JP5937968B2 - Mcl‐1を調節する小分子、並びに細胞死、細胞分裂、細胞分化を調節する方法、及び疾患を治療する方法。 - Google Patents
Mcl‐1を調節する小分子、並びに細胞死、細胞分裂、細胞分化を調節する方法、及び疾患を治療する方法。 Download PDFInfo
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Description
本発明のための財政的支援は部分的に契約番号第5P01CA92625に基づく国立衛生研究所(National Institute of Health)からの援助によってもたらされた。従って、米国政府は本発明に対してある特定の権利を有している。
R1は、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、置換若しくは非置換ヘテロシクロアルキル、−S−R2a、−SO2−R2aであり;
R2は、水素、ハロゲン、−O−R2a、−NH−R2a、−S−CN、−S−R2a、−S−CH2−R2a又は−SO2−R2aであり;
R2aは、C1〜C8アルキル、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルであり;そして
R3は、水素、C1〜C8アルキル、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルである);又はB)
R6は、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルである);又はC)
R7aは、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルである);又はD)
R8aは、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルである);又はE)
R9a及びR9bは、独立して、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルであり;そして
Wは、
−R10、
−CO−R10、
−CO−(CH2)n−R10、
−CO−NH−R10、
−CO−NH−(CH2)n−R10、
−CO−NH−CO−NH−(CH2)n−R10、
−CO−NH−SO−NH−(CH2)n−R10、
−SO−(CH2)n−R10、
−SO−NH−(CH2)n−R10、
−SO−NH−CO−NH−(CH2)n−R10、
−SO−NH−SO−NH−(CH2)n−R10、又は基
R10は、Z、又は置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルであり;
R12は、Z、又は水素、C1〜C6アルキル、又は−(CH2)n−R12aであり;
R12aは、Z、又は置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルである);又はF)
R14は、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルである(ここでR14は更にZで置換されていてもよい));又はG)
R15aは、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルであり;そして
R16は、水素、ハロゲン、ヒドロキシル、又は置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルである);又はH)
R17は、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルであり(ここで、R17は更にZで置換されていてもよい);
R18は、水素、C1〜C8アルキル、C2〜C8アルケニル、C2〜C8アルキニル、又はC1〜C6アルコキシであり(ここで、R18は更にZで置換されていてもよい);そして
R19は、水素、C1〜C8アルキル、C2〜C8アルケニル、C2〜C8アルキニル、又はC1〜C6アルコキシである(ここで、R19は更にZで置換されていてもよい));又はI)
Y2は、O、S,又はNHであり;
−−−−は、任意に二重結合を示し;
R20は、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルであり(ここで、R20は更にZで置換されていてもよい);
R21は、=S、=NH、−NHR21a、−CHR21a、=NR21a、又は=CCO−R21aを示し;そして
R21aは、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルである(ここで、R21aは更にZで置換されていてもよい));又はJ)
R23は、C1〜C8アルキル、C2〜C8アルケニル、C2〜C8アルキニル、又はC1〜C6アルコキシ、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルであり(ここで、R23は更にZで置換されていてもよい);そして
