播種した。播種後の細胞を、0、0.1、0.5、1.0、5.0及び10μM濃度のERGi−USUと2、4、6及び8日間接触させた。各期間の終了時、細胞を試験プレートから回収して洗浄し、血球計数器及びトリパンブルー染料染色法を用いて細胞密度及び細胞生存度を測定する。細胞数とERGi−USUの濃度とを相関させるグラフとして細胞成長の阻害を表した。
雄のヌードマウスに約4×106個のVCaP細胞を注射し、腫瘍成長を監視した。注射後4〜5週間の間に腫瘍が現れ始め、その時、マウスを2つの実験群と1つの対照群とに無作為化した。治療群には、150mg/kgのERGi−USUまたは100mg/kgのERGi−USUを1週当たり3回腹腔内に注射した。対照動物には、賦形薬のみを同様に1週当たり3回注射した。腫瘍成長を毎週監視した。図6Aは、対照動物(一番上の曲線)が検査を通じて最大の腫瘍容積を呈したのに対し、最大用量のERGi−USUを受けたマウス(一番下の曲線)が最小の容積を呈したことを示している。
Claims (15)
- ERG陽性癌に罹患している患者における野生型ERGタンパク質の過剰発現、変異ERGタンパク質の過剰発現、ERG遺伝子転写の亢進、またはERG mRNA翻訳の亢進に関連した前記ERG陽性癌の治療方法または予防方法であって、治療上有効量のERG発現阻害剤を前記患者に投与するステップを含む、前記方法。
- 前記阻害剤が、前記変異ERGタンパク質を選択的に阻害する、請求項1に記載の方法。
- 前記阻害剤が、ERG遺伝子転写またはERG mRNA翻訳を選択的に阻害する、請求項1に記載の方法。
- 前記阻害剤がさらに、ERG陽性癌細胞の成長を阻害する、請求項1に記載の方法。
- 前記阻害剤が、
- 前記阻害剤が、
- 前記ERG陽性癌が、前立腺癌、大腸癌、ユーイング肉腫、血管腫瘍及び白血病からなる群から選択される、請求項1から請求項6のいずれか一項に記載の方法。
- 前記ERG陽性癌が前立腺癌である、請求項1から請求項7のいずれか一項に記載の方法。
- 抗癌治療薬と同時投与することをさらに含む、請求項1から請求項8のいずれか一項に記載の方法。
- 癌に罹患している患者における野生型ERGタンパク質の過剰発現、変異ERGタンパク質の過剰発現、ERG遺伝子転写の亢進、またはERG mRNA翻訳の亢進に関連した前記癌の治療または予防に使用するためのERG発現阻害剤。
- 前記阻害剤と同時投与される抗癌治療薬をさらに含む、請求項10に記載の阻害剤。
- 癌に罹患している患者における野生型ERGタンパク質の過剰発現、変異ERGタンパク質の過剰発現、ERG遺伝子転写の亢進、またはERG mRNA翻訳の亢進に関連した前記癌を治療または予防するためのERG発現阻害剤の使用。
- 抗癌治療薬と同時投与することをさらに含む、請求項12に記載の使用。
- 癌に罹患している患者における野生型ERGタンパク質の過剰発現、変異ERGタンパク質の過剰発現、ERG遺伝子転写の亢進、またはERG mRNA翻訳の亢進に関連した前記癌を治療または予防するための薬剤の製造におけるERG発現阻害剤の使用。
- 抗癌治療薬と同時投与することをさらに含む、請求項13に記載の使用。
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