CN110913854B - mitoketoscin:靶向癌细胞中酮代谢的基于线粒体的治疗剂 - Google Patents
mitoketoscin:靶向癌细胞中酮代谢的基于线粒体的治疗剂 Download PDFInfo
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- CN110913854B CN110913854B CN201880042546.XA CN201880042546A CN110913854B CN 110913854 B CN110913854 B CN 110913854B CN 201880042546 A CN201880042546 A CN 201880042546A CN 110913854 B CN110913854 B CN 110913854B
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Abstract
本公开涉及与ACAT1/2和OXCT1/2中的至少一种结合并抑制线粒体ATP产生的化合物,在本文中称为mitoketoscin。公开了筛选用于线粒体抑制和抗癌性质的化合物的方法。还描述了使用mitoketoscin预防或治疗癌症、细菌感染和致病性酵母的方法,以及使用mitoketoscin提供抗衰老益处的方法。还公开了特定的mitoketoscin化合物。
Description
领域
本公开涉及mitoketoscin——与ACAT1/2和OXCT1/2中的至少一种结合并抑制线粒体ATP产生的非致癌化合物,以及鉴定mitoketoscin的方法,使用抑制剂靶向癌症干细胞、靶向细菌和致病性酵母并提供抗衰老益处的方法,以及含有一种或多种mitoketoscin作为活性成分用于治疗癌症、细菌感染、酵母感染和老化的药物组合物。
背景技术
研究人员努力开发新的抗癌治疗方法。常规的癌症疗法(例如辐射、烷化剂如环磷酰胺和抗代谢物如5-氟尿嘧啶)已经尝试通过干扰参与细胞生长和DNA复制的细胞机制来选择性地检测和根除快速生长的癌细胞。其他癌症疗法使用选择性结合快速生长癌细胞上的突变肿瘤抗原的免疫治疗(例如单克隆抗体)。不幸的是,在这些治疗之后肿瘤经常在相同或不同的部位复发,表明并非所有癌细胞都被根除。复发可能是由于化疗剂量不足和/或出现对治疗有抗性的癌症克隆。因此,需要新的癌症治疗策略。
酮类(3-羟基丁酸酯、乙酰乙酸酯和丙酮)是高能线粒体燃料;它们在热量限制、禁食和/或饥饿期间由肝细胞天然产生。在营养缺乏期间,分泌到血液中的酮体随后被导向大脑,其中神经元将它们转化回乙酰辅酶A(乙酰CoA),因此它们可以作为能源被有效地再利用。用于这种酮再利用过程的两种最关键的神经元酶是OXCT1/2和ACAT1/2,因为它们直接涉及酮体向乙酰CoA的转化。Martinez-Outschorn等人,Nat Rev Clin Oncol 2017;14(1):11-31。
本发明人表明,类似的“酮穿梭(ketone-shuttle)”也存在于人类肿瘤中,由此生酮的癌相关成纤维细胞(CAF)局部产生酮体,以供在相邻人乳腺癌细胞中再利用。Martinez-Outschorn等人,Cell Cycle 2012;11(21):3956-63。为了进一步支持这种“代谢偶联(metabolic-coupling)”假说,本发明人发现ACAT1/2或OXCT1/2在MDA-MB-231乳腺癌细胞中的重组过表达确实足以促进肿瘤生长和肺转移。这些数据提供了酮体再利用可以帮助驱动肿瘤进展和转移的遗传证据。
发明内容
鉴于上述背景,似乎酶ACAT1/2和OXCT1/2可以是真正的代谢致癌基因。因此,本公开的目的是证明酮再利用在许多癌症的增殖和维持中起关键作用。本公开的另一个目的是提供用于鉴定与ACAT1/2和OXCT1/2中的至少一种结合并抑制线粒体ATP产生的mitoketoscin——非致癌化合物的方法。本公开的另一个目的是鉴定具有抗癌和抗生素性质的mitoketoscin。本公开的另一个目的是鉴定具有抗衰老性质的mitoketoscin。本公开的另一个目的是作为放射敏感剂和光敏剂起作用的mitoketoscin。术语“mitoketoscin”泛指与ACAT1/2和OXCT1/2中至少一种结合并抑制线粒体ATP产生的非致癌化合物。因此,设计这些化合物以靶向负责酮再利用并且具有抗癌和抗生素性质的线粒体酶。这些化合物结合OXCT1/2和ACAT1/2中的一个或两个活性催化位点以抑制线粒体功能。本公开还涉及鉴定mitoketoscin的方法、制备这种mitoketoscin的方法、以及使用mitoketoscin用于治疗目的的方法。