R24は、C1〜C8アルキル、C2〜C8アルケニル、C2〜C8アルキニル、又はC1〜C6アルコキシ、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルである(ここで、R24は更にZで置換されていてもよい));又はK)
R25aは、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルである(ここで、R25aは更にZで置換されていてもよい));又はL)
それぞれのnは独立して、0〜4の整数であり;
それぞれのmは独立して、0〜3の整数であり;
それぞれのpは独立して、0〜2の整数であり;
それぞれのqは独立して、0〜1の整数であり;
それぞれのZ、Z’、及びZ”は独立して、ハロゲン、ヒドロキシル、C1〜C8アルキル、C2〜C8アルケニル、C2〜C8アルキニル、又はC1〜C6アルコキシ、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換シクロアルキル、又は置換若しくは非置換ヘテロシクロアルキルである);又は式M)
それぞれのT2は独立して、T1と同一又は異なっていてもよい式A〜Lの別の化合物を示し;
それぞれのQは、直接結合、T1のZ、Z’又はZ”部分がそれぞれに続くT2のZ、Z’又はZ”部分と共に結合して形成されるC1〜C8アルキレンリンカー、C2〜C8アルケニレンリンカー、C2〜C8アルキニレンリンカー、アミドリンカー、又はスルホンアミドリンカーを示し;そして
uは、0〜5の整数を示す);を有する化合物:
それぞれのT2は独立して、T1と同一又は異なっていてもよい式A〜Lの別の化合物を示し;
それぞれのQは、直接結合、T1のZ、Z’又はZ”部分がそれぞれに続くT2のZ、Z’又はZ”部分と共に結合して形成されるC1〜C8アルキレンリンカー、C2〜C8アルケニレンリンカー、又はC2〜C8アルキニレンリンカーを示し;そして
uは、0〜5の整数を示す):
を有する化合物、又はそれらの薬学的に許容される塩、溶媒和物、水和物若しくは立体異性体を包含する。
本発明をより容易に理解するために、特定の用語を便宜上最初に定義して集めた。その他の定義は本願を通して本文中に示される。
上記のように、本発明は、生存タンパク質MCL−1に高い親和性及び選択性をもって選択的に結合する化合物を提供する。
一態様では、本発明は細胞を1つ又はそれ以上の本発明化合物と接触させることを含んでいる細胞におけるMCL−1を調節する方法を包含している。このような調節はプログラム細胞死又はアポトーシス、自食性の細胞死;壊死性細胞死;細胞代謝;細胞分裂;細胞分化;細胞移動;細胞生着;組織修復;RNA転写及びプロセッシング;又はタンパク質の多量体化或いは解離の調節に有用である。
多種の感染性要因は、髄膜炎、脳炎、ブドウ膜炎、結腸炎、結核、皮膚炎、及び成人呼吸促迫症候群を包含する。非感染性要因は、外傷(熱傷、切り傷、打撲傷、圧坐損傷)、自己免疫疾患、及び臓器拒絶反応の出現を包含する。
従って、特定の態様では、炎症性疾患は:アテローム性動脈硬化症(動脈硬化症);多発性硬化症、全身性エリトマトーデス、リウマチ性多発性筋痛(PMR)、痛風性関節炎、変性性関節炎、腱炎、滑液包炎、乾癬、線維症、骨関節炎、関節リウマチ及び炎症性関節炎の別の形態、シェーグレン症候群、全身性進行性硬化症(強皮症)、強直性脊椎炎、多発性筋炎、皮膚筋炎、天疱瘡、類天疱瘡、I型糖尿病、重症筋無力症、橋本甲状腺炎、グレーブス病、グッドパスチャー病、混合性結合組織病、硬化性胆管炎、クローン病(限局性腸炎)及び潰瘍性大腸炎を含む炎症性腸疾患、悪性貧血、炎症性皮膚疾患のような、自己免疫疾患;通常型間質性肺炎(UIP)、石綿肺症、珪肺症、気管支拡張症、ベリリウム症、滑石肺症、塵肺症の全形態、サルコイドーシス(肺及びその他の臓器における)、剥離性間質性肺炎、リンパ球様間質性肺炎、巨細胞性間質性肺炎、細胞性間質性肺炎、外因性アレルギー性肺胞炎、ウェゲナー肉芽腫症及び血管炎の関連形態(側頭動脈炎及び結節性多発動脈炎);敗血症;自己免疫と思われない炎症性皮膚疾患;慢性活動性肝炎;遅延型過敏反応(例えば、毒ツタ皮膚炎);何らかの原因による肺炎又は他の呼吸器炎症;何らかの病因による成人呼吸窮迫症候群(ARDS);炎症性浮腫を伴う脳炎;これに限定されないが、喘息、花粉症、皮膚アレルギー、急性アナフィラキシーを含む即時型アレルギー過敏反応;これに限定されないが、リウマチ熱、何らかの原因による急性及び/又は慢性糸球体腎炎(特異的感染後(例えば、連鎖球菌後)糸球体腎炎を含む)、全身性エリテマトーデスの急性増悪、を含む免疫複合体の急性沈着に関連する疾患;腎盂腎炎;蜂巣炎;膀胱炎;急性及び/又は慢性胆嚢炎;及び消化管、膀胱、心臓又はその他の臓器に沿ってどこにでも生じる一過性の虚血、特に破裂しやすいものを生じる疾患;同種臓器又は組織移植による急性期における同種移植の拒絶及び慢性宿主対移植片拒絶を含む、臓器移植又は組織同種移植の後遺症を含む群から選ばれる疾患に起因している。
