TWI814723B - Kdm4抑制劑 - Google Patents
Kdm4抑制劑 Download PDFInfo
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- TWI814723B TWI814723B TW107110863A TW107110863A TWI814723B TW I814723 B TWI814723 B TW I814723B TW 107110863 A TW107110863 A TW 107110863A TW 107110863 A TW107110863 A TW 107110863A TW I814723 B TWI814723 B TW I814723B
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- kdm4
- cells
- cancer
- methyl
- cell
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本發明大體上關於用於抑制離胺酸去甲基酶4(lysine demethylase 4,KDM4)之酶活性及治療癌症的化合物及方法。本案提供具有取代基的吡啶衍生化合物及包含該化合物的藥學組成物。所請之標的化合物及組成物可用於抑制離胺酸去甲基酶4。此外,該等標的化合物及組成物可用於治療乳癌等等的癌症。
Description
本案中所述實施例係關於用於抑制離胺酸去甲基酶4(lysine demethylase 4,KDM4)之酶活性的化合物及方法。
需要可用來治療癌症的化合物及方法。
本發明實施例提供用於抑制KDM4之酶活性及治療癌症的方法及化合物。更具體而言,本發明實施例的其一方向是提供具取代基(substituted)的吡啶衍生物,該等具有取代基的吡啶衍生物抑制KDM4(稱「KDM4(i)」)並展現獨特的臨床特性。至少一個實施例提供一種強力的泛KDM4(i),化合物I,該化合物I可特異性地阻礙KDM4A、4B、4C及4D的去甲基酶活性,但不會阻礙其他KDM家族成員的去甲基酶活性。KDM4(i)的抗腫瘤性質已在概括數種病患腫瘤的條件下獲得確認。
本發明實施例的另一方向是提供一種在三重陰性乳癌幹細胞(BCSC)中篩選KDM4(i)的方法,該三重陰性乳癌幹細胞(BCSC)由前導性化療(neoadjuvant chemotherapy)後之個體病患腫瘤所製備,且在體外進行增殖。此等BCSC的有限稀釋原位異種移植體可忠實地還原出原始病患的腫瘤組織結構及基因表現。在至少一個實施例中,本發明中所述之KDM4(i)阻止了依據該方法所製備而成之BCSC的增殖、球體形成及異種移植腫瘤生長。
在另一實施例中,KDM4(i)化合物可藉由抑制KDM4A去甲基酶的活性來停止EGFR的表現(EGFR是生成具有治療抗性之三重陰性乳房腫瘤細胞的驅動因子)。此活性在來自三重陰性腫瘤的BCSC的上下文中尤其重要。
本發明實施例提供一種獨特的BCSC培養系統作為用來進行治療性化合物鑑定的依據,且本發明實施例證明了抑制KDM4是可用來治療包括三重陰性乳癌在內之癌症的治療策略。
所有專利及其他公開文獻皆以引用方式明文併入本案中以供說明及揭示目的之用,例如,在此等公開文獻中所描述的方法可與本發明合併使用。提供這些公開文獻僅為了先於本申請案之申請日而對其揭示內容進行公開。在此方面不應將任何內容視為承認本案發明人無權憑藉先前的發明或出於任何其他理由而使本發明內容早於此等公開內容。所有有關此等文獻的日期聲明或內容陳述皆基於本案申請人所能獲得的資訊,且並非承認此等文獻日期或內容的正確性。
當用於本文及申請專利範圍中,除非文中另有明確指示,否則單數形式包括複數之意,且反之亦然。在通篇本案說明書中,除非另有明確指示,否則「包括」、「包含」及「含有」作為包含性之用,而非排他之用,因此所述的整數或整數群組可包括一或更多個其他未提及的整數或整數群組。除非有修改,例如改為「兩者中之任一者(either)」,否則該用語「或」為包括之意。當本文中使用範圍來描述物理性質,例如分子量或化學性質(例如化學式)時,意在涵蓋該等範圍及具體實施例中的所有組合及子組合。除了在操作實例中或另有指示之外,本文中所有用來表示成分或反應條件之量的數目應理解為在所有情況下皆可用「約」一字加以修飾。當提及數字或數值範圍時,該用語「約」意指所提到的數字或數值範圍是落在實驗變異性範圍內(或落在統計實驗誤差內)的近似值,且因此該數字或數值範圍的變動可在所述數字或數值範圍的1%至15%之間,並容易從上下文中察覺。
除非另有定義,否則與文中所述公式搭配使用的科學術語及技術用語應具有所述領域中具有通常技藝者共同理解的含義。文中所此用的術語僅做描述具體實施例之用,且不欲限制本發明範圍,本範圍僅由申請專利範圍所界定。
本文中所述實施例提供特別是指當個體之疾病狀態(例如,癌症或腫瘤疾病)與該個體之表觀遺傳或表觀遺傳狀態有關時的治療。
在背景方面,表觀遺傳學(epigenetics)是研究由除基本(underlying)DNA序列以外之機制所導致基因表現上的遺傳性變化。參與在表觀遺傳調控中的分子機制包括DNA甲基化及染色質/組蛋白修飾。真核生物的基因組高度有序地組織在細胞的細胞核中。需要極度壓縮以將人類基因組的30億個核苷酸包裹在細胞的細胞核中。染色質是由構成染色體的DNA與蛋白質所組成的複合物。組蛋白是染色質的主要蛋白成分,用來充當供DNA纏繞用的線軸。組蛋白有六種(HI、H2A、H2B、H3、H4及H5),並且分為兩組:核心組蛋白(H2A、H2B、H3及H4)及連接組蛋白(HI及H5)。染色質的基本單元是核小體,核小體是由纏繞著核心組蛋白八聚體的約147個DNA鹼基對所組成,核心組蛋白八聚體是由核心組蛋白H2A、H2B、H3及H4每種各取兩個所組成。染色質結構的變化受到組蛋白蛋白質的共價修飾及非組蛋白之結合蛋白影響。例如,DNA甲基化、乙醯化及核小體組蛋白蛋白質的其他轉譯後修飾會改變染色質的組織架構及基因表現而不會改變基礎DNA序列。由於表觀遺傳修飾可能影響是否、在何時或何處表現特定基因,因此,不僅是原發性(primary)基因突變,細胞表觀遺傳環境的改變也在腫瘤的形成、進程及治療抗性中扮演重要角色(見Chaidos等人於6 Ther. Adv. Hematol. 128 (2015年)上所發表之論文)。表觀遺傳修飾是一種可被各種酶家族改寫、擦除及讀取的動態且可逆過程。已知有數種酶能在不同位置處修改組蛋白。(見Arrowsmith等人於11 Nature Rev. Drug Discov. 384 (2012)所發表之論文,亦可見美國專利第9,255,097號)。
組蛋白「去甲基酶(demethylase)」是可從多肽上去除至少一個甲基基團的酶,且特定的去甲基酶可使單甲基化受質、二甲基化受質或三甲基化受質去甲基化。組蛋白去甲基酶(例如在細胞層級的試驗中)可作用的受質包括經甲基化的核心組蛋白、單個核小體、二聚核小體、寡聚核小體、胜肽或染色質。示例性離胺酸特異性去甲基酶(lysine-specific demethylase)包括:離胺酸特異性去甲基酶1(LSD1或KDM1),其使用黃素(flavin)作為輔因子而可對單-及二-甲基化H3K4或H3K9進行去甲基化;及特徵是具有長度為~150個胺基酸之Jumonji C(JmjC)結構域的去甲基酶家族(例如,含Jumonji結構域的組蛋白去甲基酶1「JHDM1/KDM2A」)。請見,例如美國專利第9,255,097號;WO 2015/200709。
更明確言之,人LSD1及其同種同源物(paralog) LSD2藉由FAD依賴型胺類氧化反應對單甲基化-及二甲基化的組蛋白H3離胺酸4(H3K4)及H3K9兩者進行去甲基化。與LSD1/LSD2之FAD依賴性機制不同的是,含有Jumoji C結構域(JMJD)的蛋白質是透過雙加氧酶(dioxygenase)反應機制來作用,雙加氧酶反應機制需要F2+
、O2
及2-酮戊二酸(2-oxoglutarate)使組蛋白去甲基化。JMJD催化步驟是離胺酸甲基基團的羥化反應,該反應將離胺酸甲基基團轉化成羥甲基部位(hydroxymethyl moiety),該羥甲基部位會自發性地脫離該離胺酸的氮中心並釋出甲醛。此反應使得JMJD蛋白質原則上可對三甲基化-、二甲基化及單甲基化的離胺酸殘基(lysine residue)進行去甲基化,然而LSD1/LSD2不能攻擊三甲基化的離胺酸殘基(因為需要該甲基化的氮上具有自由電子對才行)。該等JMJD蛋白質大多數都可對H3K4、H3K9、H3K27、H3K36或H4K20進行去甲基化,但少數JMJD蛋白質的酶活性仍然未知,某些JMJD去甲基酶可能具有甲基-精胺酸去甲基酶活性,及另一些JMJD蛋白質可能完全不具有催化活性。見Berry及Janknecht發表在Cancer Res.期刊73卷(10期)2936頁(2013年)中之論文《KDM4/JMJD2 組蛋白去甲基酶:癌細胞中的表觀遺傳調節因子(KDM4/JMJD2 Histone Demethylases: Epigenetic Regulators in Cancer Cells)
》;亦參見第9圖)。除上述的JHDM1/KDM2A之外,JMJD蛋白質包括大約30個的人蛋白質成員,該等蛋白質成員依親緣(phylogenetically)歸聚為7個子家族:JMJD2、JHDM1、JHDM2、JHDM3、JARID、PHF2/PHF8、UTX/UTY,及僅JmjC結構域,例如見美國專利第9,447,046號。
最大的JMJD子家族之一,「JMJD2A-E蛋白質家族」,率先被稱為KDM4,以代表離胺酸去甲基酶4「K
(lysine)d
em
ethylase4
」。KDM4子家族包括KDM4A、KDM4B、KDM4C及KDM4D。KDM4可辨識二甲基化-及三甲基化的H3K9及H3K36以及三甲基化的H1.4K26為受質。(見Berry & Janknecht,2013)。例如, KDM4家族成員的異位表現(ectopic expression)會急遽降低三甲基化-及二甲基化-H3K9的量,並提高單甲基化H3K9的量,從而使異染色質蛋白1離開原位並降低體內異染色質蛋白的量。重要的是,KDM4去甲基酶會催化該抑制性之H3K9me3標記及該H3K36me3標記兩者的去甲基作用,而後者與轉錄延長作用(transcriptional elongation)有關。見Frank等人所發表之論文《癌症幹細胞概念的治療前景 (Therapeutic promise of cancer stem cell concept)
》,120 J. Clin. Invest. 41 (2010)。
本發明實施例提供具有取代基之(substituted)吡啶衍生化合物用於抑制KDM4酶活性及有助於治療癌症的用途。尤其,本案中所述KDM4(i)的一實施例「化合物I」在抑制乳癌腫瘤方面,且重要的是在三重陰性乳癌的腫瘤上展現出顯著的選擇性及效果。
乳癌是全球性女性因癌症死亡的主要原因。見Ferlay等人所編著之GLOBOCAN 2012年第1.0版《全球癌症發病率及死亡率 (Cancer Incidence & Mortality Worldwide)
》:IARC IARC Cancer Base No.11 (2013)。癌症進程與表觀遺傳調節因子(例如,組蛋白-離胺酸去甲基酶(KDM4))的改變有關。見Dave及Chang所發表之論文《幹細胞及乳癌的治療抗性 (Treatment resistance in stem cells & breast cancer
) 》,14 J. Mamm. Gland Biol. Neoplasia 79(2009年);Frank等人所發表之論文《癌症幹細胞概念的治療前景
(Therapeutic promise of cancer stem cell concept)
》,120 J. Clin. Invest. 41 (2010年);Pattabiraman及Weinberg所發表之論文《探討上皮 - 間葉的轉化:分化治療之案例
(Targeting Epithelial-to-MesenchymalTransition: Case for Differentiation-Based Therapy
)》, 2017年冷泉港量子生物學會議(Cold Spring Harbor Sympos. Quantitat. Biol.,2017);Sharma等人所發表之論文《具有化療抗性乳癌細胞中之 CXCR2 配體、幹細胞樣表現型及轉移的介紹(Induction of CXCR2 ligands, stem cell like phenotype, & metastasis in chemotherapy-resistant breast cancer cells
)》372 Cancer Lett. 192 (2016)。
在乳癌治療期間,經典療法無法解決抗性癌症幹細胞群,且以KDM蛋白或功能為目標的方式正逐漸成為可行的治療途徑。見Zhang等人所發表之文章《細胞起源及乳癌的演化 (Cellular orig. & evol. breast cancer)
》,冷泉港醫學專輯(Cold Spring Harbor Perspect. Med.)2017年;Chu等人所發表之論文《前列腺癌標靶 KDM4B :結構分析及利用新抑制劑進行選擇性抑制(KDM4B as target for prostate cancer: structural analysis & selective inhibition by novel inhibitor)
》,57 J. Med. Chem. 5975 (2014);Labbe等人所發表之論文《組蛋白離胺酸去甲基酶 (KDM) 子家族4 :結構、功能及治療潛力(Histone lysine demethylase (KDM) subfamily 4: structures, functions & therapeutic potential)
》,6 Am. J. Transl. Res. 1 (2013);Qiu等人所發表之論文《KDM4B 及KDM4A 藉由調控雄性素受體、c-myc 及p27kipl 促進子宮內膜癌的進展(KDM4B & KDM4A promote endometrial cancer progression by regulating androgen receptor, c-myc, & p27kip1
)》,6 Oncotarget 31702 (2015);Soini等人所發表之論文《非小細胞肺癌中的 KDM4A 、KDM4B 及KDM4C(KDM4A, KDM4B & KDM4C in non-small cell lung cancer
)》,8 Int’l J. Clin. Exper. Pathol. 12922(2015)。
