CN111770921B - 用于提高基因组编辑效率的喹喔啉酮化合物,组合物,方法和试剂盒 - Google Patents
用于提高基因组编辑效率的喹喔啉酮化合物,组合物,方法和试剂盒 Download PDFInfo
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Abstract
化合物,编辑靶基因组区域的方法,通过HDR途径修复DNA断裂的方法,抑制或阻抑通过NHEJ途径修复DNA断裂的方法和修饰基因或蛋白质的表达的方法,所述方法包括将本文公开的基因组编辑系统和DNA蛋白激酶(DNA‑PK)抑制剂施用于包含一种或多种本文公开的靶基因组区域的一种或多种细胞。用于编辑靶基因的试剂盒和组合物包含本文公开的基因组编辑系统和DNA‑PK抑制剂。
Description
相关申请的交叉引用
本申请要求2018年1月17日提交的美国临时专利申请号62/618,385的权益,该文献的全部内容通过引用并入本文。
序列表
本申请包含序列表,该序列表已经以ASCII格式电子提交,并且通过引用整体并入本文。于2019年1月16日创建的ASCII副本称作14390-687Sequence listing_ST25.txt且大小为4KB。
发明领域
本发明一般涉及用于提高基因组编辑效率的化合物,组合物,方法和试剂盒,通过对细胞施用DNA蛋白激酶(DNA-PK)抑制剂和基因组编辑系统来进行。
发明背景
需要精确的基因组靶向技术来实现遗传变异的系统工程。在过去的几年中,基因组编辑系统的应用,特别是基于CRISPR-核酸内切酶的基因组编辑技术的应用呈指数增长。II型CRISPR-Cas9细菌先天免疫系统已成为一种有效的基因组编辑工具用于靶向修饰人类基因组(Wiedenheft,B.2012;Hsu,P.D.eta.2014)。最近,已经描述了CRISPR-Cpf基因组编辑系统。基于CRISPR-核酸内切酶的基因组编辑部分取决于非同源末端连接(non-homologous end joining)(NHEJ)和同源介导修复(homology directed repair)(HDR)途径以修复DNA双链断裂。细胞修复机制对NHEJ比对HDR更有利。
尽管在某些报告中从NHEJ实现插入或缺失(indels)的有效性高达70%,但HDR的效率仍然具有挑战性,其中比率不到1%。
因此,对于提高基因组编辑效率,特别是HDR效率存在需求。
发明概述
本发明可以通过使用DNA-PK抑制剂抑制NHEJ酶,例如DNA-PK来改善HDR效率。
在一些实施方案中,本公开提供由结构式(I)表示的化合物:
或其药学上可接受的盐或共晶。
m和n独立地为1或2。
X为O或NR;其中R为H或C1-C4-烷基。
Y为价键,O或NR;其中R为H或C1-C4-烷基。
R1为C1-C4烷基。
5-或6-元芳基或包含一个或两个选自N,O和S的杂原子的杂芳基环,其中所述芳基和所述杂芳基环可以被0,1,2或3个取代基R3取代,取代基R3独立地选自CN,卤素,C1-C4-烷基,C3-C6环烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基,C(=O)NHR1’和5-或6-元杂环烷基或杂芳基环,其中每个环包含1,2或3个选自N,O和S的杂原子;其中R1’为C1-C4烷基;或其中连接至所述芳基或杂芳基环的相邻碳原子的两个R3基团可以形成可以包含选自O,N和S的杂原子的稠合5-或6-元环;或COOR4,其中R4为C1-C4-烷基或苄基。
C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基和C1-C4-卤代烷氧基各自可以进一步被OR5或NR6R7取代。
R5,R6和R7的每一个独立地为H,C1-C4烷基或C3-C6环烷基。
R6和R7与它们所连接的氮原子一起可以形成饱和5-或6-元环,其可以包含0或1个另外的选自N,O和S的杂原子,且其中所述环可以进一步被C1-C4-烷基取代。
环A选自
W为N或CR3’;且Z为O或S;其中R3’为H或C1-C4烷基。