考虑到它们的线粒体抑制特性,可以类似地将mitoketoscin用于靶向细菌和致病性酵母,提供抗衰老益处,用作放射敏化剂和/或光敏剂,使大量癌细胞和癌症干细胞对化疗剂、药物和/或其他天然物质敏感。
可以通过虚拟高通量计算机筛选,随后体外验证线粒体抑制的收敛法(convergent approach)来鉴定mitoketoscin。通过将计算机药物设计与表型药物筛选相结合,可以快速开发出mitoketoscin。
附图说明
图1显示了概述根据本方法实施方案的药物发现策略的示意图。
图2示出了在表型药物筛选后鉴定的8种候选mitoketoscin化合物1-8的化学结构。
图3A-F显示了6种候选的mitoketoscin化合物对MCF7细胞中非黏附性乳腺球群细胞(mammosphere)形成的影响。
图4A-D显示了4种候选的mitoketoscin化合物对MCF7细胞中ATP耗竭(ATP-depletion)的影响。
图5A-B和6A-B各自显示了2种候选的mitoketoscin化合物对MCF7细胞中的基础呼吸、质子泄漏、ATP连锁呼吸、最大呼吸和备用呼吸能力的影响。
图7A显示了5种候选的mitoketoscin化合物对MCF7细胞中需氧糖酵解的影响。图7B显示了5种候选的mitoketoscin化合物随时间对MCF7细胞中胞外酸化速率(ECAR)的影响。
图8A-D示出了4种候选的mitoketoscin化合物的对接图像。
图9显示了概述OXCT1和ACAT1如何起驱动ATP产生的作用的示意图。
图10A显示了用于抑制CSC增殖的4种候选的mitoketoscin化合物及其各自的IC-50。图10B显示了槟榔碱(一种天然存在的ACAT1抑制剂)的化学结构。
图11A比较了2种候选的mitoketoscin化合物的结构。图11B显示了2种候选的mitoketoscin化合物的药效基团。
图12A显示了辅酶A(CoA)的结构。图12B比较了CoA与2种候选的mitoketoscin化合物的结构。
图13显示了概述根据本方法的实施方案用线粒体底物改善mitoketoscin的潜在副作用的后续治疗策略的示意图。
具体实施方式
以下描述充分详细地示出了本方法的实施方案以实现本方法的实践。尽管参考这些特定实施方案描述了本方法,但是应当理解,本方法可以以不同的形式实施,并且本描述不应当被解释为将任何所附权利要求限制为本文阐述的特定实施方案。相反,提供这些实施方案是为了使本公开彻底和完整,并且向本领域技术人员充分传达本方法的范围。
线粒体代谢是用于治疗许多疾病(从癌症到细菌和真菌感染到衰老)的未开发的途径。功能性线粒体是癌症干细胞增殖所必需的。抑制癌细胞中的线粒体代谢阻碍这些细胞的增殖。因此,靶向作为线粒体燃料的再利用酮体的线粒体抑制剂代表了一类新的抗癌治疗剂。这些化合物还可以抑制线粒体蛋白质翻译,因此可以用作靶向细菌和致病酵母的广谱抗生素。研究还表明线粒体抑制剂具有抗衰老作用;因此,mitoketoscin也可赋予抗衰老益处。
可通过虚拟高通量筛选的收敛法,然后通过体内验证的线粒体抑制方法,来鉴定与OXCT1/2和ACAT1/2中的至少一种结合的线粒体ATP产生的新抑制剂——mitoketoscin。图1是通过使用本文公开的计算机药物筛选(in silico drug screening)和表型药物筛选鉴定mitoketoscin的方法的概述。猪OXCT1和人ACAT1蛋白的全部或部分三维结构可以在步骤S101中用于通过虚拟高通量筛选(vHTS)(即,计算机药物筛选)鉴定与这些蛋白结合的新化合物。筛选可以跨分子文库进行。例如,在初步研究期间,发明人筛选了一批30,000个小分子化合物,以寻找预期与来自猪心的琥珀酰CoA:3-酮酸CoA转移酶在任何地方结合的化合物,所述琥珀酰-CoA:3-酮酸CoA转移酶共价结合于CoA(PDB编号3OXO),或人线粒体乙酰乙酰CoA硫解酶的CoA结合位点(PDB编号2F2S)。初始vHTS可使用各种筛选程序,例如eHiTS筛选程序,以鉴定对任一蛋白质具有强结合亲和力的化合物子集。例如,本发明人使用eHiTS基于预测的结合亲和力从初始文库中鉴定出排名前1,000的化合物。eHiTS是一种筛选方法,可以系统地覆盖构象和位置搜索空间的一部分,从而避免了严重的空间冲突,从而以非常适合虚拟高通量筛选的速度生成高度精确的对接姿势。