本發明實施例提供一種具有獨特臨床前期特性(preclinical characteristic)的KDM4抑制劑。此KDM4(i)是一種強效泛-KDM4抑制劑,該KDM4抑制劑會特異性地阻斷KDM4A、KDM4B、KDM4C及KDM4D的去甲基酶活性,但不會阻斷KDM家族中其他成員的去甲基酶活性。該KDM4(i)的抗腫瘤性質已在概括數種病患腫瘤的條件下獲得確認。
本發明實施例的另一方向提供一種從經前導化療後的個體病患腫瘤中分離及生長三重陰性乳癌幹細胞(BCSC)的方法。此等BCSC的有限稀釋原位異種移植體忠實地還原了原始病患的腫瘤組織結構及基因表現。KDM4(i)阻止了BCSC的增殖、球體形成及異種移植腫瘤生長。重要的是,KDM4(i)藉由抑制KDM4A去甲基酶活性來停止EGFR的表現(EGFR是生成具有治療抗性之三重陰性乳房腫瘤細胞的驅動因子)。見Hsu及Hung所發表之論文《HER2 、EGFR 及其他受體酪胺酸激酶在乳癌中的作用(Role of HER2, EGFR, & other receptor tyrosine kinases in breast cancer)
》,35 Cancer Metast. Rev. 575 (2016)。本發明實施例提供一種獨特的BCSC培養系統以作為用於進行治療性化合物鑑定的基礎平台(basis)及演示KDM4抑制作用是一種用來治療三重陰性乳癌的新治療策略。
在包括乳癌在內的各種癌症中都有出現KDM4去甲基酶調控異常的紀錄。(見Berry & Janknecht,2013)。已證明KDM4控制著腫瘤細胞增殖,特別是在侵襲性乳癌中。見Ye等人所發表之論文《KDM4子家族的基因變異及新去甲基酶抑制劑對乳癌的治療效果(Genetic alterations of KDM4 subfamily & therapeutic effect of novel demethylase inhibitor in breast cancer) 》,5 Am. J. Cancer. Res. 1519 (2015)。治療抗性及轉移擴散是乳癌治療期間所要面對的主要問題。乳癌幹細胞被認為是造成治療抗性及轉移擴散兩者的主因。見Chu等人,2014;Ansieau所發表之論文《乳癌幹細胞生成中的EMT作用(EMT in breast cancer stem cell generation)》,338 Cancer Lett. 63 (2013)。然而,此等抗性癌幹細胞(CSC)族群的特性尚不清楚,且標靶療法還有待確定。由於KDM4去甲基酶可提供用來治療癌症的有效治療標靶,因此開始進行篩選以鑑定出新穎的KDM4抑制劑。為了在模擬癌症幹細胞族群的條件下驗證抑制劑,使用定義為無血清之條件及低氧環境來富集從經前導化療後之個體病患腫瘤中所取得的BCSC,而開發出本發明中所述新穎的3D培養方法。
如以下表1中所示,建立四種不同BCSC細胞株(BCSC1、BCSC2、BCSC3及BCSC4)的培養細胞。所有細胞株皆源自三重陰性的原代乳癌腫瘤:雌激素受體(ER)、黃體固酮受體(PR)及人表皮生長因子受體2(HER2)陰性;由此等細胞株所建立而成的所有異種移植腫瘤為三重陰性。
測定該BCSC培養細胞中的癌症幹細胞的估計頻率(利用有限稀釋細胞數移植法)範圍在1×105
個細胞中有0.26至179,如表2中所示:
在免疫低下NOD/SCID小鼠中的此等三重陰性BCSC之有限稀釋原位異種移植體所生成的三重陰性腫瘤在型態及表現型上皆與病患的原生腫瘤極為相符。見表1及表2;第1C圖;第5A圖。乳腺上皮標記細胞角蛋白8(cytokeratin 8)、E-鈣黏蛋白及波形蛋白的免疫組織化學分析,以及BCSC1及BCSC2異種移植腫瘤之增殖標記Ki67的分析,顯示該等異種移植腫瘤與親代病患腫瘤共同具有相似的模式。見第1B圖、第5B圖。的確,與該親代腫瘤比對,BCSC異種移植體在ER、PR及HER2蛋白質表現的表現情況上呈現陰性。見表1、第1C圖、第5C圖。
另外,RNA微陣列數據之非監督性階層式集群分析顯示該等腫瘤異種移植體與親代腫瘤有著接近的分佈曲線(profile),表示保存了各自的分子腫瘤亞型。見第1D圖。從宿主腫瘤及異種移植體中分別集群出該等BCSC細胞株,說明此等細胞的獨特性質。然而,該等細胞群聚在該宿主腫瘤亞型中而在三者之間繪出密切相關性。見第1D圖。
亦在3D及2D環境中培養該等BCSC,並分別成長為球體且主要為上皮細胞的群集。見第1E圖、第5D圖。當挑戰非貼附性生長試驗時,BCSC1及BCSC2細胞分別展現11%及17%的球體形成能力。見第1F圖、第5E圖。如上述方式所分離及培養出的未分類BCSC表現出不同程度的已知CSC標記,例如CD24/CD44(第1G圖、第5I圖)及CD49f/EpCAM(第1H圖、第5J圖)。綜合考慮下,該數據顯示,可從病患組織中直接分離並培養出源自三重陰性乳癌腫瘤的BCSC以提供可反映此疾病的體外細胞平台。此細胞平台允許用來在體外(in vitro)及體內(in vivo)鑑定及驗證新穎的癌症靶向策略。
利用西方墨點分析評估各種KDM4家族成員的BCSC細胞表現程度。見Metzger等人所發表之論文《LSD1使抑制性組蛋白修飾標記去甲基化以促進雄性素受體依賴性轉錄作用(LSD1 demethylates repressive histone marks to promote androgen receptor-dependent transcription)》,437 Nature 436 (2005)。如第2A圖中所示,在BCSC1及BCSC2兩種細胞中皆表現出高量的KDM4A。此等細胞亦展現不同程度的KDM4B、KDM4C及KDM4D表現量。此等觀察結果顯示KDM4是可用來治療BCSC族群的治療標靶。因此,進行篩選以鑑定KDM4(i)的特性,藉以發掘適合用於治療癌症(特別是例如具有治療抗性之選殖BCSC原發腫瘤這樣的癌症)的化合物。此篩選確認了第2B圖中所示具體KDM4(i)(化合物I)的功效。重要的是,此KDM4(i)特異性地阻斷KDM4A、KDM4B、KDM4C及KDM4D(IC50
<105 nM)的去甲基酶活性,但不影響其他KDM的去甲基酶活性。應注意,KDM4(i)對KDM5B的去甲基酶活性展現出微弱效果。表3示出抗KDM去甲基酶之化合物I的半最大抑制濃度(half-maximal inhibitory concentration,IC50
):
再者,KDM4(i)強烈抑制數種癌細胞株(包括三重陰性乳癌細胞株:MDA-MB-231)的增殖。表4示出化合物I對於7天細胞MTS試驗中所示之各種癌細胞株的半最大效應濃度(half-maximal effective concentration,EC50
):
此外,藥物動力學研究顯示KDM4(i)(例如化合物I)展現出適用於臨床上的性質。表5中示出示範的藥物動力數據。
在KDM4(i)於BCSC增殖上的功效方面,濃度低達10nM的KDM4(i)(化合物I)會抑制BCSC1及BCSC2增殖,且50nM的KDM4(i)會使BCSC1及BCSC2的存活受到強烈抑制。見第2C圖;第2D圖;第6A圖;第6B圖。此抑制效果在非貼附性生長試驗中更加明顯,在此試驗中,KDM4(i)急遽降低BCSC1細胞及BCSC2細胞兩者的球體形成能力。見第2E圖;第6C圖。再者,當將細胞播種在給予KDM4(i)治療下的MATRIGEL®基質膠中,在初代球體中,BCSC1細胞的球體形成大幅減少。當使用經KDM4(i)治療一週後的細胞再次進行播種時,繼代球體形成能力完全喪失,即使在沒有抑制劑存在的情況下亦然。見第2F圖;第6D圖。綜合考慮下,該KDM4(i)化合物I展現出足以支持該KDM4(i)化合物I用於治療BCSC致生腫瘤的獨特臨床特性。
進一步使用轉錄體(transcriptome)分析來鑑定當施以KDM4(i)治療時受到差異性調控的基因,以探索KDM4(i)抑制作用的分子機制。更具體言之,是利用RNA定序技術(RNA-seq)分析在存在及不存在KDM4(i)下所培養的BCSC1細胞,此分析顯示當使用KDM4(i)治療時,總共有580個基因受到差異性調控。在這580個基因中,254個基因受到上調及326個基因受到下調。見第3A圖。利用ChIP-seq技術使用抗-KDM4A抗體在BCSC1細胞中分析此等基因是否是直接的KDM4A目標。第3B圖中示出該等分析結果,該等分析識別出172692個高可信度的KDM4A波峰。在經抗KDM4A之siRNA治療後的BCSC2細胞中觀察到僅有3215個(1.8%)KDM4A位置,因此確認該KDM4A抗體的特異性。見第7A圖。此發現促使鑑定出該KDM4A順反組(cistrome)與該KDM4(i)轉錄體的交集。在使用KDM4(i)治療時受到差異調控的580個基因中,KDM4A出現在419個基因(72%)的啟動子處。見第3C圖。此等基因的路徑分析顯示「EGF受體訊息傳遞路徑」在得分最高的路徑之中。見第3D圖。重要的是,該等得分最高的路徑共享在以KDM4(i)治療時受到差異調控的37個KDM4A直接目標基因的共同基因印記。見第3E圖。進一步以定量反轉錄酶-聚合酶鏈鎖反應(qRT-PCR)分析證實使用KDM4(i)治療的基因降低了基因表現量,例如VCAN、PRR5、ATF4、EGR1、FST、RUNX1及重要的EGFR。見第3F圖。
EGFR是與臨床治療效果不佳之三重陰性乳癌有關的新興治療標靶。見Hsu & Hung,2016。為了解開EGFR訊息傳導在BCSC細胞生長上的重要性,使用特異性EGFR抑制劑「厄洛替尼(erlotinib)」治療BCSC1及BCSC2細胞。使用厄洛替尼治療阻止了BCSC1及BCSC2細胞兩者的增殖。見第7B圖至第7E圖。再者,當使用厄洛替尼治療時,BCSC1及BCSC2細胞兩者的3D群落形成能力急遽降低。見第7F圖、第7G圖。綜合觀之,此等數據證實EGFR控制BCSC細胞的生長。重要地,如西方墨點分析所示,當使用KDM4(i)治療時,BCSC1及BCSC2細胞兩者中的EGFR蛋白質量大幅下降。見第3G圖;第7I圖。由於EGFR是直接的KDM4A標靶,故可測定KDM4A減弱(knockdown)是否影響EGFR蛋白的量。如圖所示,腺病毒介導的KDM4A減弱導致在BCSC1及BCSC2兩者細胞中的EGFR的量降低。見第3H圖;第7I圖。此等數據顯示在BCSC中,KDM4(i)對KDM4A的抑制作用阻止EGFR表現。
由於KDM4A是抑制性H3K9me3標記的去甲基酶,當利用KDM4(i)使KDM4A失去活性時,可能觀察到H3K9me3升高。使用抗-H3K9me3抗體進行ChIP-seq試驗在未經治療的細胞中識別出141722個高可信度H3K9me3波峰及在經KDM4(i)治療的細胞中識別出144266個高可信度H3K9me3波峰。見第7J圖。在存在及不存在KDM4(i)情況下,KDM4A位置與H3K9me3位置的重疊顯示有81717個位置是被共同佔據的。見第7K圖。觀察到該H3K9me3總體增加從頭至尾蓋過(read over)該些KDM4A波峰。見第3I圖。類似地,在EGFR啟動子上,利用KDM4(i)去活性之後,也觀察到抑制性H3K9me3標記的增加覆蓋過該等KDM4A波峰。見第3J圖。此等數據與當施以KDM4(i)治療時所觀察到的轉錄抑制作用相呼應。總之,使用KDM4(i)治療BCSC會藉由抑制KDM4A去甲基酶活性而以EGFR作為標靶(EGFR是生成具治療抗性之三重陰性乳房腫瘤細胞的主要驅動因子)。
此外,以KDM4(i)對帶有新萌生異種移植腫瘤的免疫低下NOD/SCID小鼠進行為期21天的治療以研究KDM4(i)對BCSC1及BCSC2腫瘤異種移植體生長的影響。使用KDM4(i)治療會強烈影響BCSC1及BCSC2異種移植體兩者的腫瘤生長及最終腫瘤重量。見第4A圖至第4E圖;第8A圖至第8E圖。重要地,使用KDM4(i)治療不會影響小鼠的總重。見第8F圖、第8G圖。此外,KDM4(i)的治療會以如同在細胞培養中所觀察到的類似方式來影響KDM4A標靶基因的表現。見第3F圖。如第4F圖所示,在使用KDM4(i)所治療之小鼠的BCSC1異種移植腫瘤中,PRR5、ATF4、EGR1、FST、RUNX1及EGFR的表現受到影響。綜合觀之,使用KDM4(i)治療會阻止BCSC異種移植模型中的腫瘤生長。
總之,本發明實施例建立了一種新穎的培養方法,該培養方法允許用來分離及生長從經前導化療後之個體病患腫瘤中所分離出的BCSC細胞株。有限稀釋BCSC異種移植體可忠實地還原出親代病患腫瘤,且BCSC細胞株、BCSC異種移植體及該等親代腫瘤共有高度相似的轉錄體分佈曲線(transcriptome profile)。因此,此等模型是用來鑑定及驗證新穎療法的理想工具。
至少一實施例建立一種在原代乳癌幹細胞中篩選KDM4抑制性化合物之KDM4抑制活性的方法,該方法包括步驟:(1)取得乳房腫瘤材料;(2)機械性地分散該腫瘤材料;(3)使用至少一DNA水解酶(DNAse)、分散酶(dispase)或嗜熱菌蛋白酶(thermolysin)處理該腫瘤材料;(4)將該腫瘤材料稀釋在緩衝液中;(5)過濾該已分散且經處理的腫瘤材料以獲得腫瘤細胞;(6)視情況需要使用溶胞緩衝液(lysis buffer)去除紅血球細胞;(7)在細胞培養基中清洗腫瘤細胞;(8)在含有1:1比例之(a)液體培養基與(b)固體基質的幹細胞富集培養基中培養該已清洗的腫瘤細胞,其中(a)包括:乳腺上皮基底培養基(mammary epithelial basal medium)、無血清添加劑(serum-free supplement)、雙性黴素(amphotericin)、青黴素-鏈黴素(penicillin-streptomycin)、表皮生長因子(epidermal growth factor)、纖維母細胞生長因子(fibroblast growth factor)、肝素(heparin)、健大黴素(gentamicin)及Rho激酶抑制劑(Rho kinase inhibitor);(9)以37°C於低氧下培養該幹細胞富集培養液直到該經富集的細胞增殖成球體;(10)將該等增殖成球體的細胞族群擴展至擴增培養基(expansion medium)中,該擴增培養基包含98:2之比例的(a)及(b),以得到經擴增的乳癌幹細胞;(11)在包含KDM4抑制劑的幹細胞富集培養基中再次培養經擴增的乳癌幹細胞,其中相較於在不含KDM4抑制劑之情況下所再次培養的乳癌幹細胞而言,該KDM4抑制劑會抑制乳癌幹細胞增殖成球體的能力。
進一步者,本發明實施例不僅支持尋求KDM4家族成員作為新治療標靶,還提供至少一種具有獨特臨床前期特性的新穎KDM4抑制劑,該新穎的KDM4抑制劑可在體外及體內藉由以EGFR路徑做為標靶來阻止BCSC增殖。因此,調節KDM4活性是一種用來治療癌症(特別是具化療抗性之乳癌)的有潛力治療策略。化合物I,3-([(1R)-6-[甲基(苯基)胺基]-1,2,3,4-四氫萘-1-基]甲基)胺基)吡啶-4-羧酸(3-([(1R)-6-[methyl(phenyl)amino]-1,2,3,4-tetrathydronaphthalen-1-yl]methyl)amino) pyridine-4-carboxylic acid),是一種具有取代基之吡啶衍生化合物的具體實例,該化合物包括一在第4位置處被羧酸基及在第3位置處被具有取代基之胺基基團所雙取代的吡啶環。在WO 2015/200709中提供此化合物及相關之具有取代基的吡啶衍生物。