用語「炎症性疾患」は、虫垂炎、動脈炎、眼瞼炎、細気管支炎、気管支炎、子宮頸管炎、胆管炎、繊毛羊膜炎、結膜炎、涙腺炎、皮膚筋炎、心内膜炎、子宮内膜炎、腸炎、全腸炎、上顆炎、精巣上体炎、筋膜炎、結合組織炎、胃炎、胃腸炎、歯肉炎、回腸炎、虹彩炎、喉頭炎、脊髄炎、心筋炎、腎炎、臍炎、卵巣炎、精巣炎、骨炎、耳炎、膵炎、耳下腺炎、心膜炎、咽頭炎、胸膜炎、静脈炎、肺炎、直腸炎、前立腺炎、鼻炎、卵管炎、副鼻腔炎、口内炎、骨膜炎、へんとう腺炎、ブドウ膜炎、膣炎、血管炎、外陰炎、及び外陰膣炎、血管炎、慢性気管支炎、骨髄炎、視神経炎、側頭動脈炎、横断性性脊髄炎、壊疽性筋膜炎、肝炎、及び壊死性腸炎も包含する。
ある特定の実施態様では、本発明の化合物、又はその薬学的に許容される塩、溶媒和物若しくは水和物を、薬学的に許容される製剤中で対象に投与する。ある特定の実施態様では、本発明の化合物、又はその薬学的に許容される塩、溶媒和物若しくは水和物、或いは医薬組成物中の本発明化合物は、局所、静脈内、非経口又は経口投与に適している。本発明の方法は更に、本発明の化合物、又はその薬学的に許容される塩、溶媒和物若しくは水和物の治療有効量を対象に投与することを含んでいる。
本発明の化合物及び組成物は、1つ又はそれ以上の追加の治療薬と共に、本発明の化合物と別々に又は同一製剤中での何れかで、投与することができる。
T細胞受容体調節剤の例は、これに限定されないが、抗T細胞受容体抗体(例えば、抗CD−4抗体(例えば、cM−T412(Boeringer)、IDEC−CE9.1(登録商標)(IDEC and SKB)、mAB4162W94、Orthoclone及びOKTcdr4a(Janssen-Cilag))、抗CD3抗体(例えば、Nuvion(Product Design Labs)、OKT3(Johnson & Johnson)、又はRituxan(IDEC))、抗CD5抗体(例えば、抗CD5リシン−結合免疫抱合体)、抗CD7抗体(例えば、CHH−380(Novartis))、抗CD8抗体、抗CD40リガンドモノクローナル抗体(例えば、IDEC−131(IDEC))、抗CD52抗体(例えば、CAMPATH 1H(Ilex))、抗CD−2抗体、抗CD11a抗体(例えば、Xanelim(Genentech))、及び抗B7抗体(例えば、IDEC−114(IDEC))及びCTLA4免疫グロブリンを包含する。
サイトカイン受容体調節剤の例は、これに限定されないが、可溶性サイトカイン受容体(例えば、TNFアルファ受容体の細胞外ドメイン又はその断片、IL−1ベータ受容体の細胞外ドメイン又はその断片、及びIL−6受容体の細胞外ドメイン又はその断片)、サイトカイン又はその断片(例えば、インターロイキン(IL)−2、IL−3、IL−4、IL−5、IL−6、IL−7、IL−8、IL−9、IL−10、IL−11、IL−12、IL−15、TMF−アルファ、インターフェロン(IFN)−アルファ、IFN−ベータ、IFN−ガンマ、及びGM−CSF)、抗サイトカイン受容体抗体(例えば、抗IFN受容体抗体、抗IL−2受容体抗体(例えば、Zenapax(Protein Design Labs))、抗IL−4受容体抗体、抗IL−6受容体抗体、抗IL−10受容体抗体、及び抗IL−12受容体抗体)、抗サイトカイン抗体(例えば、抗IFN抗体、抗TNFアルファ抗体、抗IL−1ベータ抗体、抗IL−6抗体、抗IL−8抗体(例えば、ABX−IL−8(Abgenix))、及び抗IL−12抗体)を包含する。
経口投与に適している、本発明の化合物、又はその薬学的に許容される塩、溶媒和物若しくは水和物並びに本発明の化合物を含有している組成物は、個々の剤形、例えば、これに限定されないが、錠剤(例えば、チュアブル錠)、カプレット、カプセル及び液体(例えば、フレーバーシロップ)等にすることができる。このような剤形は活性成分の所定量を含有していて、当業者に周知の調剤方法によって製造することができる。大まかに、Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990)を参照されたい。
非経口及び血管内投与用剤形は、これに限定されないが、皮下、静脈内(急速静注法及び持続輸液を含む)、筋肉内、及び動脈内を含む各種経路によって患者に投与できる。これらの投与は通常混入物質に対する患者の自然防御能をバイパスしているので、非経口及び血管内投与用剤形は無菌であるか、又は患者に投与する前に無菌にできることが好ましい。非経口剤形の例は、これに限定されないが、注射用に準備されている溶液、注射用の薬学的に許容される賦形剤に溶解又は懸濁する準備ができている乾燥製剤(これに限定されないが、凍結乾燥粉末、ペレット、及び錠剤)、注射用に準備されている懸濁液、及び乳濁液を包含する。
本発明の経皮、局所、及び粘膜投与用剤形は、これに限定されないが、点眼液、スプレー、エアゾール、クリーム、ローション、軟膏、ゲル、溶液、乳濁液、懸濁液、又は当業者に公知のその他の形態を包含する。例えば、Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 & 1990)及びIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985)を参照されたい。口腔内の粘膜組織を治療するのに適している剤形は口内洗浄液又は口腔ゲルとして製剤化できる。更に、経皮投与用の剤形には、「貯留型」又は「マトリックス型」の貼付剤が包含され、これを皮膚に適用して、所要量の活性成分の浸透を可能にするために特定の期間貼付してもよい。