应当理解,本领域技术人员可以选择或开发用于鉴定具有所需结合亲和力的化合物子集的方法。为了有效地进行对接,可以制备对应于整个蛋白质结构的一系列片段文件,并且每个化合物顺序地对接在每个片段文件处。基于从eHiTS筛选预测的每种化合物的相同通用结合位点,可以使用AutoDock4.2进行排名居前的化合物的一致性评分。预测的结合亲和力的进一步检测和目测检查可以使用多种方法进行,包括例如从头设计程序如SPROUT。针对有关SPROUT的信息,参见Law等人,J Mol Struct.666:651-657(2003),其全部内容通过引用并入本文。根据初始文库大小和结果,多种化合物可以选择用于表型药物筛选。例如,发明人选择227种在步骤S103的表型药物筛选的这些检测步骤中表现良好的化合物。选择84种化合物用于基于OXCT1的表型筛选,选择143种化合物用于基于ACAT1的表型筛选。
表型药物筛选S103可以通过测试选定细胞系中选定化合物的线粒体抑制来完成。例如,可以使用ATP耗竭检测。本发明人测试了所选227种化合物在MCF7人乳腺癌细胞中功能性诱导ATP耗竭的能力。线粒体中大约85%的细胞ATP通常由OXPHOS产生,因此ATP耗竭是线粒体抑制的替代标记物。应当理解,本领域技术人员可以使用其他线粒体抑制替代物。然而,对于发明人所使用的ATP耗竭检测,将MCF7细胞(6,000细胞/孔)铺板到黑色透明底96-孔板中,并在处理之前温育过夜。将通过vHTS鉴定的227种化合物以20μM的浓度施用于铺板的MCF7细胞并且针对ATP耗竭进行筛选。随后在较低浓度(10μM)下重新筛选显示ATP耗竭效应的化合物以鉴定最有效诱导ATP耗竭的前8种化合物。孵育72小时后测试化合物,实验一式两份进行。处理后,从孔中吸出培养基,用补充有Ca2+和Mg2+的温磷酸盐缓冲盐水(PBS)洗涤平板。然后,将细胞与Hoechst33342(Sigma)染色溶液(10μg/ml)温育30分钟并用PBS洗涤以估计细胞生存力。用平板读数器使用355/460nm的激发/发射波长读取荧光。然后,进行CellTiter-Glo发光检测(Promega)以测量用给定化合物处理的完全相同的孔中的代谢活性(ATP含量)。根据制造商的方案进行检测。将荧光强度(Hoechst染色)和发光强度(ATP含量)相对于单独载体处理的对照标准化,并显示为对照百分比用于比较。所有8种测试化合物显著减少活细胞中的ATP水平。应当理解,本领域技术人员可选择使用相同或类似的ATP耗竭检测,修改这类检测,或可以用另一种方法(例如,耗氧量检测)替代ATP耗竭检测来针对线粒体抑制筛选选定化合物。
本方法包括证实细胞生存力的方法。本领域技术人员可以选择适于特定实施方案的一种或多种用于证实细胞生存力的方法。本发明人最初使用基于细胞蛋白质含量测量的磺酰罗丹明(SRB)检测。在96孔板中处理72小时后,将细胞用10%三氯乙酸(TCA)在冷室中固定1小时,并在室温干燥过夜。然后,将细胞与SRB温育15分钟,用1%乙酸洗涤两次,风干至少1小时。最后,将蛋白结合染料溶解在10mM Tris,pH8.8溶液中,并使用平板读数器在540nm读数。使用SRB检测,本发明人仅选择消耗ATP水平而没有显著细胞毒性的化合物用于进一步分析。显著的细胞毒性定义为少于30%的细胞仍留在平板上。当然,采用其他细胞生存力证实方法的实施方案可以基于本领域已知的其他考虑选择化合物用于进一步分析。