至少一個實施例提供具有式I結構的KDM4(i)化合物:式I 其中該化合物包括該化合物的立體異構物及藥學上可接受的鹽,及其中 X為O或CH2
,及R6
為N(R1
)(R2
)或O(R2
),其中R1
為H或C1
-C6
烷基,及 R2
為視需要可具有取代基的芳基、雜芳基、環基(cyclyl)或雜環基。
在至少一個實施例中,該化合物是R立體異構物。
在至少一個實施例中,R1
為甲基或乙基。
在至少一個實施例中, R2
為雜芳基,例如吡啶。
在至少一個實施例中,R2
為具有取代基的雜芳基,例如具有烷基取代基(例如甲基、乙基及環丙基)的吡啶。
在至少一個實施例中,R2
為芳基,例如苯基。
在至少一個實施例中,R2
為具有取代基的芳基,例如具有鹵素取代基(例如氟或氯)的苯基;或具有烷基取代基(例如甲基、丙基(propanyl)或環丙基)的苯基;或兼具鹵素及烷基兩種取代基(例如氟及甲基)的苯基;或具有胺基取代基或含N基團取代基(例如二甲胺基、氮雜環丁烷基(azetidinyl))的苯基;或具有烷氧基取代基(例如乙氧基、環丙基甲氧基、甲氧基甲基、二氟甲氧基或三氟甲氧基)的苯基;或具有雜環基取代基(例如氧雜環己烷基(oxanyl))的苯基。
在至少一個實施例中,R2
為氫茚部位(indane moiety),例如2,3二氫-1H-茚基。
在至少一個實施例中,X為CH2
及R6
為N(R1
)(R2
),其中R1
為甲基,及R2
為苯基或吡啶基。在一具體實施例中,KDM4(i)為3-([[(1R)-6-[甲基(苯基)胺基]-1,2,3,4-四氫萘-1-基]甲基]胺基)吡啶-4-羧酸。在一具體實施例中,該KDM4(i)為3-([[(1R)-6-[甲基(吡啶-2-基)胺基]-1,2,3,4-四氫萘-1-基]甲基]胺基)吡啶-4-羧酸。
在至少一個實施例中,X為CH2
及R6
為N(R1
)(R2
),其中R1
為甲基,及R2
為具有甲基取代基的苯基。在一具體實施例中,該KDM4(i)為3-([[(1R)-6-[甲基(4-甲基苯基)胺基]-1,2,3,4-四氫萘-1-基]甲基]胺基)吡啶-4-羧酸。
在至少一個實施例中,X為CH2
及R6
為N(R1
)(R2
),其中R1
為甲基,及R2
為具有二甲胺基取代基的苯基。在一具體實施例中,KDM4(i)為3-([[(1R)-6-[[4-(二甲胺基)苯基](甲基)胺基]-1,2,3,4-四氫萘-1-基]甲基] 胺基)吡啶-4-羧酸。
在至少一個實施例中,X為CH2
及R6
為N(R1
)(R2
),其中R1
為甲基,及R2
為具有甲氧基甲基、乙氧基或二氟甲氧基取代基的苯基。在一具體實施例中,KDM4(i)為3-([[(1R)-6-[[4-(甲氧基甲基)苯基](甲基)胺基]-1,2,3,4-四氫-萘-1-基]甲基]胺基)吡啶-4-羧酸。在一具體實施例中,KDM4(i)為3-([[(1R)-6-[[4-(二氟甲氧基)苯基](甲基)胺基]-1,2,3,4-四氫萘-1-基]-甲基]胺基)吡啶-4-羧酸。在一具體實施例中,KDM4(i)為3-([[(1R)-6-[[4-(二氟甲氧基)苯基](甲基)胺基]-1,2,3,4-四氫萘-1-基]-甲基]胺基)吡啶-4-羧酸。在一具體實施例中,該KDM4(i)為3 ([[(1R)-6-[(4-乙氧基苯基)(甲基)胺基]-1,2,3,4-四氫萘-1-基]甲基]胺基)吡啶-4-羧酸。
在至少一個實施例中,X為CH2
及R6
為N(R1
)(R2
),其中R1
為甲基,及R2
為具有甲基取代基的吡啶基。在一具體實施例中,KDM4(i)為3-([[(1R)-6-[甲基-[5-甲基吡啶-2-基] 胺基]-1,2,3,4-四氫萘-1-基]甲基]胺基)吡啶-4-羧酸。在另一具體實施例中,KDM4(i)為3-([[(1R)-6-[甲基[6-甲基吡啶-2-基]胺基]-1,2,3,4-四氫萘-1-基]甲基]胺基)吡啶-4-羧酸。
在至少一個實施例中,X為O及R6
為N(R1
)(R2
),其中R1
為乙基,及R2
為苯基。在一具體實施例中,KDM4(i)為3-([[(4R)-7-[乙基(苯基)胺基]-3,4-二氫-2H-1-苯并哌喃-4-基]甲基]胺基)吡啶-4-羧酸。
在至少一個實施例中,X為O及R6
為N(R1
)(R2
),其中R1
為甲基,及R2
為具有取代基的苯基。例如,該苯基經取代而具有氯或氟。在一具體實施例中,KDM4(i)為3-([[(4R)-7-[3-氟苯基](甲基)胺基]-3,4-二氫-2H-1-苯并哌喃-4-基]甲基)胺基)吡啶-4-羧酸。在另一具體實施例中,KDM4(i)為3-([[(4R)-7-[4-氟苯基](甲基)胺基]-3,4-二氫-2H-1-苯并哌喃-4-基]-甲基)胺基)吡啶-4-羧酸。在另一具體實施例中,該KDM4(i)為3-([[(4R)-7-[4-氯苯基](甲基)胺基]-3,4-二氫-2H-1-苯并哌喃-4-基]甲基)胺基)吡啶-4-羧酸。
在至少一個實施例中,X為O及R6
為N(R1
)(R2
),其中R1
為甲基,及R2
為具有取代基的苯基。例如,該苯基經取代而具有甲基、乙基、丙基或環丙基之取代基。在一具體實施例中,該KDM4(i)為3-([[(4R)-7-[甲基(4-甲基苯基)胺基]-3,4-二氫-2H-1-苯并哌喃-4-基]甲基]胺基)吡啶-4-羧酸。在一具體實施例中,該KDM4(i)為3-([[(4R)-7-[甲基(4-乙基苯基)胺基]-3,4-二氫-2H-1-苯并哌喃-4-基] 甲基]胺基)吡啶-4-羧酸。在一具體實施例中,該KDM4(i)為3-([[(4R)-7-[甲基[4-丙烷-2-基]苯基]胺基]-3,4-二氫-2H-1-苯并哌喃-4-基]甲基)胺基)吡啶-4-羧酸。
在至少一個實施例中,X為O及R6
為N(R1
)(R2
),其中R1
為甲基,及R2
為具有甲基、乙基、丙基或環丙基之取代基的吡啶基。在一具體實施例中,KDM4(i)為3-([[(4R)-7-[甲基(5-甲基吡啶-2-基)胺基]-2,3-二氫-2H-1-苯并哌喃-4-基]甲基]胺基)吡啶-4-羧酸。在一具體實施例中,該KDM4(i)為3-([[(4R)-7-[甲基 (5-甲基吡啶-2-基)胺基]-3,4-二氫-2H-1-苯并哌喃-4-基]甲基]胺基)吡啶-4-羧酸。在一具體實施例中,該KDM4(i)為3-([[(4R)-7-[(5-環丙基吡啶-2-基)(甲基)胺基]-3,4-二氫-2H-1-苯并哌喃-4-基]甲基]胺基) 吡啶-4-羧酸。在另一具體實施例中,該KDM4(i)為3-([[(4R)-7-[(4-環丙基苯基)(甲基)胺基]-3,4-二氫-2H-1-苯并哌喃-4-基]甲基]胺基)吡啶-4-羧酸。
在至少一個實施例中,X為O及R6
為N(R1
)(R2
),其中R1
為甲基,及R2
為具有取代基的苯基。例如,該苯基經取代而具有三氟乙基。在一具體實施例中,該KDM4(i)為3-({[(1R)-6-{[4-(1H-咪唑-1-基)苯基](甲基)胺基}-1,2,3,4-四氫萘-1-基]甲基}胺基)吡啶-4-羧酸。
在至少一個實施例中,X為O及R6
為N(R1
)(R2
),其中R1
為甲基,及R2
為具有取代基的苯基。例如,苯基為經取代而具有三氟甲氧基、二氟乙氧基或環丙基甲氧基。在一具體實施例中,KDM4(i)為3-([[(1R)-6-[[4-(三-氟甲氧基)苯基](甲基)胺基 3,4-二氫-2H-1-苯并哌喃-4-基]甲基]胺基]吡啶-4-羧酸。在一具體實施例中,KDM4(i)為3-([[(4R)-7-[[4-(二氟甲氧基)苯基](甲基)-胺基]-3,4-二氫-2H-1-苯并哌喃-4-基]甲基]胺基)吡啶-4-羧酸。在一具體實施例中,KDM4(i)為3-({[(1R)-6-{[4-(環丙基甲氧基)苯基](甲基)胺基}-1,2,3,4-四氫萘-1-基]甲基}胺基)吡啶-4-羧酸。
在至少一個實施例中,X為O及R6
為N(R1
)(R2
),其中R1
為甲基,及R2
為具有取代基的苯基,例如具有氮雜環丁烷基(azetidinyl)取代基的苯基。在一具體實施例中,KDM4(i)為3-([[(4R)-7-[[4-氮雜環丁烷-1-基]苯基](甲基)胺基]-3,4-二氫-2H-1-苯并哌喃-4-基]甲基)胺基)吡啶-4-羧酸。
在至少一個實施例中,X為O及R6
為N(R1
)(R2
),其中R1
為甲基,及R2
為具有取代基的苯基。例如,該苯基為經取代而具有氧雜環己烷基(oxanyl)取代基。在一具體實施例中,該KDM4(i)為3-({[(4R)-7-{甲基[4-(氧雜環己烷-4-基)苯基]胺基}-3,4-二氫-2H-1-苯并哌喃-4-基]甲基}胺基)吡啶-4-羧酸。
在至少一個實施例中,X為O及R6
為N(R1
)(R2
),其中R1
為甲基,及R2
為2,3-二氫-1H-茚基。在一具體實施例中,該KDM4(i)為3-([[(4R)-7-[2,3-二氫-1H-茚-5-基](甲基)胺基]-3,4-二氫-2H-1-苯并哌喃-4-基]甲基)胺基)吡啶-4-羧酸。
在至少一個實施例中,X為CH2
及R6
為O(R2
),其中R2
為具有氟及甲基取代基的苯基。在一具體實施例中,該KDM4(i)為3-([[(1R)-6-[2-氟-4-甲基-苯氧基]-1,2,3,4-四氫萘-1-基]甲基]胺基]吡啶-4-羧酸。
藉由以下方案1~方案3中所述的通用合成途徑製備該等具有取代基的吡啶衍生化合物。 方案1
參照以上方案1,在各種條件下混合並處理化合物A及胺類化合物B以形成化合物C。例如,可於120°C至172°C的溫度範圍下使化合物A與化合物B的混合物在合適的溶劑中接受微波照射。可使用偶合試劑(例如,HATU)在存在鹼的情況下由化合物C與醇類D製備出酯類化合物E。
參照以上方案2,在還原胺化反應條件下混合及處理化合物F與醛類化合物G以形成化合物C。可使用偶合試劑(例如,HATU)在存在鹼的情況下由化合物C與醇類D製備出酯類化合物E。
參照以上方案3,在各種條件下混合並處理化合物H及胺類化合物B以形成化合物E。例如,可於100℃至120℃的溫度範圍下使化合物H與胺類B的混合物在適當溶劑中在微波照射下進行Buchwald氏反應。可使用鹼性條件(例如,1N的NaOH水溶液)使該酯類化合物E水解以得到化合物C。
本文中所述的該等KDM4(i)化合物可採藥學上可接受之鹽的形式來製造或提供。任何該等具有取代基之吡啶衍生KDM4(i)化合物的藥學上可接受之鹽意欲涵蓋任何及所有藥學上可接受的鹽類型式,包括所屬技
術領域中熟悉之藥學上可接受鹽類,諸如酸與鹼之加成鹽。
通常,以化合物I為例,該具有取代基之吡啶衍生化合物實質上是純的,在該化合物中含有少於約5%、或少於約1%、或少於約0.1%的其他有機小分子(諸如,例如在一或更多個合成步驟中所產生的未反應中間產物或合成副產物)。
本文中所述的該等KDM4(i)通常含有一或更多個不對稱中心且因此會產生對映異構物(enantiomer)、非對映異構物(diastereomer)及其他立體異構形式,此等異構物依據絕對立體化學(absolute stereochemistry)而界定為(R)或(S)。同樣地,所有可能的異構物,以及該等異構物的消旋形式和光學純形式,及所有互變異構(tautomeric)形式亦包括在內。術語「位置異構物」意指繞中心環所產生的結構異構物,例如繞苯環所產生的鄰位-、間位-及對位-異構物。「立體異構物(stereoisomer)」意指一種由相同原子以相同鍵結方式連接但具有不同立體結構(且立體結構不能相互轉換)所構成的化合物。可利用所述技術領域中已知的工具及方法來分離立體異構物,例如掌性高效液相層析法(chiral HPLC)。因此,本發明中所提供的該等KDM4(i)化合物包括各種立體異構物及該等異構物的混合物及包括「對映異構物」,「對映異構物」意指彼此分子結構為非重疊鏡像的兩種立體異構物。此外,「互變
異構物(tautomer)」意指一種分子,其中在該分子之一原子上的質子可能可以移動到同一分子的另一個原子上。本發明中所提出的該等KDM4(i)化合物在某些實施例中可能以互變異構物的形式存在。在可互變異構化的情況下,該等互變異構物可能達成化學平衡,但該等異構物的實際比例取決於諸多因素,例如物理狀態、溫度、溶劑及酸鹼值(pH)。
本發明中所述的該等KDM4(i)可製造、獲得或調配成「前驅藥(prodrug)」。前驅藥是當在給藥時可能呈非活性但當處於生理環境下或藉由水解(即,在體內時)會轉化成生物活性化合物的一種化合物;因此前驅藥是生物活性化合物的藥學上可接受前驅物。前驅藥化合物可在個體內提供溶解度、組織相容性或延遲釋放的優點。前驅藥亦指共價鍵結載體的使用,當給予個體此種前驅藥時,共價鍵結載體會在體內釋放出活性化合物。可藉由對該活性化合物中存在的官能基進行修飾而使該等修飾在常規操作或體內任一情況下會裂解而釋出母體活性化合物,來製備出活性化合物的前驅藥。例如,前驅藥包括其中羥基、氨基或巰基(mercapto)與任一基團鍵結的化合物,且當對哺乳動物個體施用該活性化合物之前驅藥時,該等任一基團會裂解而分別形成自由羥基、自由氨基或自由巰基。前驅藥的實例包括該活性化合物中之醇官能基或胺官能基的乙酸酯衍生物、甲酸酯衍生物及苯甲酸酯衍生物。見,例如,Bundgard所著書籍,《前驅藥設計
(Design of Prodrugs)》第7-9頁、第21-24頁(Elsevier出版社,阿姆斯特丹,1985年);Higuchi等人所發表之文獻「前驅藥,新型遞送系統(Pro drugs as Novel Delivery Systems)」,《A.C.S.Symposium Series》第14卷;Edward B.Roche編著的《BIOREVERSIBLE CARRIERS IN DRUG DESIGN》(Am.Pharm.Assoc.& Pergamon Press出版社,1987年出版。)
因此,當用於本文中,提及KDM4(i)、KDM4(i)化合物或化合物I及諸如此類者時,所提及範圍包括KDM4(i)、KDM4(i)化合物或化合物I及諸如此類者的藥學上可接受之鹽、水合物、溶劑合物、N-氧化物(N-oxide)、立體異構物、互變異構物或前驅藥。
在某些實施例中,該具有取代基之吡啶衍生KDM4(i)化合物可以純化合物來給藥。在其他實施例及通常情況中,可依據所選的給藥途徑及標準製藥實務來選擇藥學上可接受之載劑與該KDM4(i)化合物組合使用,該等藥學上可接受之載劑在本文中亦稱為藥學上適合(或可接受)之輔劑、生理上適合(或可接受)之輔劑或是生理上適合(或可接受)之載劑。參見例如《雷明頓:製藥科學與實踐(REMINGTON:SCIENCE & PRACTICE OF PHARMACY)》,第21版,(Gennaro編著,Mack Pub.Co出版社,美國賓夕法尼亞州伊斯頓市,2005年).