したがって、本発明は、医師によって用いられる際に、対象の同定及び本発明の化合物又はその薬学的に許容される塩、溶媒和物若しくは水和物の患者に対する適切な量の投与を容易にすることができるキットを包含している。
1. MCL−1の強力で選択的な小分子調節剤を同定するために、競合的蛍光偏光アッセイによって小分子結合スクリーニングを実施した。小分子を、FITC−MCL−1 SAHB/MCL−1ΔNΔC相互作用及びFITC−BAD BH3/BCL−XLΔC相互作用に対して同時にスクリーニングした。FITC−MCL−1 SAHB/MCL−1ΔNΔC相互作用を選択的に妨害する化合物を第二次スクリーニングアッセイに進めた。
SAHBの合成。
BCL−2ファミリーBH3ドメインに対応する炭化水素で架橋したペプチド及びそれらのFITC−βAla誘導体を合成し、精製して、以前に記載されている方法24、27、29を用いて特徴付けた。
組み替え型でタグレスの MCL−1ΔNΔC、BCL−2ΔC、BCL−XLΔC、BCL−wΔC、及びBFL1/A1ΔCを以前に記載されている方法27、29、31を用いて製造した。
小分子スクリーニングを、Harvard Medical School の Institute for Chemistry and Cellular Biology において実施して、市販のライブラリー(Asinex, Chembridge, ChemDiv, Enamine, Life Chemicals, 及びMaybridge)を利用した。ハイスループット競合FP結合アッセイを、FITC−MCL−1SAHB(15nM)とMCL−1ΔNΔC(45nM)との相互作用を妨害する小分子をスクリーニングするために用いた。MCL−1ΔNΔCを発現してFPLCで精製し、自動化リキッドハンドラーによって384ウェルのプレートに移し、次いで、小分子ライブラリーを添加した。室温で15分間培養した後、FITC−MCL−1 SAHB(15nM)をリキッドハンドラーで各ウェルに添加して、平衡状態で(例えば、1時間)FPを読み取った。ヒットした小分子を、化合物の連続希釈を用いてこのアッセイで再試験して用量反応性のFITC−MCL−1 SAHB結合阻害を確認した。
最も強くヒットしたものを結合活性及び特異性の厳密な定量化に進めた。最初に、小分子の連続希釈3組をFITC−MCL−1 SAHB(15nM)と混合した後、結合緩衝液(50mMのTris、100mMのNaCl、0.0625%のCHAPS、pH8.0)に希釈したMCL−1ΔNΔC(45nM)を含有する384ウェルの黒色Costerプレートに添加した。プレートを暗所において室温で平衡状態に達する(すなわち、結合等温線の安定化)まで培養して、マイクロプレートリーダー(例えば、Spectramax)を用いてFP(mP単位)を確認した。Prismソフトウェア(Graphpad)を用いる用量反応性曲線の非線形回帰分析によってKi値を算出した。次いで、ヒットした小分子は、小分子希釈物をFITC−BAK BH3(25nM)及びMCL−1ΔNΔC(250nM)の溶液に添加して阻害性MCL−1タンパク質からアポトーシス促進性BAKへの生理学的置換をシミュレートする以外は上記のように実施した、競合FPアッセイでMCL−1ΔNΔCからFITC−BAK BH3を解離するそれらの能力について試験した。精密な特異性分析のために、ヒットした小分子の連続希釈を汎抗アポトーシス(pan-anti-apoptotic)結合剤FITC−BID BH3(15nM)と混合した後、MCL−1ΔNΔC、BCL−2ΔC、BCL−XLΔC、BCL−wΔC、又はBFL1/A1ΔCの何れかを含有しているプレートに添加すること以外は、同じ競合FPタイプ実験を実施した。GST−MCL−1ΔNΔC、BCL−2ΔC、BCL−XLΔC、BCL−wΔC、及びBFL1/A1ΔCを発現するためにpGEXベクターを用いた後、トロンビン切断及びFPLCによるゲル濾過クロマトグラフィーを行った。特に、C末端アルファ螺旋をこれらの構築物それぞれから欠失させてタンパク質発現及び精製を促進させ;MCL−1の追加的N末端欠失を実施してさらに発現、精製、及び安定性を増強した。上記のようにFP分析を実施して、MCL−1ΔNΔCに対して排他結合活性を示すこれらの分子を構造結合試験及び機能試験に進めた。
MCL−1ΔNΔC(2μM、500mL)を化合物(先に確認したEC50値をはるかに超える比率で)と室温で1時間、FP緩衝液(100mMのNaCl、50nMのTris、pH8)中で培養した。少量の試料を希釈前の対照として採取した。次いで、化合物で処理したタンパク質及び非修飾タンパク質を20mLの容量に希釈し、続いて10K遠心濾過機ユニット(Amicon)を用いて500mLまで再濃縮した。希釈前と後の両方で、化合物で修飾したMCL−1及び非修飾MCL−1の連続希釈を、次いでFITC−BID BH3(15nm)を96ウェルの黒色平底プレート(Costar)に添加して、上記のようにFP結合分析を実施した。次いで、FP測定及び分析を上記のように実施した。