本方法还包括在步骤S105的功能验证方法,在该方法中可以确认化合物作为线粒体抑制剂的功能。许多方法可用于功能验证,包括例如代谢通量分析、非黏附性乳腺球群细胞检测、生存力检测以及抗生素(抗细菌和/或抗真菌)活性。例如,本发明人使用海马细胞外通量(XF96)分析仪(Seamar Bioscience,MA,USA)测定MCF7细胞的细胞外酸化速率(ECAR)和实时氧消耗速率(OCR)。MCF7细胞保持在补充有10%FBS(胎牛血清)、2mMGlutaMAX和1%Pen-Strep的DMEM中。将每孔5,000个细胞接种到XF96孔细胞培养板中,并在37℃在5%CO2湿润的气氛中培养过夜。24小时后,用所选择的化合物处理细胞,所述化合物在各种浓度(或单独的载体)下显示ATP耗竭而没有显著的细胞毒性。处理72小时后,将细胞在预热的XF测定培养基中洗涤(对于OCR测量,XF检测培养基补充有10mM葡萄糖、1mM丙酮酸盐、2mM L-谷氨酰胺并调节至pH7.4)。将细胞在非CO2培养箱中于37℃的175μL/孔XF检测培养基中保存1小时。在温育期间,将XF检测培养基中的25μL的80mM葡萄糖、9μM寡霉素、1M的2-脱氧葡萄糖(用于ECAR测量)和25μL的10μM寡霉素、9μM FCCP、10μM鱼藤酮、10μM抗霉素A(用于OCR测量)装入XFe-96传感器盒的注射口。在实验期间,仪器在给定时间点将这些抑制剂注入孔中,同时连续测量ECAR/OCR。ECAR和OCR测量通过蛋白质含量标准化(使用磺酰罗丹明B检测)。使用单向ANOVA和Student’s t-检验计算,通过XFe-96软件分析数据集。所有实验均一式三份进行,结果验证了本文所述的mitoketoscin化合物的线粒体抑制作用。应当理解,已知许多用于功能验证的方法,并且本领域技术人员可以根据验证需求(例如,其他测量或估计线粒体功能的检测)来选择一种或多种方法。
总之,本方法可包括使用计算机药物筛选和表型药物筛选鉴定潜在的mitoketoscin的方法。可以测试使用该方法鉴定的新化合物的抗癌活性(例如,抑制非黏附性乳腺球群细胞形成和细胞迁移的能力),并且可以在不同的细菌和/或酵母菌株上进一步测试以研究抗微生物活性。图1总结了根据本方法的实施方案的用于药物筛选和验证的一般方法,但是应当理解,本领域技术人员可以在不脱离本方法的情况下偏离本文公开的具体实施方案。
本方法已经鉴定了具有抗癌性质的mitoketoscin,并且本方法的实施方案可以采取这些化合物中的一种或多种的形式,以及包括有效量的这些化合物中的一种或多种的药物组合物,以及使用这些化合物中的一种或多种的各种治疗方法。基于本发明人的初步筛选和验证,图2中鉴定的化合物具有抗癌性质,因此是mitoketoscin。考虑到本发明人的研究,因此这些mitoketoscin是临床试验的候选物。应当理解,图2中鉴定的mitoketoscin不是穷举性的,而仅仅是迄今使用本文所述的新方法鉴定的那些化合物。本领域技术人员应当理解,用于特定治疗的每种化合物的治疗有效量可以通过应用本领域已知的直接方法来确定。
一些实施方案可以采用一种或多种mitoketoscin的形式。该实施方案可以包括在用于治疗癌症、细菌感染和/或致病性酵母感染的药物组合物中。例如,mitoketoscin可以是具有以下结构的通用药效基团(或其盐):
作为另一个实例,mitoketoscin可以是具有以下结构的通用药效基团(或其盐):
其中每个R可以相同或不同并且选自由以下组成的组:氢、碳、氮、硫、氧、氟、氯、溴、碘、羧基、烷烃、环烷烃、基于烷烃的衍生物、烯烃、环状烯烃、基于烯烃的衍生物、炔烃、基于炔烃的衍生物、酮类、基于酮的衍生物、醛类、基于醛的衍生物、羧酸、基于羧酸的衍生物、醚类、基于醚的衍生物、酯类、基于酯的衍生物、胺类、基于氨基的衍生物、酰胺类、基于酰胺的衍生物、单环或多环芳烃、杂芳烃类、基于芳烃的衍生物、基于杂芳烃的衍生物、酚类、基于酚的衍生物、苯甲酸以及基于苯甲酸的衍生物。
作为另一个实例,mitoketoscin可以是具有以下结构的通用药效基团(或其盐):
作为另一个实例,mitoketoscin可以是具有以下结构的通用药效基团(或其盐):
其中每个R可以相同或不同并且选自由以下组成的组:氢、碳、氮、硫、氧、氟、氯、溴、碘、羧基、烷烃、环烷烃、基于烷烃的衍生物、烯烃、环状烯烃、基于烯烃的衍生物、炔烃、基于炔烃的衍生物、酮类、基于酮的衍生物、醛类、基于醛的衍生物、羧酸、基于羧酸的衍生物、醚类、基于醚的衍生物、酯类、基于酯的衍生物、胺类、基于氨基的衍生物、酰胺类、基于酰胺的衍生物、单环或多环芳烃、杂芳烃类、基于芳烃的衍生物、基于杂芳烃的衍生物、酚类、基于酚的衍生物、苯甲酸以及基于苯甲酸的衍生物。
作为另一个实例,mitoketoscin可以是具有以下结构的通用药效基团(或其盐):