因此,本發明中提供一種藥學組成物,該藥學組成物包括至少一種具有取代基之吡啶衍生KDM4(i)化合物或其立體異構物、藥學上可接受的鹽、水合物、溶劑合物、互變異構物或N-氧化物及搭配一或更多種藥學上可接受之載劑。若該載劑可與組成物中的其他成分相容且對受試者無害,則該(等)載劑(或輔劑)為可接受或合適的。一個實施例提供一種包含化合物I的藥學組成物。
提到「藥劑」、「治療劑」、「藥學活性」、「藥學的」、「藥物」、「醫藥」、「活性藥劑」、「活性藥」、「活性藥學成分」及諸如此類術語時,意指在廣義上可用於醫學及科學領域中的物質,包括例如藥物、生物製品、診斷劑(例如,染劑或對比劑)或其他用於治療、診斷或預防性(例如,疫苗)或研究目的之物質。示例性的藥劑包括小分子、化療劑、對比劑、麻醉劑、干擾RNA、基因載體、生物製品、免疫原、抗原、干擾素、多株抗體製品、單株抗體、胰島素或上述藥劑之任意組合。應注意,藥學組成物或藥學配方可包括一或更多種活性治療劑或由活性藥劑與診斷劑的組合物,等等,通常進一步包括合適的(多種)輔劑。
進一步地,本案中所揭示的藥學組成物可調配成能與預定的給藥途徑相配合。給藥途徑的實例包括非胃腸道途徑,例如經靜脈、皮內、皮下、口腔(例如,吸入)、經皮膚(即,外用)、經黏膜及經直腸給藥。用於非胃腸道、皮內或皮下應用的溶液或懸浮液可包括以下成分:滅菌稀釋劑,例如注射水、生理食鹽溶液、不揮發油、聚乙二醇、甘油、丙二醇或其他合成溶劑;抗菌劑,例如苯甲醇或對羥苯甲酸甲酯;抗氧化劑,例如抗壞血酸或亞硫酸氫鈉;螯合劑,例如乙二胺四乙酸(EDTA);緩衝液,例如乙酸鹽、檸檬酸鹽或磷酸鹽;及用於調整滲壓性的試劑,例如氯化鈉或右旋糖。pH可用酸或鹼來加以調整,例如用氫氯酸或氫氧化鈉。非胃腸道用藥製品可封裝在由玻璃或塑膠所製成的安瓿、拋棄式注射器或多劑型小瓶中。
適用於注射用途的藥學組成物包含滅菌水溶液(水溶性)或分散液(dispersion)及用於製備滅菌注射溶液或分散液的滅菌粉末。對於靜脈給藥方面,合適的載劑包括生理食鹽水、抑菌水、Cremophor EL™ (巴斯夫公司(BASF),美國紐澤西州帕西帕尼市(Parsippany))或磷酸鹽緩衝液(PBS)。在所有情況下,組成物必須為滅菌的且應為流體的以便易於注射。藥學組成物在製造及儲存條件下必須保持穩定且必須能防止微生物(例如細菌及真菌)污染。該載劑可為含有例如水、乙醇、多元醇(例如,甘油、丙二醇及液體聚乙二醇及諸如此類者)或上述之適當混合物的溶劑或分散介質(dispersion medium)。例如,可藉由使用包衣(例如卵磷脂)、在分散液的情況中可藉由維持所需的顆粒尺寸及藉由使用界面活性劑來維持適當的流動性。可藉由各種抗菌劑及抗真菌劑來防止微生物活動,該等各種抗菌劑及抗真菌劑例如對羥苯甲酸酯、氯丁醇、酚、抗壞血酸、乙汞硫柳酸鈉(thimerosal)及諸如此類者。在諸多情況下,組成物中較佳可包括等滲劑,例如蔗糖、多元醇,例如甘露醇、山梨醇、氯化鈉。可使該組成物中含有延遲吸收(例如,單硬脂酸鋁及明膠)的試劑以為該注射用組成物帶來延長吸收作用。
可藉著在合適的溶劑中加入規定量的活性化合物及依需要搭配以上枚舉的一種成分或數種成分之組合物,接著經過過濾滅菌,而製備出滅菌注射用溶液。通常,可藉由在含有基礎分散介質的滅菌媒介中加入活性化合物及來自以上枚舉成分中的其他所需成分而製備出分散液。在可供製備滅菌注射溶液用的滅菌粉末之情況中,製備方法為將前述組成物之過濾滅菌溶液經真空乾燥及冷凍乾燥來得到該活性成分加上任何附加所欲成分的粉末。
就吸入給藥而言,是以來自含有適當推進劑(例如,氣體,例如二氧化碳)之加壓容器或分配器或噴霧器的氣溶膠噴霧的形式來遞送該等化合物。
亦可經黏膜或經皮膚做到全身性給藥。就經黏膜或經皮膚給藥而言,在該配方中使用適合滲入障壁中的滲透劑。此種滲透劑通常在所屬技術領域中為人所知悉,且包括(用於經黏膜給藥方面)例如清潔劑、膽鹽及梭鏈孢酸(fusidic acid)衍生物。可透過使用鼻腔噴霧或塞劑來實現經黏膜給藥。就經皮膚給藥方面,將該等活性化合物調配成所屬技術領域中通常皆知的軟膏、藥膏、凝膠或乳霜。該等化合物亦可製備成塞劑(例如,使用傳統的塞劑基體,例如椰子油及其他甘油酯)或保留灌腸注劑(retention enemas)形式以用於直腸投遞。
就此點而言,在本發明所述的實例中是經口服給藥而有效地施用該KDM4(i)化合物I。口服組成物通常包括惰性稀釋劑或可食用載劑。該等口服組成物可封裝在明膠膠囊中或壓製成錠劑。為了達到口服治療給藥的目的,該活性化合物可混合多種輔劑且以錠劑、片劑或膠囊形式使用。亦可使用流體載劑來製備口服組成物而可如漱口劑般使用,其中流體載劑中的化合物是以口服使用且沖刷口腔並吐掉或嚥下。可包含藥學上相容的黏結劑及/或佐劑材料以作為該組成物的一部分。錠劑、丸劑、膠囊、片劑及諸如此類者可包含任何以下成分或具有類似性質的化合物:黏結劑,例如微晶纖維素、黃芪膠(tragacanth gum)或明膠;賦形劑,例如澱粉或乳糖;崩散劑,例如藻酸、PRIMOJEL®(羧甲基澱粉鈉(sodium starch glycolate),DFE製藥公司)或玉米澱粉;潤滑劑,例如硬脂酸鎂、硬脂酸鈣、硬脂酸棕梠酸甘油酯或二十二酸甘油酯(glyceryl behenate);助滑劑,例如二氧化矽膠體(colloidal silicon dioxide);甜味劑,例如蔗糖或糖精(saccharin);或香味劑,例如薄荷、柳酸甲酯或柳橙香味。因此,示例性的藥學組成物可調配成合適的口服劑型,包括例如錠劑、丸劑、藥包,或由明膠、甲基纖維素或易於溶解在消化道中的其他適當材料所製成的軟式或硬式膠囊。在某些實施例中,可使用的適當無毒性固體載劑包括例如,藥用級的甘露醇、乳糖、澱粉、硬脂酸鎂、糖精鈉、滑石、纖維素、葡萄糖、蔗糖、碳酸鎂及諸如此類者。見REMINGTON, 2005。
例如,錠劑可藉由混合48重量%之化合物I、45重量%之微晶纖維素、5重量%之低取代羥丙基纖維素及2重量%之硬脂酸鎂製備而成。可藉由直接壓製來製備錠劑。此壓製錠劑實例的總重維持在250毫克至500毫克間。口服劑量範圍通常可在約1.0毫克至約1000毫克,每日用藥一次至四次或更多次。
在一個實施例中,使用可保護該化合物免於被身體快速排出的載劑來製備該等KDM4(i)化合物,該等載劑可例如持續/控制釋放型配方,包括植入物及微膠囊遞送系統。可使用生物可分解、生物相容性的聚合物,例如乙烯醋酸乙烯酯、聚酐、聚乙醇酸、膠原蛋白、聚原酸酯及聚乳酸。所屬技術領域中熟悉該項技藝者將可瞭解用於製備此等配方的方法。例如,在膠體藥物遞送系統(例如,微脂體、白蛋白微球、微乳液、奈米顆粒及奈米膠囊)或在粗滴乳液(macroemulsion)中,該等活性成分可分別包裹在例如藉由凝聚技術或藉由界面聚合反應所製備而成的微膠囊中,例如羥甲基纖維素或明膠-微膠囊及聚-(甲基丙烯酸甲酯)微膠囊。
可製備持續釋放型製品,且持續釋放型製品的適當實例包括含有抗體的固態親水性聚合物的半透性基材,該等基材為塑形物品的形式,例如膜或微膠囊。持續釋放型基材的實例包括聚酯、水凝膠(例如,聚(2-羥乙基-甲基丙烯酸酯)或聚(乙烯醇))、聚乳酸(見美國專利第3,773,919號)、L-麩胺酸與γ乙基-L-麩胺酸(γ ethyl-L-glutamate)、不可降解性乙烯-醋酸乙烯酯、可降解性乳酸-乙醇酸共聚物(例如,LUPRON DEPOT®,一種由乳酸-乙醇酸共聚物及醋酸柳菩林(leuprolide acetate)所組成的注射用微球體)及聚-D-(-)-3-羥丁酸。儘管諸如乙烯-醋酸乙烯酯及乳酸-乙醇酸之聚合物能夠在100天內持續釋放分子,但某些水凝膠持續釋放蛋白質的時間較短。此種材料亦可從市面上取得(例如,Alza公司;Nova製藥公司)。脂質體懸浮液(包括使用單株抗體來鎖定受感染之細胞的脂質體)亦可用來作為藥學上可接受的載劑。可根據所屬領域中熟悉該項技藝者已知的方法來製備此等製品。
口服或非胃腸道組成物可調配成劑量單元形式以便於給藥及達到劑量一致性。當用於本文中時,劑量單元形式意指適合作為可供待治療個體所使用之單位劑量的物理離散單元;每個單元含有經計算可產生期望治療效果的預定量之活性化合物及所需的藥學載劑。用於本發明所揭示之劑量單元形式的規格取決於且直接取決於該活性化合物之獨特特性及所欲達到之特定療效,及調配此種活性化合物以用來治療個體時之所屬技術領域中的固有局限性而定。
該等藥學組成物或劑量單元可裝在容器、包裝或分配器中並附上用藥說明書。
若因需要治療特別適應症時,該配方亦可包含超過一種的活性化合物,較佳為該些具有互補活性且彼此間無不良影響的活性化合物。或者,或附加地,該組成物可包含能增強該組成物功能的試劑,例如免疫刺激劑、化療劑、細胞介素(cytokine)、抗體或生長抑制劑。組合物中存在的此等分子的含量較佳為可有效達到所欲目標的量。
「藥學配方(pharmaceutical formulation)」、「配方(formulation)」或「藥學組成物(“pharmaceutical composition)」意指含有至少一種活性藥劑且可進一步包括至少一種藥學上可接受的輔劑、載劑、緩衝劑、安定劑或所屬領域中熟悉該項技藝者熟知的其他材料的藥物產品。例如,典型的注射用藥學配方包括非胃腸道的可接受水性溶液,該水性溶液不含致熱原且具有適當的pH、等滲性及安定性。藥學組成物在各種物種(例如,人類病患或個體)上可具有診斷、治療或研究用途。在至少一個實施例中,藥學組成物包括溴結構域抑制劑及化療劑,例如替莫唑胺(temozolomide)、蛋白結合型太平洋紫杉醇(protein-bound paclitaxel)或羅米帝辛(音譯自romidepsin)。例如,溴結構域抑制劑可為4-[2-(環丙基甲胺基)-5-甲基磺醯基苯基]-2-甲基異喹啉-1-酮 (4-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one)。可藉由任習知方式使用所接受之文獻中所述的一或更多種藥學可接受載劑或輔劑調配出本發明中所述之試劑及組成物。見例如,《雷明頓:製藥科學與實踐(REMINGTON: SCIENCE & PRACTICE OF PHARMACY)》,第22版,Lloyd編著,英國倫敦Pharmaceutical Press出版社,2012年出版。此等配方包含治療有效量的本發明中所述該(等)活性藥劑(較佳為經純化之形式)且搭配適當量的載劑以為該等受試者提供適當的給藥形式。
藥學配方可包括治療有效量的至少一種活性藥劑。所屬領域中具有通常技藝者可部分根據投藥劑型的效果或一試劑與一或更多種附加活性藥劑(若使用一種以上之藥劑時)的綜合效果而輕鬆決定此有效量。亦可根據諸多因素,例如可根據個體的疾病狀態、年齡、性別和體重以及該藥劑(及一或更多種附加活性藥劑)在該個體內引起期望反應的能力(例如,改善至少一種疾病參數)來改變活性藥劑的治療有效量。例如,一劑型的治療有效量可抑制(減輕疾病之嚴重度或消除疾病的發生)、預防一特定疾病或減輕所屬領域中已知或本文中所述之特定疾病的任一症狀。治療有效量亦可為有益之治療效果超過該活性藥劑或劑型之任何毒性或有害作用的量。
以適合該待治療疾病的方式來投予藥學組成物(見下文)。可依據該個體的狀況、該個體之疾病的種類及嚴重度、該活性化合物的具體形式及給藥方法來決定合適的劑量及適當的給藥持續時間及頻率。通常,一適當劑量及治療方案所提供之活性組成物的量足以提供治療或預防益處(例如,改善臨床結果,例如較快地完全或部分緩解,或無病率或總體存活率較長,或減輕症狀嚴重度,見下文)。通常使用實驗模型或臨床試驗來決定最佳劑量,隨後根據受試者的身體質量、體重或血量做調整。
因此,包含至少一種具有取代基之吡啶衍生KDM4(i)化合物的藥學組成物之劑量可能依據受試者(例如,人類病患)的狀況,例如疾病階段、總體健康狀態、年齡及其他因素而有所不同。
應注意,可採聯合治療方式,即結合其他藥劑,例如結合用於治療病理狀況或失調症狀(例如,各種形式的癌症、自體免疫疾病及發炎疾病)的治療劑來投予本發明所揭示之該等KDM4(i)化合物。術語「合併使用(in combination)」在此上下文中意指該等藥劑實質上是同期給藥,可為同時給藥(simultaneously)或先後給藥(sequentially)其中任一者。若為先後給藥,則在開始給予該第二化合物時,該兩化合物中的第一化合物較佳仍可在治療處測得有效濃度。
例如,該聯合治療可包括使本發明中所揭示的一或更多種抗體與一或更多種附加治療劑(例如,一或更多種細胞介素及生長因子抑制劑、免疫抑制劑、抗發炎劑、代謝抑制劑、酶抑制劑或細胞毒性劑或細胞增殖抑制劑)調配在一起或一同給藥。此等聯合治療可有利於使用較低劑量的給藥治療劑,從而避免各種單一療法可能帶來的毒性及併發症。例如,本發明揭示的治療性KDM4(i)化合物可與抗體合併使用且可進一步包括該些介入發炎反應之不同階段的藥劑。本發明所述的一或更多種KDM4(i)化合物可與一或更多種附加藥劑調配在一起或一同給藥,該一或更多種附加藥劑可例如其他化療劑或生物製品(例如疫苗)、免疫毒素(immunotoxin)、細胞介素或生長因子拮抗劑(例如,可溶性受體、胜肽抑制劑、小分子、配體融合物);抗體或該抗體的抗原結合部位(例如,與腫瘤標記、細胞介素或生長因子或其受體結合的抗體);及抗發炎細胞介素或其促效劑。
在至少一個實施例中,KDM4(i)化合物可與至少一種附加化療劑調配在一起或一同給藥。該化療劑可為溴結構域抑制劑(見,例如WO 2015058160;美國專利公開案第20150111885號;美國專利第9,034,900號)、烷化劑或有絲分裂抑制劑。
因此,可採單一療法、或與其他活性藥劑在一組合劑型中以聯合治療方式、或採附加治療(例如,對同一疾病、相關疾病或附加疾病進行另一治療)的方式對受試者施用活性藥劑(即,KDM4(i))。例如,KDM4(i)化合物可與化療劑在同一配方中合併使用或在不同配方中同時給藥或先後給藥,該化療劑例如溴結構域抑制劑、羅米帝辛、替莫唑胺、蛋白結合型太平洋紫杉醇及諸如此類者。此外,聯合治療可包括對該受試者(例如,人類病患)施用一或更多種為受試者提供治療益處的藥劑(例如,抗生素、抗凝血劑、抗高血壓藥物或抗發炎藥物)。在另一實例中,聯合治療可包括對該受試者施用KDM4(i)化合物及可為患有癌症(例如三重陰性乳癌或抗性乳癌)之受試者提供治療益處的一或更多種附加藥劑。同樣地,在另一實例中,聯合治療可包括對受試者施用一KDM4(i)化合物、蛋白結合型太平洋紫杉醇或一包含KDM4(i)化合物與太平洋紫杉醇的組合物,及可為患有癌症之受試者提供治療益處的一或更多種附加藥劑。在其他實施例中,先給予一活性藥劑及隨後給予一附加的活性藥劑。在某些實施例中,一或更多種附加活性藥劑是同時給藥,但使用不同的藥物遞送裝置或遞送模式,例如提供包括給予KDM4(i)化合物與替莫唑胺,或包含KDM4(i)化合物與太平洋紫杉醇,或包含KDM4(i)化合物與羅米帝辛的聯合治療。在至少一個實施例中,該KDM4(i)化合物為化合物I。