MCL−1ΔNΔC(90μM)を1:1.25比の化合物と室温で2時間、150mMのNaCl、50mMのTris、pH7.4中で培養した。過剰の化合物をゲル濾過で除去してタンパク質をトリプシンで1晩37℃で消化した。Ficarro et al., 200934に記載されているように通気式カラム装置を用いて、ナノ−LC/ESI/MSによってペプチドを分析した。すなわち、オートサンプラー及びHPLC(Water NanoAquity)を用いて、ペプチドを自動充填プレカラム(4cm、100μmI.D.、POROS10R2, Applied Biosystems)上に注入し、分解カラム(自動充填式30μmI.D.、12cm、5μm Monitor C18、Column Engineering)に、濃度勾配溶出して(0〜30%Bを20分、A=0.2M酢酸水溶液、B=0.2M酢酸含有アセトニトリル)、ESI(スプレー電圧=2.2kV)を介して質量分析計(Thermo Fisher LTQ-Orbitrap XL)に導入した。各MSスキャン(イメージ電流検出、分解能=30,000)中で量が多い上位8つの前駆体をCAD(電子増倍管検出、衝突エネルギー=35%)に付した。化合物で修飾したペプチド(例えば、TINQES*CIEPLAESITDVLVR〔*C=修飾したシステイン〕)を用いて別個の標的化ナノ−LC/ESI/MS実験を実施して、これをHCD(高エネルギー衝突活性化解離)に付した。
既に詳細に述べられている(Pitter et al., 2008)31ようにミトコンドリア外膜の組成を反映する脂質の混合物からリポソームを調製した。混合した脂質の一定量(合計1mg)をグラスの中で、窒素雰囲気下−20℃で保存して、使用前に、12.5mMの蛍光染料ANTS(8−アミノナフタレン−1,3,6−トリスルホン酸二ナトリウム塩)及び45mMの消光剤DPX(p−キシレン−ビス−ピリジニウムブロマイド)を用いて、リポソームアッセイ緩衝液(10mMのHEPES、200mMのKCl、1mMのMgCl2、pH7)に再懸濁した。得られた懸濁液を10分間ボルテックスして、液体窒素中と40℃の水浴中の間を5回繰り返して凍結溶解した。次いで溶液を、100nmのフィルターを備えたアバンティ ミニ−エクストルーダー セット(Avanti Mini-Extruder Set; #610000)に通した後、セファロースカラム(GE Healthcare)に通して残余のANTS/PDXを除去した。リポソームを3mLの容量にして最終リポソームストックを作った。リポソーム放出アッセイのために、384ウェルの黒色平底プレート(Costar)で総容量30μLを用い、8μLリポソームの蛍光測定基準値を、Tecan Infinite M1000(励起;355nm、放出;520nm)を用いて10分間作成する。基準値を読み取った後、1:1の比の化合物と前培養した組み替えMCL−1ΔNΔCをリポソームに添加する。次に、20nMのカスパーゼ切断マウスBID(R&D systems)及び250nMの精製した組み替え単量体BAXを加えて、蛍光測定値(F)をゼロ時点(F0)から放出読み込みが平坦になるまで毎分記録する。次いで、リポソームを1%のトリトンX−100でクエンチして(100%放出;F100)、ANTS/DPX放出パーセントを((F−F0)/F100−F0))×100として算出する。
マウス肝臓ミトコンドリア(0.5mg/mL)を単離して記述されている31ようにして放出アッセイを実施する。ミトコンドリアをMCL−1標的小分子の連続希釈物の、単独又はBID BH3と組合わせたものと共に培養して、40分後に、ペレット及び上澄画分を単離して、比色ELISAアッセイ(R&D Systems)を用いてチトクロームcを定量する。放出可能なミトコンドリアプールから上澄液内へのチトクロームc放出パーセント(%cytoCsup)を次の式:%cytoc=〔cytocsup−cytocbackgr)/(cytoctotal−cytocbackgr)〕*100:に従って算出した。ここで、バックグラウンド放出は、賦形剤(1%DMSO)で処理した試料の上澄液中で検出されたチトクロームcを表し、総放出は1%トリトンX100で処理した試料中で測定されたチトクロームcを表す。観察された野生型ミトコンドリアからのチトクロームc放出がBAK活性化に由来していることを保証するために、全ての実験条件をBak−/−ミトコンドリア上でも試験する。