其中每个R可以相同或不同并且选自由以下组成的组:氢、碳、氮、硫、氧、氟、氯、溴、碘、羧基、烷烃、环烷烃、基于烷烃的衍生物、烯烃、环状烯烃、基于烯烃的衍生物、炔烃、基于炔烃的衍生物、酮类、基于酮的衍生物、醛类、基于醛的衍生物、羧酸、基于羧酸的衍生物、醚类、基于醚的衍生物、酯类、基于酯的衍生物、胺类、基于氨基的衍生物、酰胺类、基于酰胺的衍生物、单环或多环芳烃、杂芳烃类、基于芳烃的衍生物、基于杂芳烃的衍生物、酚类、基于酚的衍生物、苯甲酸以及基于苯甲酸的衍生物。
mitoketoscin的另一个实例是具有以下结构的通用药效基团(或其盐):
mitoketoscin的另一个实例是具有以下结构的通用药效基团(或其盐):
mitoketoscin的另一个实例是具有以下结构的通用药效基团(或其盐):
其中每个R可以相同或不同并且选自由以下组成的组:氢、碳、氮、硫、氧、氟、氯、溴、碘、羧基、烷烃、环烷烃、基于烷烃的衍生物、烯烃、环状烯烃、基于烯烃的衍生物、炔烃、基于炔烃的衍生物、酮类、基于酮的衍生物、醛类、基于醛的衍生物、羧酸、基于羧酸的衍生物、醚类、基于醚的衍生物、酯类、基于酯的衍生物、胺类、基于氨基的衍生物、酰胺类、基于酰胺的衍生物、单环或多环芳烃、杂芳烃类、基于芳烃的衍生物、基于杂芳烃的衍生物、酚类、基于酚的衍生物、苯甲酸以及基于苯甲酸的衍生物。
mitoketoscin的另一个实例是具有以下结构的通用药效基团(或其盐):
其中每个R可以相同或不同并且选自由以下组成的组:氢、碳、氮、硫、氧、氟、氯、溴、碘、羧基、烷烃、环烷烃、基于烷烃的衍生物、烯烃、环状烯烃、基于烯烃的衍生物、炔烃、基于炔烃的衍生物、酮类、基于酮的衍生物、醛类、基于醛的衍生物、羧酸、基于羧酸的衍生物、醚类、基于醚的衍生物、酯类、基于酯的衍生物、胺类、基于氨基的衍生物、酰胺类、基于酰胺的衍生物、单环或多环芳烃、杂芳烃类、基于芳烃的衍生物、基于杂芳烃的衍生物、酚类、基于酚的衍生物、苯甲酸以及基于苯甲酸的衍生物。
mitoketoscin的另一个实例是具有以下结构的通用药效基团(或其盐):
mitoketoscin的另一个实例是具有以下结构的通用药效基团(或其盐):
其中每个R可以相同或不同并且选自由以下组成的组:氢、碳、氮、硫、氧、氟、氯、溴、碘、羧基、烷烃、环烷烃、基于烷烃的衍生物、烯烃、环状烯烃、基于烯烃的衍生物、炔烃、基于炔烃的衍生物、酮类、基于酮的衍生物、醛类、基于醛的衍生物、羧酸、基于羧酸的衍生物、醚类、基于醚的衍生物、酯类、基于酯的衍生物、胺类、基于氨基的衍生物、酰胺类、基于酰胺的衍生物、单环或多环芳烃、杂芳烃类、基于芳烃的衍生物、基于杂芳烃的衍生物、酚类、基于酚的衍生物、苯甲酸以及基于苯甲酸的衍生物。应当理解,可以选择mitoketoscin单独用于治疗用途,或与一种以上特定的mitoketoscin和/或与其他物质组合以增强其他治疗剂的功效。该治疗剂可以常规药物组合物的形式使用,该药物组合物可以使用一种或多种已知方法制备。例如,药物组合物可以通过使用稀释剂或赋形剂制备,例如本领域已知的一种或多种填充剂、膨胀剂(bulking agent)、粘合剂、润湿剂、崩解剂、表面活性剂、润滑剂等。可根据治疗目的选择各种类型的施用单位形式。药物组合物形式的实例包括但不限于片剂、丸剂、粉剂、液体、混悬剂、乳剂、颗粒剂、胶囊剂、栓剂、注射制剂(溶液和混悬剂)、局部乳膏和本领域已知的其他形式。为了形成片剂形式的药物组合物,可以使用任何已知的赋形剂,例如载体如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、环糊精、结晶纤维素、硅酸等;粘合剂如水、乙醇、丙醇、简易糖浆、葡萄糖溶液、淀粉溶液、明胶溶液、羧甲基纤维素、shelac、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等。另外,可以使用崩解剂,例如干燥淀粉、藻酸钠、琼脂粉末、层状粉末、碳酸氢钠、碳酸钙、聚氧乙烯脱水山梨糖醇的脂肪酸酯、月桂醇硫酸钠、硬脂酸的单甘油酯、淀粉、乳糖等。崩解抑制剂,例如白糖、硬脂精(stearin)、椰子油、氢化油;可以使用吸收促进剂如季铵碱、月桂醇硫酸钠等。可以使用润湿剂如甘油、淀粉和本领域已知的其他润湿剂。可以使用吸附剂,例如淀粉、乳糖、高岭土、膨润土、胶状硅酸等。可以使用润滑剂,例如纯化的滑石、硬脂酸盐、硼酸粉末、聚乙二醇等。如果需要片剂,它们可以进一步用常规包衣材料进行包衣以制备糖衣片剂、明胶薄膜包衣片剂、肠溶衣片剂、薄膜包衣片剂、双层片剂和多层片剂。适于局部施用的药物组合物可以配制成软膏剂、乳膏剂、混悬剂、洗剂、粉剂、溶液剂、糊剂、凝胶剂、泡沫剂、喷雾剂、气雾剂或油剂。这种药物组合物可包括常规添加剂,其包括但不限于防腐剂、有助于药物渗透的溶剂、助溶剂、润肤剂、推进剂、粘度调节剂(胶凝剂)、表面活性剂和载体。