可使用包括投予KDM4(i)化合物之療法來治療的癌症包括癌、肉瘤、生殖細胞瘤、淋巴癌或白血病、胚母細胞瘤或其他癌症。癌包括上皮瘤及腺瘤、移行性細胞癌、腺樣囊狀癌、胰島素瘤、肝細胞癌、膽管癌、闌尾類癌瘤、革囊胃、喉癌、咽癌、口腔癌、下咽癌、唾液腺癌、舌癌、胃癌、泌乳素瘤、嗜酸細胞瘤、肝細胞癌、腎實質癌、乳突狀腎細胞癌、膽囊癌、支氣管癌、格拉維茨氏瘤(Grawitz tumor)、原發部位不明癌症、多發性內分泌腺瘤、子宮內膜樣腺瘤、附件瘤及皮膚附件瘤、黏液表皮樣瘤、囊性、黏液及漿液性瘤、囊腺瘤、腹膜假黏液瘤、乳腺管、乳葉及髓質瘤、腺泡細胞瘤、複雜性上皮瘤、華生氏瘤(Warthin’s tumor)、胸腺瘤、特異性性腺瘤、性索基質瘤、實體瘤、唇瘤、粒層細胞瘤、雄胚瘤、史托力狄雷格細胞瘤(Sertoli Leydig cell tumor)、球形瘤、副神經節瘤、嗜鉻細胞瘤、球形瘤、黑色素細胞痣。肉瘤包括阿金氏瘤(Askin’s tumor)、葡萄狀肉瘤、尤文氏肉瘤(Ewing’s sarcoma)、卡波西氏肉瘤(Kaposi’s sarcoma)、惡性血管內皮瘤、惡性神經鞘瘤、骨肉瘤、軟組織肉瘤(包括肺泡狀軟組織肉瘤、血管肉瘤、葉狀囊性肉瘤、皮膚纖維肉瘤、硬纖維瘤、促纖維增生性小圓細胞瘤、上皮樣肉瘤、骨外軟骨肉瘤、骨外股肉瘤、血管外皮細胞瘤、血管肉瘤、淋巴管肉瘤、淋巴肉瘤、惡性纖維組織細胞瘤、神經纖維肉瘤及滑膜肉瘤)。淋巴癌及白血病包括急性淋巴胚母細胞白血病、急性骨髓性白血病、髮樣細胞白血病、多發性骨髓瘤、慢性骨髓性白血病、慢性骨髓增殖性疾病、慢性淋巴細胞白血病/小淋巴細胞白血病、B-細胞前淋巴細胞白血病、淋巴漿細胞淋巴癌(例如,華氏巨球蛋白白血症(Waldenstrom macroglobulinemia))、脾邊緣區淋巴瘤、漿細胞性骨髓癌、漿細胞瘤、單株免疫球蛋白沈積疾病、重鏈病、結外邊緣區B-細胞淋巴癌(亦稱為黏膜相關淋巴組織(malt)淋巴瘤)、結內邊緣區B-細胞淋巴癌、伯基特氏淋巴瘤(Burkitt’s lymphoma)、非霍奇金氏淋巴瘤(non-Hodgkin lymphoma,包括瀰漫性大B-細胞淋巴瘤、濾泡性淋巴瘤、蕈狀肉芽腫及塞澤里綜合症(Sézary syndrome)、被套細胞淋巴瘤、瀰漫性大B-細胞淋巴瘤、原發滲出性淋巴瘤、血管內大B-細胞淋巴瘤、肝脾T-細胞淋巴瘤、結外NK-/T-細胞淋巴瘤)、縱隔(胸線)大B-細胞淋巴瘤、T-細胞前淋巴細胞性白血病、T-細胞大顆粒淋巴細胞白血病、侵襲性NK-細胞白血病、成人T-細胞白血病/淋巴瘤、腸壁型T-細胞淋巴瘤、芽球性NK-細胞淋巴瘤、皮膚T-細胞淋巴瘤、原發性皮膚CD-30陽性T-細胞淋巴增生疾病、原發性皮膚間變性大細胞淋巴瘤、淋巴瘤樣丘疹病、血管免疫母細胞性T-細胞淋巴瘤、周邊T-細胞淋巴瘤(非特定)、間變性大細胞淋巴瘤、典型霍奇金淋巴瘤(結節硬化型、混合細胞型、多淋巴球型、淋巴球缺乏型/未淨除型、結節樣淋巴球為主型的霍奇金淋巴瘤)、HIV相關淋巴瘤(例如,原發滲出性淋巴瘤)。生殖細胞腫瘤包括但不限於胚細胞瘤、無性胚細胞瘤、非生殖性生殖細胞腫瘤、內胚竇腫瘤、顱外生殖細胞腫瘤(extracranial germ cell tumor)、性腺外生殖細胞瘤、畸胎瘤、多胚瘤及性腺胚母細胞瘤。胚母細胞瘤包括室管膜母細胞瘤、嗅神經母細胞瘤及腎胚細胞瘤。
可使用包括投予KDM4(i)化合物之療法來治療的其他癌症包括肺癌,例如非小細胞肺癌及小細胞肺癌(包括小細胞癌(燕麥細胞癌)、混合性小細胞/大細胞癌及複合性小細胞癌)、肝癌、胃癌、神經膠質母細胞瘤、頭頸鱗狀細胞癌、骨髓瘤、腎上腺皮質癌、甲狀腺癌(髓質及乳頭狀甲狀腺癌)、腎癌、子宮頸癌、子宮體癌、子宮內膜癌、絨毛膜癌、睪丸癌、泌尿系統癌、黑色素瘤、基底細胞癌、畸胎瘤、脈絡膜黑色素瘤、顱咽管瘤、古肉瘤、基肉瘤及漿細胞瘤、肛門癌、闌尾癌、非典型畸胎/橫紋肌腫瘤、膀胱癌、腦瘤(包括腦幹膠質細胞瘤、中央神經系統非典型畸胎/橫紋肌瘤、中央神經系統胚胎細胞瘤、顱咽管瘤、室管膜瘤、髓上皮瘤、中間分化松果體實質瘤、大腦鐮原始神經外胚層腫瘤及松果體母細胞瘤)、乳房癌、支氣管腫瘤、原發位置不明癌症、類癌腫瘤、中央神經系統非典型畸胎/橫紋肌腫瘤、中央神經系統胚胎細胞瘤、兒童期癌症、內分泌胰島細胞瘤、子宮內膜癌、肝外膽管癌、膽囊癌、胃部(胃)癌、胃腸道類癌腫瘤、胃腸道基質細胞癌、胃腸道基質瘤(GIST)、妊娠滋養細胞腫瘤、頭頸癌、心癌、眼內黑色素瘤、胰島細胞腫瘤、朗格罕組織細胞增生症(Langerhans cell histiocytosis)、喉癌、唇癌、肝癌、惡性纖維組織細胞骨癌、髓上皮瘤、梅克爾細胞癌(Merkel cell carcinoma)、原發不明轉移性鱗狀細胞頸部癌、多發性內分泌腺瘤綜合症、多發性骨髓瘤、多發性骨髓瘤/漿細胞瘤、骨髓增生異常綜合症、骨髓增殖性腫瘤、鼻腔癌、鼻咽癌癌、口腔癌、口咽癌、骨肉瘤、其他腦部及脊髓腫瘤、卵巢上皮癌、卵巢生殖細胞瘤、卵巢低惡行潛在腫瘤、乳頭狀瘤、鼻竇癌、副甲狀腺癌、骨盆癌、陰莖癌、中間分化松果體實質瘤、松果體母細胞瘤、腦下垂體腫瘤、漿細胞瘤/多發性骨髓瘤、胸膜肺母細胞瘤、原發性中央神經系統(CNS)淋巴瘤、直腸癌、直腸癌、呼吸道癌、小腸癌、鱗狀細胞頸癌、大腦鐮原始神經外胚層腫瘤、胸腺癌、胸腺瘤、甲狀腺癌;移行細胞癌;腎盂及輸尿管移行細胞癌;滋養細胞瘤;輸尿管癌;尿道癌;子宮肉瘤;陰道癌;外陰癌。
可使用具有取代基之吡啶衍生KDM4(i)化合物治療之硬瘤相關癌症的具體實例包括乳房癌、纖維肉瘤、黏液肉瘤、脂肪肉瘤、軟骨肉瘤、骨原性肉瘤、脊索瘤、血管肉瘤、內皮肉瘤、淋巴管肉瘤、淋巴管內皮瘤、滑膜瘤、間皮瘤、尤文氏腫瘤、平滑肌肉瘤、橫紋肌肉瘤、大腸癌、大腸直腸癌、腎癌、胰腺癌(例如,胰升糖素瘤、胃泌素瘤、胰腺神經內分泌瘤(VIPoma))、骨癌、卵巢癌、前列腺癌、食道癌、胃癌、口腔癌、鼻腔癌、喉癌、鱗狀細胞癌、基底細胞癌、腺癌、汗腺癌、皮脂腺癌、乳突癌、乳突狀腺癌、囊腺癌、髓樣癌、支氣管癌、腎細胞癌、肝細胞瘤、膽管癌、絨毛膜癌、精原細胞癌、胚胎性癌、威爾姆氏腫瘤(Wilms’ tumor)、子宮頸癌、子宮癌、睪丸癌、膀胱癌、上皮癌、神經膠瘤、腦瘤(例如,神經膠母細胞瘤、多形性神經膠母細胞瘤、星狀細胞瘤、腦脊髓膜瘤、神經管胚母細胞瘤及周邊神經外胚瘤)、顱咽管瘤、室管膜瘤、松果體瘤、血管母細胞瘤、聽神經瘤、寡樹突神經膠細胞瘤、腦脊髓膜瘤、皮膚癌、黑色素瘤(惡性黑色素瘤、結節性黑色素瘤、發育異常性母斑、斑點樣惡性黑色素瘤、淺表擴散性黑色素瘤及惡性肢端斑點樣黑色素瘤)、神經胚細胞瘤及視網膜胚細胞瘤。尤其,KDM4(i)化合物可用來治療EGFR-路徑的相關癌症。
通常以功能性、化學結構及與另一藥物的關聯性來描述化療劑的特徵。化療劑包括例如:烷化劑(例如,阿札胞苷(azacitidine)、氮芥類化合物:甲基二(氯乙基)胺(mechlorethamine)、苯丁酸氮芥(chlorambucil)、環磷醯胺(cyclophosphamide,Cytoxan®)、異環磷醯胺(ifosfamide)、苯達莫斯汀(bendamustine,Levact®)及美法侖(melphalan);亞硝基脲類化合物(nitrosoureas):鏈脲菌素(streptozocin)、卡莫斯汀(carmustine,BCNU)、洛莫斯汀(lomustine)及二氯乙基亞硝基脲(bischloroethylnitrosurea);磺酸烷酯類化合物(alkyl sulfonates):白消安(busulfan)、三嗪類化合物(triazines):達卡巴嗪(dacarbazine,DTIC)及替莫唑胺(Temodar®);次乙亞胺(ethylenimines):賽替派(音譯thiotepa)及六甲蜜胺(六甲基三聚氰氨);鉑類藥物(例如,順鉑)、卡鉑、賽特鉑(satraplatin,JM-216)、CI‑973及奧沙利鉑(oxalaplatin);抗代謝藥物(例如,5-氟脲嘧啶,5‑FU))、6-巰基嘌呤(6-mercaptopurine,6‑MP)、卡培他濱(capecitabine,Xeloda®)、阿糖胞苷(cytarabine,Ara-C®)、阿札胞苷(azacitidine)、地西他濱(decitabine,Dacogen®)、5-氮雜-2’-脫氧-胞苷(5-aza-2’-deoxy-cytidine)、胞苷類似物及低甲基化劑)、氟脲苷(floxuridine)、氟達拉濱(fludarabine)、吉西他濱(gemcitabine,Gemzar®)、羥基脲(hydroxyurea)、胺甲喋呤(methotrexate)及培美曲塞(pemetrexed,Alimta®);蒽環類藥物(例如,道諾柔比星(dauno-rubicin,道諾黴素、柔紅黴素或左柔比星(cerubidine))、阿黴素(doxorubicin,Adriamycin®)、泛艾黴素(epirubicin)、艾達黴素(idarubicin)、放線菌素-D(actinomycin-D)、博來黴素(bleomycin);絲裂黴素-C(mitomycin-C)及米托蒽醌(mitoxantrone,其亦作為拓樸異構酶II抑制劑);拓樸異構酶抑制劑(例如,拓樸異構酶I抑制劑:托普樂肯(topotecan)、愛萊諾迪肯(irinotecan,CPT‑11);拓樸異構酶II抑制劑:依託泊苷(etoposide,VP-16)、喜樹鹼(camptothecin)、替尼泊苷(teniposide)及米托蒽醌(mitoxantrone);核分裂抑制劑(例如,紫衫烷類:紫杉醇(Taxol®)及歐洲紫杉醇(docetaxel,Taxotere®));埃博黴素類(epothilones):依沙比酮(ixabepilone,Ixempra®);長春花生物鹼類,例如:長春花鹼(vinblastine,Velban®)、長春新鹼(vincristine,Oncovin®)及溫諾平(vinorelbine,Navelbine®);雌莫斯汀(estramustine,Emcyt®);嘌呤或嘧啶拮抗劑,例如6-巰基嘌呤、5-氟脲嘧啶、阿糖胞苷、克羅拉濱(clofarabine)及吉西他濱(gemcitabine);細胞催熟劑(例如,三氧化二砷(arsenic trioxide)及維甲酸(tretinoin));DNA修復酶抑制劑(例如,鬼臼脂素(podo-phyllotoxines)、依託泊苷(etoposide)、愛萊諾迪肯(irinotecan)、托普樂肯(topotecan)及替尼泊苷(teniposide);阻止細胞存活的酶(例如,天冬醯胺酶(asparaginase)及培門冬酶(pegaspargase));皮質類固醇類(例如,強體松(prednisone)、甲基培尼皮質醇(methylprednisolone,Solumedrol®)及地塞米松(dexamethasone,Decadron®));HDAC抑制劑(例如,羅米地辛(romidepsin,Istodax®)、伏立諾他(vorinostat,Zolinza®));其他抗代謝劑,例如L-天冬醯胺酶(L‑asparaginase,Elspa®)、2‑脫氧-D-葡萄糖(2‑deoxy-D-glucose)、甲基芐肼(procarbazine,Matulane®)及硼替佐米(bortezomib,Velcade®);其他細胞毒性劑(例如,雌莫斯汀磷酸(estramustine phosphate)、潑尼莫斯汀(prednimustine)及甲基芐肼(procarbazine));荷爾蒙(例如,泰莫西芬(tamoxifen)、亮丙瑞林(leuprolide)、氟他胺(flutamide)及甲地孕酮(megestrol));荷爾蒙促效劑或拮抗劑、部分促效劑或部分拮抗劑;單株抗體(例如,吉妥珠單抗奧唑米星(gemtuzumab ozogamicin,Mylotarg®)、奧英妥珠單抗奧唑米星(inotuzumab ozogamicin,CMC-544)、阿倫單抗(alemtuzumab)、利妥昔單抗(rituximab)及釔-90-依替莫單抗(yttrium‑90-ibritumomab tiuxetan);免疫調節劑(例如,沙利竇邁(thalidomide)及來那度胺(lenalidomide));激酶抑制劑,例如Bcr‑Abl激酶抑制劑(例如,AP23464、AZD0530、CGP76030、PD180970、SKI-606、伊馬替尼(imatinib)、達沙替尼(dasatinib,BMS354825))、尼羅替尼(nilotinib,AMN107)及VX680/MK‑0467(奧羅拉激酶抑制劑))。
可與BET抑制劑治療合併使用的附加抗癌治療包括手術、放射線療法(例如,伽瑪射線、中子束放射治療、電子束放射治療、質子治療、近程放射治療(brachytherapy)及全身性放射性同位素)、內分泌治療、生物反應調節劑(例如,干擾素、介白素及腫瘤壞死因子)、熱療法及冷凍療法,及可緩解任何負面作用的藥劑(例如,止吐劑)。
本案中提及的化療劑泛指化療劑及其衍生物,且根據本發明可思及和包括此等實施例(藥劑;藥劑或其衍生物)中的任一者。化療劑的「衍生物(derivative)」或「類似物」或其他化學部位包括,但不限於,結構類似於該化療劑或部位的化合物,或與該化療劑或部位屬於相同的概括化學分類。在某些實施例中,該化療劑或部位的衍生物或類似物保有與該化療劑或部位相似的化學性質或物理性質(包括例如,功能性)。
包含KDM4(i)化合物之藥學組成物的給藥可能替換或加入先前或目前給予的治療。例如,當使用一種藥學配方進行治療時,附加活性藥劑的給藥可以停止或減少,例如以較低的濃度或較長之給藥間隔給藥。在某些實施例中,可維持給予先前治療。在某些實施例中,維持先前的治療,直到活性藥劑的濃度達到足以提供療效的濃度為止。因此,兩種治療可先後或同時地合併使用。再者,KDM4(i)與一附加活性藥劑合併給藥可提供增效(synergistic)的治療結果。所提供的合併治療可同時給予或間隔一段時間而分多次給予。應瞭解,治療的精確劑量及時間可能隨著接受治療之病患的年齡、體重及健康狀況而改變,且可利用已知的試驗程序憑經驗而決定或由活體內或體外的試驗或診斷數據來決定。進一步瞭解到,就任何特定個體而言,應根據該個體的需要及依據實施或監督給予該配方之人士的專業判斷,隨時間調整具體的劑量方案。
當用於本文中,該等術語「受試者」或「病患」意指任何有關診斷、預後或治療癌症(例如,乳癌,特別是三重陰性乳癌)的受試者,特別是哺乳動物受試者。該等術語「受試者」或「病患」可包括如內文中所提及的任何人或非人動物。
當用於本文中,「治療(treat)」、「治療(treatment)」、「治療(treating)」、「減緩」、「改善」或「治療(treatment of)」可互換使用且大體是指治療上的益處或預防上的益處,例如降低疾病的潛在可能性、降低疾病的發生率或減輕疾病的嚴重性。例如,治療可意指當給予受試者藥物時,防止腫瘤進一步生長或惡化、或治癒或緩解至少一部分疾病症狀、跡象或原因的治療能力。此等術語意指獲得益處或期望結果(包括但不限於治療益處或預防益處)的方式。
「治療益處(therapeutic benefit)」大體上意指根除或緩解正接受治療的潛在疾病。藉由根除或緩解與該潛在疾病相關的一或更多種生理症狀,儘管該病患仍為該潛在疾病所苦,但在病患身上觀察到改善情形,亦為達到治療益處。因此,治療益處未必治癒特定癌症,而是包括下列最典型的結果:緩解;提高存活率;消除腫瘤;減輕癌症相關症狀;預防或減輕因發生癌症所造成的續發疾病、病症或狀況;或防止轉移。在預防益處方面,對具有發生特定疾病之風險的病患或告知有一或更多種疾病之生理症狀的病患投予組成物,即便尚未確診患有此疾病。
因此,當用於本文中時,「治療劑」意指任何施用給受試者以產生所期望之通常有益功效的治療活性物質。術語治療劑包括例如典型的低分子量治療劑,通常指小分子藥物;及生物製品,包括但不限於,抗體及抗體的功能活性部位、胜肽、脂質、蛋白質藥物、蛋白質綴合藥物、融合蛋白質、酶、核酸、核糖酶、遺傳物質、病毒、細菌、真核細胞及疫苗。治療劑亦可為前驅藥物。治療劑亦可為放射性同位素。治療劑可為藉由諸如光或超音波之能量形式活化的藥劑,或利用其他以全身性或局部給藥之循環分子而加以活化的藥物。此外,該治療劑可進行製藥調配。 實例 實例1:乳癌幹細胞株