MCL−1発現癌細胞(10×106)をMCL−1標的小分子又は賦形剤と共に、無血清培地中、37℃で4時間、次いで血清に置き換えて更に6時間培養した。50mMのTris(pH7.4)、150mMのNaCl、1mMのEDTA、1mMのDTT、0.5%のNP40及びコンプリートプロテアーゼインヒビタ−ペレット(complete protease inhibitor pellet)中で細胞溶解した後、細胞残屑を14,000g、4℃で10分間ペレット化する。上澄液を前もって平衡化してあるタンパク質A/Gセファロースビーズに触れさせて、次に前もって精製した上澄液を、抗MCL−1抗体と4℃で1.5時間、その後プロテインA/Gセファロースビーズを加えて1時間培養した。ビーズをペレット化して溶解緩衝液で10分間、4℃で洗浄する。次いで洗浄したビーズをペレット化し、SDS負荷緩衝液中、90℃で10分間加熱し、SDS/PAGEで分析し、次いでMCL−1及びBAKについて免疫ブロットする。
主な小分子−MCL−1ΔNΔC複合体の結晶化条件は、96ウェルのシッティングドロッププレートでPhoenix結晶化ロボットを用いてスクリーニングする。初期条件は、HT Index Screen、JSCG+Suite、及びPro−Complex Suiteを包含する。pH、塩、及び洗浄濃度を変えることを含む、最良ヒット周辺のスクリーニングを実施して結晶の生育に対する最良の条件を確認する。生成したら、結晶を除去し、結晶化緩衝液中で洗浄し、質量分析に付して結晶内の化合物とタンパク質の存在を検証する。次いで結晶を抗凍結剤に浸し、急速冷凍して液体窒素中で保存する。適当な結晶を、Argonne National Laboratory シンクロトロン施設で試験する。分子置換、次いでデータ分析及び純化によって相を得る(Phaser, Phenix, amd Coots ソフトウェア)。
MCL−1の小分子阻害剤を、OPM−2(多発性骨髄腫)細胞のような、MCL−1発現癌細胞株中でスクリーニングした。細胞は小分子MCL−1阻害剤単独で又は治療量以下のアポトーシス促進刺激剤(例えば、TRAIL、Fasリガンド、ABT−737)と併用して処理して、製造会社(Roche)のプロトコールに従って実施するMTTアッセイによって、48時間時点に細胞生存能力を測定して、ELISAマイクロプレートリーダー(Biorad)によって定量する。IC50値を、Prismソフトウエア(Graphpad)を用いる非線形回帰分析によって確認した。次いで、細胞生存能力を減少する小分子を、アネキシンV結合及びFACS分析によって、そして記載されている28ようにして、細胞分割法によるミトコンドリアのチトクロームc放出によって、細胞アポトーシス誘導についてスクリーニングする。アポトーシスは、上記のように実施されるMCL−1/BAK複合体のin situ 解離(免疫沈降)にも相関している。小分子のMCL−1特異性の更なる測定として、小分子の選択的MCL−1標的能力をアポトーシスの感作と明確に関連付けるために、野生型対McL−1−/−MEFにおいて同一実験を実施する。小分子活性のカスパーゼ依存性も、汎カスパーゼ阻害剤Z−VADとの同時処理による活性の妨害をモニタリングすることによって確認する。
主要な小分子は、DF/HCC Clinical Pharmacology Core と協力して実施した、マウスにおける薬物動態(PK)解析を受ける。血清中の化合物濃度を検出及び定量するためにLC/MSによる分析的アッセイを展開する。PK解析のために、小分子(例えば、10、50、100mg/kg)を、雄生C57/BL6マウスの尾静脈内又は腹腔内に注射する。血液試料を多種の時点で後眼窩出血によって採取して、血漿を単離して、化合物を定量したのち、血漿半減期、最高血漿濃度、総血漿クリアランス、及び分配の見掛け容量を算出する。細胞において選択的MCL−1標的性を示して、好ましい薬物動態プロファイルを示す小分子をインビボ試験に進める。
小分子感受性癌細胞株をレトロウィルスで形質導入して、安定なルシフェラーゼ発現(pMMP−LucNeo)を達成して、既に記載されている27、32ようにしてSCIDベージュマウスに移植する。最初の異種移植研究では、賦形剤単独、低及び高用量の小分子単独、治療量以下のアポトーシス促進刺激剤(例えば、TRAIL、ABT−737、ドキソルビシン、エトポシド、デキサメタゾン)と組合わせた低/高用量小分子の何れかで処置した、マウスの5群(n=10)を試験する。実験第1日から、1日1回マウスに小分子(例えば、併用処置あり又はなしで、25又は100mg/kg)を尾内注射する。隔日のインビボ腫瘍画像化のために、マウスをイソフルラン吸入で麻酔して、D−ルシフェリンの腹腔内投与で併用処置する。光子放出を、Xenogen In Vivo Imaging Systemを用いて画像化(2分間照射)して、Xenogen’s Living Image Softwareを用いて光子束(光子/秒)を積分して、総身体生物発光を定量する。実験マウスの生存分布を、Kaplan−Meier法を用いて測定し、ログランク検定を用いて比較する。フィッシャーの正確確立検定を、処置に失敗したマウス(ここで、処置の失敗は進展又は死亡と定義する)と安定した疾患又は回復として成功したマウスの割合を比較するために用いる。特定の小分子で処置応答が観察された場合は、賦形剤、小分子、又は小分子組合せの何れかで処置する追加の3群を、TUNEL及び活性化カスパーゼ−3免疫組織化学的染色によって組織におけるアポトーシス促進活性を評価する薬力学的研究のために用いる。