在一些实施方案中,本公开提供由结构式(I)表示的化合物或其药学上可接受的盐或共晶,其中R2为5-或6-元芳族环或包含一个或两个选自N,O和S的杂原子的杂芳族环,其中所述芳族或杂芳族环可以被0,1或2个取代基R3取代,取代基R3独立地选自CN,卤素,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基和C(=O)NHR1’,其中R1’为C1-C4烷基;或其中连接至所述芳族或杂芳族环的相邻碳原子的两个R3基团可以形成可以包含选自O,N和S的杂原子的稠合5-元环;或COOR4,其中R4为C1-C4-烷基或苄基。
在一些实施方案中,R2为:
其中#表示R2连接至式(I)的化合物的其余部分的位置;且o为0,1或2。
在一些实施方案中,化合物由结构式(II),结构式(II’),结构式(II”)或结构式(II”’)表示:
或其药学上可接受的盐或其共晶。
在一些实施方案中,环A选自 且R2为:
在其它实施方案中,式(I)的化合物由结构式(III),结构式(III’),结构式(III”)或结构式(III”’)表示:
在一些实施方案中,R2为:
在一些实施方案中,所述化合物为共晶,其包括具有式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)的结构的化合物和选自己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸的共晶形成剂。
本公开还提供编辑一种或多种靶基因组区域的方法,该方法包括对具有一种或多种靶基因组区域的一种或多种细胞施用基因组编辑系统和由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物或其药学上可接受的盐或共晶。
在一些实施方案中,本公开提供编辑一种或多种靶基因组区域的方法,该方法包括对具有一种或多种靶基因组区域的一种或多种细胞施用基因组编辑系统和由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物或其药学上可接受的盐或共晶。
在一些实施方案中,本公开还提供通过同源介导修复(HDR)途径修复一种或多种靶基因组区域中的DNA断裂的方法,该方法包括对具有一种或多种靶基因组区域的一种或多种细胞施用基因组编辑系统和由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物或其药学上可接受的盐或共晶。
所述基因组编辑系统与靶基因组区域的核酸相互作用,导致DNA断裂,且其中DNA断裂至少部分通过HDR途径修复。
本公开还提供抑制或阻抑通过NHEJ途径修复一种或多种靶基因组区域中的DNA断裂的方法,该方法包括对具有一种或多种靶基因组区域的一种或多种细胞施用基因组编辑系统和由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物或其药学上可接受的盐或共晶。
所述基因组编辑系统与所述一种或多种靶基因组区域的核酸相互作用,导致DNA断裂,且其中抑制或阻抑通过NHEJ途径修复DNA断裂。
本公开还提供修饰一种或多种基因或蛋白质的表达的方法,该方法包括向包含一种或多种靶基因组区域的一种或多种细胞施用基因组编辑系统和由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物或其药学上可接受的盐或共晶。
所述基因组编辑系统与靶基因的一种或多种靶基因组区域的核酸相互作用,导致编辑所述一种或多种靶基因组区域,且其中编辑修饰与所述靶基因相关的下游基因和/或蛋白质的表达。
在一些实施方案中,DNA断裂包括DNA双链断裂(DSB)。
在一些实施方案中,所述化合物为共晶,其包括具有式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)的结构的化合物和选自己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸的共晶形成剂。
附图简述
图1描绘基因编辑测定的设计。
图2为显示用DNA-PK抑制剂处理的BEC中基因编辑比例的示意图。
图3A和3B为显示在来自两个不同供体的CD34+细胞中DNA-PK抑制剂处理后的基因编辑比例的示意图。