在病患同意下從弗賴堡大學醫學中心(University Medical Centre Freiburg)取得病患的乳癌腫瘤材料(倫理規章(Ethics vote)307/13)。所有原始腫瘤皆來自在收集組織之前已接受化療的受試者,且被歸類為三重陰性。所有手術皆在弗賴堡大學醫學中心的婦產科部門進行。所有用來移植及石蠟包埋的腫瘤組織樣本皆是同一時間由病理學家自弗賴堡綜合癌症中心的腫瘤庫所取得。在加入本案中所述研究之前,從所有病患獲得書面知情同意書。
藉由機械性地分散該腫瘤材料及在添加有6單位之DNAse I(MACHERY-NAGEL GmbH & Co. KG,德國丟倫(Düren))及1毫克之Liberase™釋放酶(Roche Diagnostics GmbH,德國,曼海姆(Mannheim))的5毫升Dulbecco’s PBS緩衝液(DPBS,GIBCO®培養基,Thermo Fisher Scientific Inc公司,美國麻州沃爾瑟姆市)中於37°C下進行酶剪切1小時,而分離出原代乳癌幹細胞(BCSC)株。隨後,使用10毫升的DPBS稀釋該剪切液並使用細胞過濾網(40微米,Becton Dickenson,美國加州喀斯巴德)加以過濾,以及使用取自2毫升注射針筒的活塞搗碎留下的組織團塊。在以200g
離心5分鐘之後,拋棄上清液,並使用MEBM培養基(Gibco)清洗細胞團塊一次。若團塊中可看見紅血球,則於該細胞團塊中加入1毫升的ACK溶胞緩衝液(Gibco)。於室溫下培育一分鐘後,添加最多6毫升的MEBM,及以200g
離心該製備物5分鐘。拋棄上清液之後,將該細胞團塊重新懸浮在1毫升的MEBM中並以40微米的細胞過濾器過濾之。接著以200g
離心5分鐘,拋棄上清液,並將留下的細胞團塊放入乳腺幹細胞(MSC,見下文)培養基中。在Neubauer室(血球計數器)中計算細胞,隨後在使細胞在1:1混合MSC培養基與Matrigel®基質膠(Corning,#354230)的冰冷培養基中,以每孔2×104
個細胞的量,將細胞種入24-孔的低附著孔盤(CORNING®,Corning公司,美國紐約)中。使Matrigel®基質膠在37°C下固化30分鐘之後,於每孔中加入500微升的MSC培養基。於37°C的低氧環境(3%的O2
、5%的CO2
、92%的N2
)下培養該等細胞。當細胞穩定地以3D進行增殖時,以2D培養方式培養該等細胞以用於細胞擴增。
本文中所述的基礎MSC(乳腺幹細胞)培養基是添加有B27®無血清細胞培養補充劑(Gibco, #17504-044)、雙性黴素B(Sigma-Aldrich, #A2942)及青黴素-鏈黴素(Gibco, #15140122)的乳腺上皮基礎培養基(Gibco, #31331-028)。於此培養基中進一步添加表皮生長因子(f.c. 20奈克/毫升, #AF‑100-15,PeproTech公司,美國紐澤西州,羅基希爾(Rocky Hill))、肝素(f.c. 4微克/毫升,Sigma-Aldrich公司,#H3149)、纖維母細胞生長因子(f.c. 20奈克/毫升, PeproTech公司,#AF-100-18B)、健大黴素(f.c. 35微克/毫升,Gibco公司,#15750-045)及Rho激酶抑制劑(f.c. 500nM,Calbiochem® #555550,Merck KGaA,德國,達母斯塔特(Darmstadt)),以完成該MSC培養基。
為了在3D環境中將該等BCSC培養成球體,在24孔的低附著孔盤中以每孔2×104
個細胞將細胞接種在100微升的Matrigel®基質膠:MSC培養基為1:1之混合物中。使Matrigel®基質膠在37°C下固化30分鐘之後,於皿中加入500微升的MSC培養基。使細胞在如上述低氧環境中生長。兩天之後,加入1毫升的MSC培養基。每週以用於分解殘餘的Matrigel基質膠的Corning分散酶和用於球體解體的Accutase®細胞脫離溶液(Innovative Cell Technologies, Inc.美國加州聖地牙哥),來分裂(split)細胞。藉由Neubauer室計算細胞。
為了在2D環境中擴增BCSC,在10毫升的培養皿中以每盤4×105
個細胞將細胞接種在2毫升之含有2%Matrigel基質膠的MSC培養基(冰冷的)中。使Matrigel基質膠在37°C下固化30分鐘之後,於培養皿中加入8毫升的MSC培養基。使細胞在如上述低氧環境中生長。三天之後,更換培養基。在重新接種之前,每週使用Accutase溶液分離細胞以進行脫附及計數。
從Vector BioLabs公司(美國賓州,莫爾文(Malvern)取得高力價的腺病毒製備物。(在MSC培養基中)加入腺病毒顆粒,以使BCSC1細胞的感染複數(multiplicity of infection,MOI)為300及BCSC2細胞的MOI為150。 實例2:體外試驗
在甲基纖維素上進行癌幹細胞成球試驗,使用Accutase溶液使細胞脫附並計數細胞。在96孔超低附著孔盤(Corning, #3474)的各個孔中,將3×103
個單(single)BCSC1細胞及1×103
個單BCSC2細胞接種在含有1%甲基纖維素(Sigma-Aldrich,#M0512)的無血清MSC培養基中。7天後,計數所有大於四個細胞的球體以得到球體形成能力,及對於該經KDM4(i)治療細胞及對照組細胞兩者計數直徑超過50微米的球體。
在Matrigel基質膠中進行癌幹細胞成球試驗,使用Accutase溶液使細胞脫附並計數細胞。在96孔超低附著孔盤(Corning, #3474)的各個孔中,將1×103
個細胞(三份)及4×104
個的單BCSC1細胞及單BCSC2細胞接種在含有50%Matrigel基質膠的MSC培養基中。KDM4(i)的濃度如該等圖式中所示。7天後,針對具有1×103
個細胞之孔中的經KDM4(i)治療細胞及對照組細胞兩者,計數直徑超過50微米的球體。該些具有4×104
個細胞的孔則如所述般地進行分裂(split)及計數;由這些4×104
個細胞,如文中所述般一式三份地接種1×103
個的單BCSC1細胞及單BCSC2細胞以評估在無抑制劑存在下的繼代球體形成率。
進行劑量反應試驗,利用Accutase溶液分離作用使細胞脫附並計數細胞。用10微升之含2% Matrigel基質膠(354230, Corning)的MSC培養基塗覆黑色384孔盤(Greiner Bio-One公司,美國北卡羅來納州,門羅(Monroe))的該等孔。在37°C下培育30分鐘使Matrigel基質膠固化後,以每384-孔1×103
個的單BCSC1細胞,將細胞接種在40微升的培養基中。在常規培養條件下培養24小時後,將體積50微升的KDM4(i)抑制劑(化合物I,Celgene Quanticel Research, Inc.)加入每個孔中以達到最終指定濃度。在常規培養條件下培育96小時後,使用PBS沖洗該等細胞一次,並使用冰冷的甲醇於−20°C固定該等細胞至少15分鐘。以PBS進行另一清洗步驟之後,使用DAPI (Sigma-Aldrich)染色該等細胞及使用ScanR顯微鏡成像平台(Olympus Deutschland GmbH,德國,漢堡)讀取結果。測得每孔的總DAPI細胞核計數。
進行細胞增殖試驗,使用經穩定NLS-mCherry螢光信號(細胞核定位胜肽)標記的BCSC細胞進行此試驗。利用Accutase分離作用使細胞脫附並計數細胞。用10微升之含2% Matrigel基質膠的MSC培養基塗覆黑色384孔盤(Greiner)的每個孔。在37°C下培育30分鐘使Matrigel基質膠固化後,在40微升的培養基中接種1×103
個的單細胞/每孔。在常規培養24小時後,將體積50微升的KDM4(i)加至每個孔中以達到最終指定濃度。之後,使用基於ScanR顯微鏡成像平台(Olympus)開始進行第一次讀取,在60%濕度及5%之CO2
下,評估在每個孔之9個扇形區塊中的mCherry螢光細胞核。持續7天每24小時重複一次此讀取作業。使用ScanR軟體(Olympus)完成分析。
進行微陣列分析,依據製造商說明書使用GeneMATRIX通用RNA純化試劑套組(Roboklon GmbH,德國柏林)從病患材料,異種移植體及細胞中分離出總RNA。按製造商所述使用Ambion™ WT 表現試劑套組(Thermo-Fisher)處理所分離出的RNA,及按照標準程序使該RNA與Illumina®HT‑12 v.4表達微珠晶片進行雜合反應(Illumina, Inc.公司,美國加州聖地牙哥)。使用R/Bioconductor微珠陣列套裝軟體(PMID:17586828)版本2.22處理該等表現數據及對該表現數據進行分位數標準化。見Dunning等人所發表之論文,《微珠陣列: Illumina 微珠數據的 R 分類及方法 (Beadarray: R classes & methods for Illumina bead-based data)
》,23卷,Bioinformatics,2183頁(2007年)。經考慮僅使透過Bioconductor套裝軟體illuminaHumanv4.db(版本1.26)配對至EntrezID的引子組(probeset)進行進一步下游分析。在有多個引子組配對到同一個EntrezID的情況中,選擇在所有樣本中具有各別最高四分位距(interquartile range)的引子組。根據該等樣本之間的歐幾里德距離(Euclidean distance),該樹狀圖(見圖式)繪出完全連接階層集群(complete-linkage hierarchical clustering)。
實質上如所述地進行染色質免疫沈澱(ChIP)KDM4(i)試驗。見Metzger等人所發表之論文《LSD1 使抑制性組蛋白修飾標記去甲基化以促進雄性素受體依賴性轉錄作用 (LSD1 demethylates repressive histone marks to promote androgen receptor-dependent transcription)
》,437 Nature 436(2005年)。在不存在或存在5×10−10
M之KDM4(i)的情況下培養BCSC1細胞18小時。在收穫細胞前三天,依據製造商說明書,使用會表現抗KDM4A之shRNA或亂序(scrambled)對照shRNA (Ad-GFP-U6-hKDM4AshRNA及Ad-U6-RNAi- GFP,Vector Biolabs)的腺病毒來感染細胞。在GammaBind™ G-Sepharose™ (GE-Healthcare公司)上使用下列特異性抗體進行免疫沈澱:抗-KDM4A抗體(Schuele Lab. #5766,批號5766)、抗-H3K9me3抗體(#C15410056,批號A1675-001P, Diagenode)。根據標準方法從免疫沈澱而得的DNA製備出DNA庫。使用HiSeq 2000 (Illumina)定序該等ChIP-seq資料庫,及使用Bowtie2軟體(例如,約翰·霍普金斯大學,美國馬里蘭州巴爾的摩)將該等ChIP-seq資料庫配對(mapped)到hg19參考基因組中。見Langmead等人所發表之文獻,《短 DNA 序列與人類基因組的超快及記憶高效比對 (Ultrafast & memory-efficient alignment of short DNA sequences to the human genome)
》,10卷Genome Biol. R25(2009年)。使用波峰搜尋演算法MACS1.41版(ChIP-Seq之模型分析)(見例如,美國國家醫學圖書館的國家生物技術資訊中心)利用輸入數據(input)作為對照組來進一步分析數據。見Zhang等人所發表之文獻,《ChIP-Seq 之模型分析 (MACS)(Model-based analysis of ChIP-Seq (MACS))
》,9卷 Genome Biol.(2008年)。在進一步的分析中排除掉所有FDR大於1%的波鋒。使用唯一配對讀值(uniquely mapped read)來產生全基因組強度分佈(genome-wide intensity profile),並可使用整合式基因組查看器(Integrative Genomics Viewer ,IGV)基因組瀏覽軟體(例如,Broad Inst.研究所,美國麻薩諸塞州劍橋市)使該強度分佈可視化。見Thorvaldsdottir等人所發表之文獻,《整合性基因體查看器 (IGV) :高效基因體數據可視化及探查 (Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration)
》,14卷,Brief Bioinform.,178頁(2013年)。HOMER軟體(例如,聖地牙哥加利福尼亞大學)用來注釋波鋒、計算不同波鋒檔案之間的重疊部分及進行功能域(motif)搜尋。見Heinz等人所發表之文獻,《巨噬細胞及 B 細胞身份識別所需之譜系轉錄因子主要順式調控元件的簡單組合 (Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities)
》,38卷,Mol. Cell,576頁(2010年)。使用參考序列(RefSeq)資料庫(例如,美國國家醫學圖書館的國家生物技術資訊中心)及HOMER軟體界定及計算基因組特徵(啟動子、外顯子、內含子、3’UTR及基因間隔區)。
為測驗KDM4在細胞週期進程及細胞凋亡或壞死上的抑制效果,於不同時間點(24小時、48小時、72小時及96小時)使用50nM的KDM4(i)處理BCSC1細胞株及BCSC2細胞株。在接觸藥物之後,收集4×105
個細胞,並依據製造商說明書使用PI/RNase溶液(Cell Signaling Technol. #4087)用50微升的碘化丙啶(propidium iodide,PI)對該等細胞進行染色。使用BD LSR Fortessa及BD FACS Diva軟體(Becton Dickinson)分析細胞。使用FlowJo軟體第6版從1×105
個未被圈選(ungated)的細胞中測定處於亞G1期(subG1)、G0/G1期、S期及G2/M期之細胞的百分比。
為分析所建立之癌幹細胞標記的表現情形,如上述般使細胞脫附並計數細胞。使用FACS緩衝液(PBS+1%的BSA)沖洗1×105
個細胞,及在室溫下於黑暗中使用稀釋在FACS緩衝液中的下列抗體染色20分鐘:抗-CD24(eBioscience,46-0247;稀釋比例1:100)、抗-CD44(eBioscience,12-0441-81;稀釋比例1:1000)、抗‑EpCAM(eBioscience,660 50-9326;稀釋比例1:100)及抗-CD49f (eBioscience,46-0495;稀釋比例1:200)。使用BD LSR Fortessa及BD FACS Diva軟體(Becton Dickinson)分析細胞。
依照製造商說明書使用FITC Annexin V細胞凋亡偵測試劑套組I(BD Bioscience)偵測細胞凋亡。簡言之,使用0.05%的胰蛋白酶‑EDTA溶液收集細胞,清洗細胞,及在1×結合緩衝液(binding buffer)中將細胞稀釋至每毫升含1×106
個細胞。藉由在100微升之結合緩衝液的細胞中加入5微升的FITC-偶連抗體溶液及5微升的PI,在室溫下於黑暗中染色15分鐘。之後,加入400微升的結合緩衝液,並使用BD LSR Fortessa及BD FACS Diva軟體(Becton Dickinson)分析細胞。總共計數1×105