FITC−MCL−1 SAHB及びMCL−1ΔNΔCを用いる競合的蛍光偏光結合アッセイによるMCL−1選択的小分子の同定。
ハイスループットな競合的FP結合アッセイを用いて、FITC−MCL−1 SAHB/MCL−1ΔNΔCとFITC−BAD BH3/BCL−XLΔCの間の相互作用を妨害した小分子をスクリーニングした(図1)。BCL−XLΔCを上回ってMCL−1ΔNΔCを標的とするそれらの選択性に基づいて化合物を順位付けして、表にした(表1(副表1−A〜1−Pを含む)を参照されたい)。
MCL−1ΔNΔCの結晶構造を用いて、同定された小分子をMCL−1ΔNΔCのBH3結合ポケットにドッキングさせて、相互作用の位置及びエネルギー有利性(energetic favorability)を分析した。化合物はBH3結合ポケットトポグラフィーの個々の小区域をカバーし(図2)、複合体とMCL−1の延長されたBH3結合表面を結合するための分子又はその小断片の組合わせを組み込んだ、選択的な、より大きい分子を設計する青写真を提供した。
MCL−1に結合する小分子のメカニズムを試験するために、化合物を急速希釈アッセイに付した(図2C)。つまり、MCL−1ΔNΔCを緩衝液で希釈する前に小分子阻害剤と前培養した。溶液をその元の容量まで濃縮して、蛍光偏光を実施した。共有結合する化合物はタンパク質との結合を保持するのに対して、可逆的に結合する化合物は希釈によって交換されるだろう。陽性対照として、急速希釈アッセイは、ゴシポール(1570G15)がMCL−1ΔNΔCと可逆的に結合することを確認した(図2C、上図)。対照的に、1725P16及び1597E07は希釈によって交換されず、この化合物がMCL−1ΔNΔCと結合して共有結合的に修飾することを示唆している(図2C、中、下図)。
共有結合的修飾の部位を突き止めるために、小分子で処理したMCL−1ΔNΔC(例えば、1929A19)を質量分析に付した。共有結合的に拘束された化合物の分子量に対応する質量の増加と共に、小分子に拘束されたタンパク質に対して追加のMALDIピークが観察された。MCL−1ΔNΔC付加物を更にタンデムMS/MSに付し、システイン286が1929A19に対する修飾部位であることが明らかになった(図2D)。重要なことは、システイン286が基準のBH3結合ポッケトに位置していないことで(図2D)、この新規な結合部位への結合がMCL−1の抗アポトーシス/BH3結合活性をアロステリックに調節できることを示唆している。C286結合の機能的重要性を確認するために、MCL−1ΔNΔCのC286構築物を部位特異的突然変異誘発法によって作成して、FITC−BID BH3及び野生型並びに突然変異MCL−1ΔNΔCタンパク質を用いる競合的FPアッセイで、小分子の結合活性を比較した。MCL−1ΔNΔC結合に対して1929A18及び1616N08がFITC−BID BH3と競合したのに対して、化合物の存在において、MCL−1ΔNΔCC286Sに対して結合活性を保持するFITC−BID BH3の能力によって明らかにされたように、分子はMCL−1ΔNΔCのC286S構築物と結合しなかった。
同定された小分子のMCL−1ΔNΔCを選択的に標的にする能力を確認するために、ヒットした小分子は、MCL−1ΔNΔC C、BCL−2ΔC、BCL−XLΔC、BCL−wΔC、及びBFL1/A1ΔCを包含する、抗アポトーシスタンパク質のパネルからFITC−BID BH3を解離するそれらの分化能力について試験した。図3及び4に例示したように、MCL−1ΔNΔC選択性であるとして同定された小分子は実際に、試験した他の抗アポトーシスタンパク質と比べてMCL−1ΔNΔCから優先的にFITC−BID BH3の転移を示した。
クラスA(図4C)とJ(図4D)分子の化学誘導体は結合活性において有意差を明らかにした。重要なことは、クラスAのR1位にある5員のチアゾール環が、より小さい、非芳香族の置換基と比べてMCL−1ΔNΔCに対する結合親和性を増大した。R2位において芳香族残基は、フェニル環のパラ位に小さい疎水性側鎖又は水素結合受容体を有しているのが好ましい。クラスJに関して、小さい脂肪族基がR1位で良好な耐用性を示し、R2位のトリヒドロキシフェニル環がMCL−1ΔNΔCに対して優れた結合親和性を示した。最後に、R3位の5員又は6員の芳香族環が好ましい。特に、R3にメチル置換基を含有している類縁体はR1位の大きい脂肪族基と対にならなければ活性を示さない。
生存についてMCL−1に依存している癌細胞を、他のアポトーシス促進剤と組合わせた選択的小分子MCL−1ΔNΔC結合剤で処理して相乗性の抗腫瘍活性について評価した。図5に例示したように、小分子の生物活性は、MTT生存率アッセイ及びCalcuSynソフトウェアを用いる併用治療分析によって評価されたように、TRAILと相乗的にOPM2多発性骨髄腫細胞を殺傷した。