在一些实施方案中,本方法可以涉及针对抗癌性质测试化合物(特别是mitoketoscin)的方法。如上所述,vHTS和计算化学可用于鉴定候选线粒体抑制剂。可以测试这些候选物的特异性抗癌性质。例如,本发明人平行比较了7种候选化合物抑制MCF7细胞中非黏附性乳腺球群细胞形成的能力。图3表明所测试的6种化合物抑制非黏附性乳腺球群细胞形成。化合物2和8(分别为图3A和3B)是在25μM的浓度降低非黏附性乳腺球群细胞数(癌症干细胞活性的量度)的两个最有效的候选物。化合物6和3也是有效的(分别为图3C和3D),而化合物5和1(分别为图3E和3F)是较低效的非黏附性乳腺球群细胞生长抑制剂。
表1 mitoketoscin抑制MCF7细胞内非黏附性乳腺球群细胞形成
表1总结了7种候选化合物的非黏附性乳腺球群细胞形成抑制结果。表1示出了7种化合物以10μM至170μM之间的半数最大抑制浓度(IC-50)抑制非黏附性乳腺球群细胞形成。化合物1至4由OXCT1筛选鉴定,化合物5、6和8由ACAT1筛选鉴定。
在一些实施方案中,本方法可涉及mitoketoscin化合物的功能验证方法。例如,本发明人使用Seahorse分析仪评估了4种候选物的功能验证,该分析仪定量测量耗氧率(OCR)和细胞外酸化率(ECAR)。OCR是OXPHOS的替代标记物,ECAR是糖酵解和L-乳酸产生的替代标记物。
本发明人的结果表明化合物2、3、6和8都剂量依赖性地抑制MCF7细胞中的线粒体氧消耗。图4A和4B显示了即使在低至5μM的剂量下,化合物2和8显著降低线粒体呼吸。化合物6和3也是有效的抑制剂(图4C和4D)。如图5和6所示,这些化合物剂量依赖性地降低基础呼吸、质子泄漏、ATP连锁呼吸和最大呼吸。图7显示与对照相比,四种化合物如何显著抑制糖酵解。
本方法的一些实施方案可包括通过考虑化合物对非黏附性乳腺球群细胞形成的影响来测试化合物的抗癌性质。应当理解,本领域技术人员可以使用本领域已知的其他方法来评估候选线粒体抑制剂对特定细胞系的作用,而不背离本方法。还应当理解,本领域技术人员可以评估候选线粒体抑制剂对其他癌症类型的作用,因为该抑制剂靶向癌症干细胞(CSC)。CSC在大多数癌症类型中显示保守的或相似的特征。
图8A-8D示出了化合物2、8、3和6的分子建模。分子建模的目的是预测化合物与已知三维结构的主要结合模式。图8A和8C分别显示了化合物2和3在OXCT1的3D晶体结构内的琥珀酰CoA结合位点处的分子对接。图8A和8C的比较显示,预测至少一个氨基酸ASN-373直接结合化合物2和3。图8B和8D分别显示了化合物8和6在ACAT1的3D晶体结构内的CoA结合位点的分子对接。图8B和8D的比较显示,预测至少两个氨基酸LEU-184和HIS-192直接结合化合物8和6。这些预测的显性结合模式对于进一步优化可能是非常宝贵的。
酮体在功能上表现为线粒体燃料,其可以主动驱动肿瘤生长和转移。在本文中,如图9所总结,OXCT1和ACAT1是参与酮再利用的两种线粒体蛋白。发明人分子靶向OXCT1和ACAT1以防止癌细胞将酮体再循环到乙酰CoA中,乙酰CoA通常进入TCA循环,驱动线粒体ATP产生。
如图10A所示,除了次要的官能侧基,OXCT1筛选的最高命中(hit)(化合物2)和ACAT1筛选的命中(化合物8)具有类似的化学结构。如图11B所示,下面的“化学支架(chemical scaffold)”或药效基团对于两种小分子是相同的。图12中还将化合物2和8的结构与辅酶A的分子结构进行比较以证明结构相似性。
如图11A所示,来自OXCT1筛选的两种化合物(化合物3和4)在结构上彼此相似。然而,基于观察到的它们的IC-50值,化合物3在靶向CSC增殖的能力方面比化合物4强近4倍。在结构上区分这两种分子的独特化学基团(由图11A中的箭头突出显示)可能是其IC-50中观察到的抑制CSC增殖所观察到的差异的原因。