個細胞。使用FlowJo軟體第6版進行分析。 實例3:在帶有原位BC異種移植體之NOD/SCID小鼠中進行體內致腫瘤性試驗
所有小鼠的管理及實驗皆根據德國動物福利法規進行並經當地政府批准(動物使用計畫G13/114)。
使用異氟醚(isoflurane)吸入器麻醉NOD/SCID雌鼠(鼠齡4~5週)。在經除毛及消毒的腹部上切出小的矢狀切口(不超過1.0公分)以允許觸及兩側的乳腺#4。使腫瘤細胞各自與數種的1x106
個經輻照纖維母細胞(人類新生兒包皮纖維母細胞(NuFF)、p11、GlobalStem、GSC-3002)混合,並使之懸浮在1:1的Matrigel基質膠:MSC培養基之混合物中。用於每個乳腺的各移植體積為40微升(μL),該體積中含有既定數目的BCSC及1x106
個纖維母細胞。使用配有細針頭的1毫升針筒將該移植體注入該動物兩側之該#4乳腺的乳腺脂肪墊中。各移植體的所在位置遠離該乳腺中的淋巴結。使用5/0縫線(Ethicon,Z995)進行縫合以閉合手術切口。每週兩次監測動物們的動物體重及腫瘤生長情形,其利用測徑器(caliper)測量。使用下列公式計算腫瘤體積:4/3×π×r3
。
使用小動物高解析超音波系統(Vevo3100)及40MHz的換能器(MX550D,VisualSonics公司,加拿大多倫多)收集超音波測量值以用於監測腫瘤尺寸。為了建立3D腫瘤模型,使該換能器以0.076毫米(mm)的步長沿著該腫瘤自動移動。代表性的照片示出在治療開始及結束時使用Vevo LAB v.1.7.1軟體進行可視化後的定量腫瘤差異。
用於活體內治療時,在治療前一刻將KDM4(i)溶解在由50%之聚乙二醇(SIGMA)與50%之DPBS(pH=9,Gibco)所組成的溶劑中並施以超音波振盪(diagenode bioruptor公司)直到形成澄清溶液。當腫瘤直徑達到2毫米的可察覺尺寸時,將小鼠隨機分派至不同組別(n=8,每組)。藉由口服灌餵方式每日以10毫克/公斤的劑量對NOD/SCID小鼠施用該抑制劑。對照動物僅接受溶劑。每週兩次監測動物們的體重及腫瘤生長情形,其利用測徑器測量。
在免疫組織化學染色方面,立即以福馬林(formalin,10%)固定組織檢體。以福馬林固定並以石蠟包埋之後,切取2微米厚的切片並放置在蓋玻片上。所有蓋玻片在58°C的乾燥箱中存放兩天,隨後使用二甲苯去除石蠟及用乙醇進行水合。使用即用型抗體對人腫瘤組織及對應的移植腫瘤組織進行染色,該等抗體為雌激素受體蛋白抗體(兔抗人雌激素受體α單株抗體,殖株(clone) EP1,代碼IR084)、黃體固酮受體蛋白抗體(小鼠抗人黃體固酮受體單株抗體,殖株PgR 636,代碼IR068)、HER2抗體(兔抗人c-erbB-2致癌蛋白多株抗體,代碼A0485)、Ki-67抗體(小鼠抗人Ki-67抗原之單株抗體,殖株MIB-1,代碼IR626)、波形蛋白抗體(小鼠抗波形蛋白單株抗體,殖株V9,代碼IR630)、E-鈣黏蛋白抗體(小鼠抗人E-鈣黏蛋白單株抗體,殖株NCH-38,代碼IR059)及細胞角蛋白8/18抗體(兔抗人細胞角蛋白8/18單株抗體,殖株EP17/EP30,代碼IR094)。對於(宿主依賴性)辣根過氧化酶偵測EnVision®Flex過氧化酶阻斷試劑(DAKO公司,SM801),使用EnVision®Flex+兔抗體(連接子)(DAKO公司,K8019)或EnVision® Flex+小鼠抗體(連接子)(DAKO公司,K8021)及EnVision®Flex/HRP(DAKO公司,SM802)。先使用礬紫(hemalum)進行對比染色,隨後加上蓋玻片。使用源自病患的生理乳腺進行ER、PR、Ki-67(細胞核染色)、細胞角蛋白8/18及E-鈣黏蛋白(細胞質膜染色)染色以作為內部陽性對照組。使用乳腺周圍的肌上皮層作為波形蛋白的內部對照組。從HER2陽性乳癌病患(依據Ref20
評分為3分)取得組織檢體以作為每個HER2染色場合(staining session)的外部陽性對照組。三重陰性乳癌定義為ER、PR及HER2皆為陰性(評分<2分)的乳癌。見Goldhirsch等人,《患有早期乳癌之女性個人化治療: St Gallen 早期乳癌初期治療國際專家共識錦集
(Personalizing the treatment of women with early breast cancer: highlights of the St Gallen Int’l Expert Consensus on Primary Therapy of Early Breast Cancer 2013)
》,24卷,Ann. Oncol.2206頁(2013年)。
如以下文獻所述般分離RNA。見Metzger等人,《甲基化之 KDM1A 與 CHD1 的組裝驅動雄性素受體依賴性轉錄作用及易位 (Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation)
》,23卷,Nat. Str’l Mol. Biol.,132頁(2016年)。根據供應商操作程序使用Abgene SYBR Green PCR試劑套組(Invitrogen)進行定量RT-PCR,使用HPRT進行標準化並使用HPRT.Id的引子序列。下表中示出用於VCAN、PRR5、ATF4、EGR1、FST、EGFR、RUNX1的引子:
在收穫細胞以用於進行RNA定序(RNA-seq)之前,在不存在或存在有5x10−10
M之所述KDM4(i)的情況下培養BCSC1細胞18小時。在DKFZ之定序核心設施上使用標準Illumina程序定序RNA樣本以建立原始序列檔案(.fastq檔案)。使用TopHat軟體第2版將此等讀取序列(reads)與人基因組hg19版本進行排比。使用Homer軟體(用來分析RNA)計算該已排比的讀取序列,及使用EdgeR及DESeq版本1.8.3來鑑定差異表現(DEG)。將數據存在GSE下。 實例4:具有取代基之吡啶衍生物的化學合成
除非另有註解,否則所使用的試劑及溶劑是從市售供應商處所取得。無水溶劑及烤箱乾燥的玻璃器皿是用於對水分及/氧氣敏感的合成轉化反應。產率未經最佳化。反應時間為粗估值並未最佳化。除非另有註明,否則在矽膠(silica gel)上進行管柱色層分析及薄層色層分析(TLC)。光譜以ppm(δ)標示,及耦合常數J以赫茲(Hertz)表示。就質子光譜而言,使用溶劑波峰作為參考波峰。可例如根據美國專利第9,447,046號中所描述的方法進行3-({[6-[甲基(苯基)胺基]-1,2,3,4-四氫萘-1‑基]甲基}胺基)吡啶-4-羧酸(化合物I)的化學合成。簡言之,可根據以下製備方法來製備化合物I: 製備產物1a:6-溴-1,2,3,4-四氫萘-1-酮 (6-bromo-1,2,3,4-tetrahydronaphthalen-1-one)。
於0°C下將含NaNO2
(2.35克,34毫莫耳)的水(10毫升)溶液逐滴加入含6-胺基-1,2,3,4-四氫萘-1-酮(5.0克,31毫莫耳)的25%之HBr(16毫升)溶液中。隨後於0°C下將該懸浮液轉移至在48%HBr(30毫升)中含CuBr(8.9克,62毫莫耳)的攪拌混合物中。使所產生的混合物回溫至室溫並攪拌1小時。使用EtIAc萃取該混合物,以(Na2
SO4
)乾燥並濃縮。利用矽膠色層分析(0%~60%的EtOAc/Hex)純化該殘餘物以得到5.6克(80%)的標題化合物(淺黃色油狀物)。1
H NMR (400 MHz, CDCl3
):δ 2.10-2.16 (2H, m), 2.64 (2H, t, J=6.4 Hz), 2.94 (2H, t, J=6.0 Hz), 7.42 (1H, s), 7.44 (1H, s), 7.87 (1H, d, J=8.9 Hz)。計算出C10
H9
BrO的[M+H]:225、227;找到:225、227。 製備產物1b:6-[甲基(苯基)胺基]-1,2,3,4-四氫萘-1-酮 (6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-one)。
在含6-溴-1,2,3,4-四氫萘-1-酮(2.0克,8.9毫莫耳)的甲苯(20毫升)溶液中加入N-甲苯胺(N-methylaniline,960毫克,8.9毫莫耳)、Cs2
CO3
(4.4克,13.4毫莫耳)、BINAP(310毫克,0.5毫莫耳)及Pd(OAc)2
(110毫克,0.5毫莫耳)。在N2
下於100°C攪拌該混合物過夜。過濾及濃縮該混合物,及使用矽膠色層分析(30%~80%的EtOAc/Hex)純化該殘餘物以得到1.52克(68%)的標題化合物(淺棕色油狀物)。計算出C17
H17
NO的[M+H]:252;找到:252。 製備產物1c:5-(胺甲基)-N-甲基-N-苯基-7,8-二氫萘-2‑胺,氯化氫 (5-(aminomethyl)-N-methyl-N-phenyl-7,8-dihydronaphthalen-2‑amine, hydrochloride)。
於室溫下在含有製備產物1b(1.52克,6.0毫莫耳)及ZnI2
(150毫克)的甲苯(20毫升)溶液中加入TMSCN(1.2克,12毫莫耳)。在60°C下加熱該混合物持續2小時,隨後使之冷卻至室溫並添加THF(20毫升)以稀釋該混合物。於室溫下緩慢地加入LAH溶液(5毫升,於THF中的濃度為2.4 M,12毫莫耳),及攪拌該溶液持續0.5小時。添加EtOAc(10毫升)停止該反應,且隨後加入水(1毫升)及1M的NaOH水溶液(1毫升)。乾燥(用Na2
SO4
)並濃縮該溶液以得到1.52克(89%)的白色固體狀的粗製1-(胺甲基)-6-[甲基(苯基)胺基]-1,2,3,4-四氫-萘-1-酚 (1-(aminomethyl)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydro-naphthalen-1-ol)。
在含此中間產物(1.52克,5.4毫莫耳)的甲醇(20毫升)溶液中打入乾HCl氣體氣泡持續2分鐘同時加以冷卻以維持反應溫度≤30°C。於室溫下攪拌該混合物1小時。在減壓下蒸發甲醇以得到1.4克(98%)之標題化合物的HCl鹽。計算出C18
H20
N2
的[M+H]:265; 找到:265。 製備產物1d:5-(胺甲基)-N-甲基-N-苯基-5,6,7,8‑四氫萘‑2‑胺 (5-(aminomethyl)-N-methyl-N-phenyl-5,6,7,8‑tetrahydronaphthalen‑2‑amine)。
於室溫在N2
環境下在含製備產物1c(1.4克,5.3毫莫耳)的MeOH(30毫升)與濃HCl(三滴)的溶液中加入10%的Pd/C(200毫克)。於50 psi的氫氣下於室溫攪拌該懸浮液16小時。該反應混合物經由矽鈣石(celite)加以過濾,使用飽和Na2
CO3
調整至pH約8~9,以(Na2
SO4
)進行乾燥並加以濃縮而得到830毫克(59%)的標題化合物(黃色油狀物)。計算出C18
H22
N2
的[M+H]:267;找到:267 製備產物1e:3-[({6-[甲基(苯基)胺基]-1,2,3,4-四氫萘-1‑基}甲基)胺基]吡啶-4-羧酸甲酯 (methyl 3-[({6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1‑yl}methyl)amino]pyridine-4-carboxylate)。
在含製備產物1d(500毫克,1.88毫莫耳)的DMA(12毫升)溶液中加入3-氟異菸鹼酸甲酯(methyl 3-fluoroisonicotinate,300毫克,1.93毫莫耳)。於170°C下在微波中攪拌該反應混合物1小時,隨後倒入水中並以EtOAc進行萃取。該等有機層用鹽水加以清洗,以(Na2
SO4
)進行乾燥並濃縮。利用矽膠色層分析(20%~80%的EtOAc/Hex)純化該殘餘物以得到200毫克(26%)的標題化合物(黃色油狀物)。計算出C25
H27
N3
O2
的[M+H]:402;找到:402。 製備產物1f:3-({[(1S
)-6-[甲基(苯基)胺基]-1,2,3,4-四氫萘-1‑基]甲基}胺基)吡啶-4-羧酸甲酯 (methyl 3-({[(1S
)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1‑yl]methyl}amino)pyridine-4-carboxylate)。及 製備產物2f:3-({[(1R
)-6‑[甲基(苯基)胺基]-1,2,3,4-四氫萘-1‑基]甲基}胺基)吡啶-4‑羧酸甲酯 (methyl 3-({[(1R
)-6‑[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1‑yl]methyl}amino)pyridine-4‑carboxylate)。
利用掌性HPLC(管柱:Chiralcel IA,250毫米*4.6毫米,5微米;移動相:Hex:EtOH=85:15;F:1.0毫升/分鐘;W:230奈米;T=30°C)分離製備產物1e(200毫克),以得到95毫克(47%)的製備產物1f(6.54分鐘)及92毫克(46%)的製備產物2f(7.91分鐘),兩者各為黃色油狀物。 製備產物1g:3-({[(1S
)-6-[甲基(苯基)胺基]-1,2,3,4-四氫萘-1-基] 甲基}胺基)吡啶-4-羧酸 (3-({[(1S
)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl] methyl}amino)pyridine-4-carboxylic acid)。
於室溫下在含製備產物1f(95毫克,0.24 毫莫耳)的THF(6毫升)與H2
O(2毫升)溶液中加入LiOH.H2
O(31毫克,0.72毫莫耳),並攪拌該反應混合物過夜。濃縮該反應混合物以去除THF,及用水稀釋該殘餘物並使用0.1N的HCl水溶液進行酸化至達到pH約3~4。利用過濾收集該沈澱物及用EtOAc/醚清洗該沈澱物。於真空下乾燥該固體以獲得52毫克(56%)的標題化合物(黃色固體)。1
H NMR (400 MHz, DMSO-d6): δ 1.64-1.67 (1H, m), 1.77-1.84 (3H, m), 2.65-2.68 (2H, d, J=5.6 Hz), 3.04-3.07 (1H, m), 3.21 (3H, s), 3.41-3.47 (1H, m), 3.56-3.60 (1H, m), 6.78-6.92 (5H, m), 7.21-7.25 (3H, m), 7.55 (1H, d, J=5.2 Hz), 7.82 (1H, d, J=5.2 Hz), 8.36 (1H, s)。計算出C24
H25
N3
O2
的[M+H]:388;找到=388。 製備產物2g:(3-({[(1R
)-6-[甲基(苯基)胺基]-1,2,3,4-四氫萘-1‑基]甲基}胺基)吡啶-4-羧酸(3-({[(1R
)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1‑yl]methyl}amino)pyridine-4-carboxylic acid)(化合物I)。
根據製備產物1g之程序由製備產物2f所製備而成的標題化合物產率為53%。1