リポソーム放出アッセイを、ミトコンドリア外膜内にBAXを含有する孔を形成してミトコンドリアチトクロームc機能的放出を模倣するように設計する。ここで、組み替え全長BAXを、MCL−1ΔNΔCの存在下又は非存在下で、組み替えtBIDと培養した。図6に示したように、tBIDは、リポソームからフルオロフォアのBAX介在放出を時間依存的に誘発した。MCL−1ΔNΔCは、フルオロフォア放出を阻害する、BAXの活性化を妨害した。MCL−1ΔNΔCを阻害することによる、1929A19及び1616N08がフルオロフォアのtBID誘発性のBAX介在リポソーム放出を、容量依存的に回復させて、この小分子MCL−1阻害剤のMCL−1の抗アポトーシス活性を妨害する能力を強調している。
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Claims (19)
- 細胞におけるMCL−1の阻害が、細胞におけるアポトーシス細胞死を調節し、それによって当該細胞におけるアポトーシス細胞死を制御することを含む、請求項1に記載の医薬組成物。
- 細胞におけるMCL−1の阻害が、細胞におけるオートファジーを調節し、それによって当該細胞におけるオートファジーを制御することを含む、請求項1に記載の医薬組成物。
- 細胞におけるMCL−1の阻害が、細胞における壊死性細胞死を調節し、それによって当該細胞における壊死性細胞死を制御することを含む、請求項1に記載の医薬組成物。
- 細胞におけるMCL−1の阻害が、細胞における代謝を調節し、それによって当該細胞においてエネルギー産生又は消費を制御して当該細胞における細胞の生存をもたらすことを含む、請求項1に記載の医薬組成物。
- 細胞におけるMCL−1の阻害が、細胞における細胞分裂を調節し、それによって当該細胞における増殖を制御することを含む、請求項1に記載の医薬組成物。
- 細胞におけるMCL−1の阻害が、細胞における転写を調節し、それによって当該細胞における転写を制御することを含む、請求項1に記載の医薬組成物。
- 細胞におけるMCL−1の阻害が、細胞におけるRNAプロセッシングを調節し、それによって、当該細胞におけるRNAプロセッシングを制御することを含む、請求項1に記載の医薬組成物。
- 細胞におけるMCL−1の阻害が、幹細胞又は前駆細胞における分化を調節し、それによって細胞における系統又は表現型を制御することを含む、請求項1に記載の医薬組成物。
- 細胞におけるMCL−1の阻害が、細胞におけるMCL−1の多量体化を調節し、それによって当該細胞におけるMCL−1の多量体化を制御することを含む、請求項1に記載の医薬組成物。
- MCL−1に関連する疾患又は障害を治療するための医薬組成物であって;
該治療はMCL−1を阻害することを含み;
該疾患は、過剰増殖性疾患、血管新生性疾患、炎症性疾患又は障害、感染性疾患又は障害、細胞周期調節疾患又は障害、オートファジー調節疾患又は障害及び自己免疫性疾患又は障害からなる群より選ばれ;
1つ又はそれ以上の請求項1に記載された式:A)の化合物又はその薬学的に許容される塩、溶媒和物、水和物若しくは立体異性体、及び薬学的に許容される希釈剤又は担体を含んでいる、医薬組成物。 - 過剰増殖性疾患が癌である、請求項11に記載の医薬組成物。
- 過剰増殖性疾患が難治性の癌である、請求項11又は12に記載の医薬組成物。
- 癌が、乳房、呼吸器、脳、生殖器官、消化管、尿管、眼、肝臓、皮膚、頭頸部、甲状腺、副甲状腺又は固形癌の遠位転移の癌である、請求項12又は13に記載の医薬組成物。
- 癌が、リンパ腫、肉腫、又は白血病である、請求項12又は13に記載の医薬組成物。
- 細胞を第2活性成分による治療に感作するための医薬組成物であって、1つ又はそれ以上の請求項1に記載された式:A)の化合物又はその薬学的に許容される塩、溶媒和物、水和物若しくは立体異性体、及び薬学的に許容される希釈剤又は担体を含み、かつ細胞におけるMCL−1を選択的に阻害する、医薬組成物。
- 第2活性成分が、死受容体刺激剤、制酸薬、抗生物質、制吐薬、抗鬱薬、抗真菌剤、抗炎症薬、抗ウィルス薬、抗癌剤、免疫調節薬、ベータインターフェロン、ホルモン又はサイトカインである、請求項16に記載の医薬組成物。
- 哺乳動物における細胞生着を増強するための医薬組成物であって、1つ又はそれ以上の請求項1に記載された式:A)の化合物又はその薬学的に許容される塩、溶媒和物、水和物若しくは立体異性体、及び薬学的に許容される希釈剤又は担体を含み、かつ細胞におけるMCL−1を選択的に阻害する、医薬組成物。
- 哺乳動物における創傷修復を増進するための医薬組成物であって、1つ又はそれ以上の請求項1に記載された式:A)の化合物又はその薬学的に許容される塩、溶媒和物、水和物若しくは立体異性体、及び薬学的に許容される希釈剤又は担体を含み、かつ細胞におけるMCL−1を選択的に阻害する、医薬組成物。
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US20130035304A1 (en) | 2013-02-07 |
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WO2011094708A2 (en) | 2011-08-04 |
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