最近的研究提供了ACAT1作为致癌基因的作用的另外证据,因为这些研究鉴定了槟榔碱作为潜在的ACAT1抑制剂。Garcia-Bermudez等人,Mol Cell(分子细胞)2016,64(5):856-857。槟榔碱是在槟榔中发现的基于烟酸的生物碱,槟榔是槟榔树(Areca catechu)的果实。槟榔碱已显示出抗肿瘤活性,进一步证实靶向ACAT1的药物作为抗癌剂可能有价值。然而,发明人未评估其靶向CSC的能力。由于槟榔碱是非常小的分子(与化合物6和3相比示于图10B中),因此可能需要通过药物化学对其进行显著修饰以增加其效力。槟榔碱不是mitoketoscin,因为已知该化合物具有致癌性。
尽管正常的酮代谢是在机体饥饿和/或严重营养缺乏的条件下发生的,但是这种调节在人类肿瘤中丧失了,并且酮代谢似乎是组成性地在癌细胞中发生。在正常饮食条件下,预计靶向人类肿瘤中的酮代谢具有最小的代谢副作用。尽管如此,通过包括一个“救援”步骤,可显著改善或“控制”酮抑制剂的潜在副作用,该步骤包括用其他线粒体支持底物(例如葡萄糖、丙酮酸盐、乳酸盐、脂肪酸和/或乙酰肉碱)进行后续处理,如图13所示。无菌D-葡萄糖和L-乳酸静脉内溶液(D5W、D5NS、乳酸林格氏溶液)已经在医院中常规用于其他临床和治疗适应症;因此,后续治疗在临床上是可行的。
本发明人已经表明诱导癌细胞中急性ATP耗竭的化合物可以使那些细胞对辐射、紫外光、化疗剂、天然物质和/或热量限制敏感。如本文所讨论的,已经证实了ATP耗竭效应。基于这些初步结果,也可以将mitoketoscin用作放射敏感剂和/或光敏剂。作为放射敏感剂和/或光敏剂的用途可以与其他治疗载体组合,包括但不限于本领域已知的其他癌症治疗方法,和如本文公开的通过抑制线粒体生物发生的癌症治疗。类似地,可以使用mitoketoscin使大量癌细胞和癌症干细胞对化疗剂、药物和/或其他天然物质如膳食补充剂和热量限制功能性敏感。
除了抗癌和抗菌行为之外,可通过本方法鉴定的线粒体抑制剂具有减缓哺乳动物衰老过程的可能性。线粒体蛋白质翻译的遗传抑制已经显示具有有益的副作用,特别是减缓模型生物的衰老过程和增加其寿命的副作用。稳态水平较低的Mrps5(一种线粒体核糖体蛋白)与更长的鼠类寿命具有强烈的功能相关性,导致寿命显著增加约250天。此外,在秀丽隐杆线虫(C.elegans)中选择性敲减Mrps5极大地增加了寿命。Mrps5敲减蠕虫显示线粒体呼吸和ATP产生显著降低。同样,敲除线粒体复合物I、III、IV和V的蠕虫同系物以及几种TCA循环酶,都有力地延长了寿命,进一步暗示了降低的OXPHOS活性和较低的ATP水平是其机制。最后,线粒体生物发生的药理学抑制(使用强力霉素的脱靶效应)也显著增加了秀丽隐杆线虫的寿命。因此,可以使用mitoketoscin治疗性靶向衰老过程并延长寿命。
也可以使用mitoketoscin来最小化和/或逆转癌细胞中的抗药性。耐药性被认为至少部分基于癌细胞中线粒体功能的增加。特别地,对如他莫昔芬等内分泌疗法表现出抗性的癌细胞预期具有增强的线粒体功能。mitoketoscin抑制线粒体功能,因此可用于降低和在一些情况下逆转癌细胞中的抗药性。
这里在本发明的描述中使用的术语仅用于描述特定实施方案的目的,而不旨在限制本发明。如在本发明的说明书和所附权利要求书中所使用的,单数形式“一(a、an)”和“该/所述(the))”也旨在包括复数形式,除非上下文另外清楚地指示。本发明包括考虑到下面的详细描述将变得显而易见的许多替换、修改和等同物。
应当理解,尽管术语“第一(first)”、“第二(second)”、“第三(third)”、“a”、“b”和“c”等可在本文中用于描述本发明的各种要素,但不应被这些术语限制。这些术语仅用于将本发明的一个要素与另一个要素区分开。因此,下面讨论的第一要素可以被称为要素方面,类似地,不脱离本发明教导的第三要素。因此,术语“第一”、“第二”、“第三”、“a”、“b”和“c”等不旨在必然地将顺序或其他层次结构传达给相关联的要素,而是仅用于标识目的。操作(或步骤)的顺序不限于权利要求中给出的顺序。