H NMR (400 MHz, DMSO-d6):δ 1.64-1.68 (1H, m), 1.77-1.84 (3H, m), 2.65-2.68 (2H, d, J=5.6 Hz), 3.04-3.07 (1H, m), 3.21 (3H, s), 3.41-3.47 (1H, m), 3.56-3.60 (1H, m), 6.78-6.92 (5H, m), 7.21-7.25 (3H, m), 7.56 (1H, d, J=4.8 Hz), 7.82 (1H, d, J=5.2 Hz), 8.36 (1H, s)。計算出C24
H25
N3
O2
的[M+H]:388;找到:388。
無
第1A圖至第1H圖示出乳癌幹細胞(BCSC)特性分析的相關數據,及源自乳癌幹細胞的細胞株及異種移植體。第1A圖示出在免疫低下小鼠體內進行BCSC細胞異種移植體之有限稀釋試驗的生長數據。第1B圖示出原始BCSC1病患腫瘤及BCSC1異體移植腫瘤的免疫組織化學染色分析(immunohistochemical analyses),其包括蘇木素及伊紅(hematoxylin及eosin,H & E)、抗-CK8、抗Ki67、抗-E-鈣黏蛋白(anti-E-cadhrtin)及抗-波形蛋白(anti-vimentin)的染色。比例尺:100微米(μm)。第1C圖示出原始BCSC1病患腫瘤、BCSC1異種移植腫瘤及陽性對照組(positive control)樣本的抗-ER抗體、抗-PR抗體及HER2免疫組織化學染色。ER:雌激素受體(estrogen receptor);PR:黃體固酮受體(progesterone receptor);HER2:人表皮生長因子受體2;比例尺:100微米。第1D圖提供以集群樹狀圖所呈現的RNA微陣列數據之非監督性階層式集群分析(unsupervised hierarchical clustering analysis)。樣本為原始病患腫瘤BCSC1、BCSC2、BCSC3及BCSC4;所衍生的BCSC1~BCSC4細胞株;及源自該等BCSC細胞株1~BCSC細胞株4的BCSC1~BCSC4異種移植腫瘤。第1E圖示出在3D(上圖)及2D(下圖)環境下培養出BCSC1細胞之細胞表現型的示例性圖式。比例尺為100微米。第1F圖示出在甲基纖維素試驗中之BCSC1細胞的球體形成能力(n=3)。使用單因子變異數分析(one-way ANOVA)來進行比較。數據代表平均值±平均值標準誤差(means ± s.e.m.)。*P<0.05,**P<0.01,***P<0.001。第1G圖及第1H圖示出利用FACS分析BCSC1細胞中之癌症幹細胞標記的示例性表現模式(n=3):第1G圖示出CD24及CD44標記的表現情形;第1H圖示出CD49f及EpCAM標記的表現情形。
第2A圖至第2F圖圖示KDM4抑制劑(「KDM4(i)」)是BCSC1細胞的強力抑制劑。第2A圖示出抗-KDM4A、抗-KDM4B、抗-KDM4C、抗-KDM4D及抗-微管蛋白的西方墨點圖。樣本為取自於HEK293T細胞;經會表現KDM4A、KDM4B、KDM4C或KDM4D之表現質體所轉染的HEK293T細胞;BCSC1細胞;及BCSC2細胞的溶胞產物(lysate)。第2B圖示出KDM4(i)之具體實施例「化合物I」的化學式/結構。第2C圖示出在化合物I存在或不存在下所培養出之BCSC1細胞的示例性細胞增殖試驗(n=3)。●:溶劑;■:10nM的化合物I;▲:50nM的化合物I;數據代表平均值±標準偏差(means ± s.d.)。第2D圖是KDM4(i)作用在BCSC1細胞上的示例性劑量反應曲線(n=3)。數據代表平均值±標準偏差(means ± s.d.)。第2E圖示出在非貼附性生長試驗(anchorage-independent growth assay)中於不存在或存在所指示濃度之KDM4(i)情況下的BCSC1之3D球體形成能力(n=3);其中0:溶劑;10:10nM之化合物I;50:50nm之化合物I。第2F圖示出BCSC1細胞在Matrigel基質膠中的原代(primary,1°球體)及繼代(secondary,2°球體)球體形成能力(n=3);其中10:10nM之化合物I;50:50nM之化合物I;使用單因子變異數分析進行比較;數據代表平均值±平均值標準誤差(means±s.e.m.)。* P<0.05,* * P<0.01,* * * P<0.001。
第3A圖至第3J圖示出KDM4(i)能夠透過EGFR調控而針對BCSC作用。第3A圖為圓形圖,該圓形圖示出以KDM4(i)處理後在BCSC1細胞中受到不同調控的基因數目:有或沒有暴露於KDM(i)下的BCSC1細胞的轉錄體(580個基因,p<1e-5):上調的基因有254個及下調的基因有326個。第3B圖的圓形圖示出以染色質免疫沈澱定序分析(ChIP-seq)測定BCSC1細胞中之KDM4A的基因分佈:KDM4A波峰(172692個波峰):12.5%的啟動子;40.5%的基因間隔區;41.0%的內含子;3.3%的外顯子;及2.7%的3’UTR。第3C圖為文氏圖(Venn diagram),該文氏圖示出在啟動子區域上出現KDM4A的基因與該些經KDM4(i)處理後在BCSC1細胞中受到不同調控之基因間的交集及數目。超幾何試驗(hypergeometric test)計算出重疊部分的顯著性(c;p<1e-5)。第3D圖示出KEGG路徑分析(路徑富集分析/共同路徑)(針對第3C圖中所述419個基因的集合
進行路徑富集)。第3E圖反映出mRNA表現程度分析(mRNA level analysis),更明確而言,是反映出在無(-)KDM4(i)及存在(+)KDM4(i)情況下所培養的BCSC細胞中發現之mRNA表現程度的熱圖。該KDM4A的37個直接目標基因代表第3D圖中所示所有路徑的共同基因印記(gene signature)。第3F圖是在KDM4(i)不存在(黑色長條)及存在(灰色長條)下培養BCSC1細胞所取得之樣本中的表現分析條形圖(n=3)。利用雙尾司圖頓檢驗法(two-tailed Student’s test)進行檢定,數據代表平均值±標準偏差,* * * p<0.0001;* * p<0.001。第3G圖及第3H圖是使用以下溶胞產物所產生的抗-EGFR、抗-KDM4A及抗-微管蛋白之西方墨點照片:在不存在(-)及存在(+)KDM4(i)下所得之BCSC1細胞的溶胞產物(第3G圖);或經對照用shRNA(對照組)或抗-KDM4A shRNA處理之BCSC1細胞的溶胞產物(第3H圖)。第3I圖之圖式示出根據在存在(灰色)或不存在(黑色)KDM4(i)下所培養的BCSC1細胞中之KDM4A波峰附近的H3K9me3染色質免疫沈澱序列(H3K9me3 ChIPseqs)進行定序讀取密度(sequencing read density)的統合分析(meta-analysis)。進行超幾何試驗以計算出該等重疊部分的顯著性(p<1e-5)。第3J圖示出在不存在(深色)或存在(淺色)KDM4(i)情況下之BCSC1細胞的ChIP-Seq軌跡分析。經標準化後的H3K9me3表現程度軌跡位在EGFR啟動子處。
第4A圖至第4F圖示出KDM4(i)抑制來自BCSC1細胞的異種移植腫瘤生長。連續21天使用溶劑或KDM4(i)治療帶有BCSC1異種移植腫瘤的小鼠。第4A圖是經21天治療之後,從個別動物身上所取出之示例性異種移植BCSC1腫瘤的照片。第4B圖之圖式繪出腫瘤隨時間的發展情況,測量單位為立方毫米(mm3
)(n=11)(溶劑);(n=12)(KDM4(i)治療)。數據代表平均值±平均值標準誤差。第4C圖示出實驗結束時的腫瘤重量(n=11(溶劑),n=12(KDM4(i)治療過))。藉由單因子變異數分析進行比較。數據=平均值±平均值標準誤差。*P<0.05,**P<0.01,***P<0.001。第4D圖示出腫瘤的示例性影像;及第4E圖為腫瘤體積大小的條形圖,圖中數據是在治療開始時(第0天)及治療21天之後(第21天)利用超音波影像所取得(n=11(溶劑),n=12(KDM4(i)治療)。使用單因子變異數分析進行比較。數據代表平均值±平均值標準誤差。*P<0.05,**P<0.01,***P<0.001。第4F圖為示出BCSC1異種移植體之表現分析的條形圖。樣本得自於經溶劑(-)或KDM4(i)(+KDM4(i))所治療之小鼠的BCSC1異種移植腫瘤。利用雙尾司圖頓檢驗法進行檢定,誤差線為標準偏差(s.d.);生物重複次數(n=3),***p<0.0001;**p<0.001。
第5A圖至第5G圖圖示BCSC2細胞及異種移植體概括說明了原始腫瘤病患。第5A圖繪示使用BCSC2異種移植體在免疫低下小鼠模型中進行有限稀釋/BCSC2異種移植體形成試驗的示例性生長曲線。第5B圖示出蘇木素及伊紅(H & E)、抗-CK8、抗-Ki67、抗-E-鈣黏蛋白及抗-波形蛋白的免疫組織化學染色。樣本為原始BCSC2病患腫瘤及BCSC2異種移植腫瘤。第5C圖示出原始BCSC2病患腫瘤及BCSC2異種移植腫瘤的抗-ER、抗-PR及HER2免疫組織化學染色照片。ER:雌激素受體;PR:黃體固酮受體;HER2:人表皮生長因子受體2;比例尺:100微米。第5D圖示出在3D及2D環境中所培養出之BCSC2細胞的示例性照片。第5E是示出在甲基纖維素試驗中BCSC2細胞之球體形成能力(n=3)的條形圖。藉由單因子變異數分析進行比較;數據代表平均值±平均值標準誤差;* P<0.05,* * P<0.01,* * * P<0.001。第5F圖及第5G圖為利用FACS分析BCSC2細胞中之下列癌症幹細胞標記(CSC marker)的示例性表現模式(n=3):CD24及CD44(第5F圖);及CD49f和EpCAM(第5G圖)。
第6A圖至第6F圖示出KDM4(i)是BCSC2細胞的強力抑制劑。第6A圖為反映出細胞增殖試驗之圖式,於該試驗中,是在KDM4(i)不存在(●)或存在有10nm(■)或50nm(▲)之KDM4(i)情況下培養BCSC2細胞。第6B圖為繪示KDM4(i)作用在BCSC2細胞上的示例性劑量反應曲線(n=3)。數據代表平均值±平均值標準誤差。第6C圖是在非貼附性生長試驗中於KDM4(i)不存在(左側長條)或存在有10nM(中間長條)或50nM(右側長條)之KDM4(i)情況下的BCSC2球體形成之條形圖(n=3)。第6D圖是BCSC2細胞在Matrigel基質膠中之原代(primary)及繼代(secondary)球體形成能力(n=3)的條形圖。對於首週(primary week),在KDM4(i)不存在(-)或存在有(50nM)之KDM4(i)的情況下培養細胞。藉由單因子變異數分析進行比較。數據代表平均值±平均值標準誤差。*P<0.05,**P<0.01,***P<0.001。第6E圖及第6F圖之圖式示出利用FACS分析在不存在有KDM4(i)(溶劑)或存在有KDM4(i)之情況下的BCSC1細胞(第6E圖)及BCSC2細胞(第6F圖)的細胞凋亡試驗(n=3)。數據代表平均值±平均值標準誤差。
第7A圖至第7K圖圖示出KDM4(i)的一實施例透過EGFR調控而針對BCSC2作用。第7A圖為BCSC1細胞及KDM4A位置的文氏圖,該文氏圖示出在對照組BCSC1細胞(對照組(172639))中及經會表現抗KDM4A之shRNA的腺病毒感染後的BCSC1細胞(KDM4A KD(3215))中的位置數目,並顯示有1110個位置重疊。第7B圖及第7C圖示出BCSC細胞的增殖試驗數據,更具體而言,是在不存在厄洛替尼(溶劑)及存在有10μM厄洛替尼(音譯Erlotinib)情況下的BCSC1細胞(第7B圖)及BCSC2細胞(第7C圖)的示例性增殖試驗(n=3)。數據代表平均值±平均值標準誤差(means ± s.e.m.)。第7D圖及第7E圖是BCSC1細胞(第7D圖)及BCSC2細胞(第7E圖)暴露在厄洛提尼下的示例性劑量反應圖(n=3)。數據代表平均值±平均值標準誤差(means ± s.e.m.)。第7F圖及第7G圖示出在非貼附性生長試驗中於不存在厄洛替尼(左側長條)及存在有1μM厄洛替尼(中間長條)或10μM厄洛替尼(右側長條)情況下之BCSC1(第7F圖)及BCSC2(第7G圖)的3D球體形成能力。藉由單因子變異數分析來進行比較;平均值±s.e.m.;*P<0.05,**P<0.01,***P<0.001。第7H圖及第7I圖示出抗-EGFR、抗-KDM4A及抗-微管蛋白的西方墨點圖。樣本是來自於在不存在或存在KDM4(i)情況下所培養之BCSC2細胞的溶胞產物(第7H圖);或經用shRNA(Ctrl,對照組)對照或抗KDM4A之shRNA處理後之BCSC2細胞的溶胞產物(第7I圖)。第7J圖為兩個圓形圖,該兩圓形圖示出以染色質免疫沈澱定序(ChIP-seq)分析測定的在沒有KDM4(i) (H3K9me3波峰:141,722個波峰)或存在有KDM4(i) (H3K9me3波峰:144,266個波峰)情況下在BCSC1細胞中之H3K9me3的基因分佈:溶劑:6.2%的啟動子、47.3%的基因間隔區、41.2%的內含子、2.8%的外顯子及2.4%的3’UTR;+KDM4(i):6.2%的啟動子、47.7%的基因間隔區、40.7%的內含子、2.9%的外顯子及2.4%的3’UTR。第7K圖為文氏圖,該文氏圖示出在沒有KDM4(i)或存在有KDM4(i)情況下所培養之BCSC1細胞中的KDM4A與H3K9me3位置之間的交集及數目。進行超幾何試驗以計算出該等重疊部分的顯著性(i;p<10-50
)。
第8A圖至第8G圖示出經連續21天使用溶劑或KDM4(i)治療帶有BCSC2異種移植腫瘤的小鼠,KDM4(i)抑制了該等小鼠體內之異種移植腫瘤的生長。第8A圖是經21天治療之後,從個別動物身上所取出之示例性異種移植BCSC2腫瘤的照片。第8B圖之圖式示出腫瘤的發展情況(測量單位為立方毫米,mm3
)(n=6)。數據代表平均值±s.e.m。第8C圖示出為期21天之實驗結束時的腫瘤重量條形圖(n=6)。藉由單因子變異數分析進行比較;數據代表平均值±s.e.m。*P<0.05,**P<0.01,***P<0.001。第8D圖示出腫瘤的示例性影像;及第8E圖是在治療開始時(第0天)及治療21天之後(第21天)利用超音波影像取得所有腫瘤的體積量化條形圖(n=6)。藉由單因子變異數分析進行比較。數據代表平均值±s.e.m.。*P<0.05,**P<0.01,***P<0.001。第8F圖及第8G圖示出在使用溶劑或KDM4(i)進行連續21天的治療時段內,帶有BCSC1異種移植腫瘤(第8F圖)或帶有BCSC2異種移植腫瘤(第8G圖)之小鼠的體重。
第9圖呈現一系列有關KDM4結構及功能的圖解。(A)是四種KDM4蛋白的概要結構。JmjN結構域對於JmjC催化中心的活性來說是必要的。(B)示出KDM4作為去甲基酶或與酶催化活性無關的功能模式。(C)示出在克氏循環(Krebs cycle)中的SDH、FH及IDH。當SDH或FH突變時,琥珀酸(Succinate)會累積,而新效型(neomorphic)IDH突變導致產生2-羥基戊二酸(2-hydroxyglutarate)。此圖是從Berry及Janknecht發表在Cancer Res.期刊73卷(10期)2936頁(2013年)中之論文「KDM4/JMJD2組蛋白去甲基酶:癌細胞中的表觀遺傳調節因子(KDM4/JMJD2 Histone Demethy1ases:Epigenetic Regulators in Cancer Cells)」複製而來。
國內寄存資訊 (請依寄存機構、日期、號碼順序註記) 無
國外寄存資訊 (請依寄存國家、機構、日期、號碼順序註記) 無
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