除非另外定义,否则本文使用的所有术语(包括技术和科学术语)具有与本发明所属领域的普通技术人员通常理解的相同含义。还应当理解,诸如在常用词典中定义的那些术语应当被解释为具有与它们在本申请和相关领域的上下文中的含义一致的含义,并且不应当被解释为理想化或过于正式的含义,除非在此明确地如此定义。这里在本发明的描述中使用的术语仅用于描述特定实施方案的目的,而不旨在限制本发明。本文提及的所有出版物、专利申请、专利和其他参考文献均全文引入作为参考。在术语冲突的情况下,以本说明书为准。
也如本文所用,“和/或”是指并涵盖一个或多个相关所列项目的任何和所有可能的组合,以及当以备选方式(“或”)解释时缺少组合。
除非上下文另有说明,本文所述的本发明的各种特征可以任何组合使用。此外,本发明还意图,在本发明的一些实施方案中,可以排除或省略在此阐述的任何特征或特征的组合。为了说明,如果说明书陈述复合体包括组分A、B和C,则特别意图可以省略和放弃A、B或C中的任何一个或其组合。
如本文所用,过渡短语“基本上由……组成”(和语法变体)应解释为涵盖所列举的材料或步骤“和不会实质上影响所要求保护的发明的基本和新颖特征的那些材料或步骤”。因此,本文所用的术语“基本上由……组成(consisting essentially of)”不应被解释为等同于“包含(comprising)”。
本文所用的术语“约”当涉及可测量值时,例如量或浓度等,意指包括特定量的±20%、±10%、±5%、±1%、±0.5%或甚至±0.1%的变化。本文提供的用于可测量值的范围可包括其中的任何其他范围和/或单个值。
已经如此描述了本发明的某些实施方案,应当理解,由所附权利要求限定的本发明不限于在以上描述中阐述的特定细节,因为在不脱离所附权利要求的精神或范围的情况下,其许多明显的变化是可能的。
Claims (31)
2.根据权利要求1所述的mitoketoscin,其中R为氟。
3.根据权利要求1所述的mitoketoscin,其中所述mitoketoscin具有抗衰老活性。
4.根据权利要求1所述的mitoketoscin,其中所述mitoketoscin具有放射敏感活性和光敏活性中的至少一种。
5.根据权利要求1所述的mitoketoscin,其中所述mitoketoscin具有抗微生物活性。
6.根据权利要求1所述的mitoketoscin,其中所述mitoketoscin使癌症干细胞对化疗剂敏感。
7.根据权利要求1所述的mitoketoscin,其中所述mitoketoscin使癌症干细胞对天然物质敏感。
8.根据权利要求1所述的mitoketoscin,其中所述mitoketoscin使癌症干细胞对热量限制敏感。
9.根据权利要求1所述的mitoketoscin,其中所述mitoketoscin结合OXCT1、OXCT2、ACAT1和ACAT2中的至少一种。
11.根据权利要求10所述的用途,其中R为氟。
13.根据权利要求12所述的用途,其中R为氟。
15.根据权利要求14所述的用途,其中R为氟。
17.根据权利要求16所述的药物组合物,其中R为氟。
19.根据权利要求18所述的mitoketoscin,其中R为氟。
20.根据权利要求18所述的mitoketoscin,其中所述mitoketoscin具有抗衰老活性。
21.根据权利要求18所述的mitoketoscin,其中所述mitoketoscin具有放射敏感活性。
22.根据权利要求18所述的mitoketoscin,其中所述mitoketoscin具有光敏活性。
23.根据权利要求18所述的mitoketoscin,其中所述mitoketoscin使癌症干细胞对化疗剂敏感。
24.根据权利要求18所述的mitoketoscin,其中所述mitoketoscin使癌症干细胞对天然物质敏感。
25.根据权利要求18所述的mitoketoscin,其中所述mitoketoscin使癌症干细胞对热量限制敏感。
26.根据权利要求18所述的mitoketoscin,其中所述mitoketoscin结合OXCT1、OXCT2、ACAT1和ACAT2中的至少一种。
28.根据权利要求27所述的用途,其中R为氟。
29.根据权利要求27所述的用途,当所述药物被施用时,还施用线粒体支持底物,所述线粒体支持底物包含葡萄糖、丙酮酸盐、乳酸盐、脂肪酸和乙酰肉碱中的至少一种。
31.根据权利要求30所述的药物组合物,其中R为氟。
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