图4为显示用DNA-PK抑制剂处理的iPSCs中基因编辑比例的示意图。
图5为显示在DNA-PK抑制剂ECmax下的BEC中基因编辑动力学的示意图。
图6为显示在DNA-PK抑制剂EC50下的BEC中基因编辑动力学的示意图。
图7为显示在BEC中通过脂质介导的转染递送的基因编辑组分的HDR比例的条形图。
详细描述
除非另有定义,否则与本公开结合使用的科学和技术术语应具有本领域普通技术人员通常理解的含义。通常,与本文所述的细胞和组织培养,分子生物学以及蛋白质和寡核苷酸或多核苷酸化学以及杂交技术相关的术语是本领域公知的和常用的。使用标准技术进行重组DNA,寡核苷酸合成以及组织培养和转化(例如电穿孔,脂转染)。酶促反应和纯化技术根据制造商的说明或如本领域通常完成的或如本文所述进行。前述技术和方法通常根据本领域公知的常规方法进行,并且如在本公开全文中引用和讨论的各种一般性和更具体的参考文献中所述。参见,例如Sambrook et al.,Molecular Cloning:A Laboratory Manual(第2版,Cold Spring HarborLaboratory Press,Cold Spring Harbor,N.Y.(1989))。本文所述的与分析化学,合成有机化学以及药物和药物化学结合使用的术语和实验室方法和技术是本领域众所周知的和通常使用的那些。标准技术用于化学合成,化学分析,药物制备,患者的制剂和递送及治疗。通常,化学元素根据元素周期表(Periodic Table of theElements)CAS版和Handbook of Chemistry and Physics,第75版1994鉴定。另外,有机化学的一般原理描述在“Organic Chemistry,”Thomas Sorrell,University ScienceBooks,Sausalito:1999和“March’s Advanced Organic Chemistry,”第5版,Smith,M.B.and March,J.,eds.John Wiley&Sons,New York:2001中,这些文献的全部内容通过引用并入本文。作为本公开中使用的,在本公开中定义的术语,除非另有指示,否则应当理解具有如本文所定义的含义。
在一些实施方案中,与在除了不使用所述化合物之外其他方面都相同的细胞中的情况相比,编辑所述一种或多种细胞中靶基因组区域的效率提高。
在一些实施方案中,与在除了不使用所述化合物之外其他方面都相同的细胞中的情况相比,通过HDR途径修复所述一种或多种细胞中所述靶基因组区域处的DNA断裂的效率提高。
在一些实施方案中,与在除了不使用所述化合物之外其他方面都相同的细胞中的情况相比,抑制或阻抑通过NHEJ途径修复所述一种或多种细胞中所述靶基因组区域处的DNA断裂的效率提高。
在一些实施方案中,与在除了不使用所述化合物之外其他方面都相同的细胞中的情况相比,效率提高至少2-倍,3-倍,4-倍,5-倍,10-倍,15-倍,20-倍,25-倍,30-倍,40-倍,50-倍或100-倍。
在一些实施方案中,通过靶向多核苷酸整合的频率来测定所述效率。在一些实施方案中,通过靶向的诱变的频率来测定所述效率。在一些实施方案中,靶向的诱变包含点突变,缺失和/或插入。
在一些实施方案中,与施用前所述一种或多种细胞中的基线表达水平相比,与所述靶基因相关的下游基因和/或蛋白质的表达提高。例如,与施用前所述一种或多种细胞中的基线表达水平相比,所述表达提高至少10%,20%,30%,40%,50%,60%,70%,80%,90%,1-倍,1.5-倍,2-倍,2.5-倍,3-倍,3.5-倍,4-倍,4.5-倍,5-倍或10-倍。
在一些实施方案中,与施用前所述一种或多种细胞中的基线表达水平相比,与所述靶基因相关的下游基因和/或蛋白质的表达降低。例如,与施用前所述一种或多种细胞中的基线表达水平相比,所述基因表达降低至少10%,20%,30%,40%,50%,60%,70%,80%,90%,95%,96%,97%,98%或99%。
在一些实施方案中,与所述靶基因相关的下游基因和/或蛋白质的表达在所述一种或多种细胞中基本上消除。
在一些实施方案中,所述细胞在S或G2细胞周期阶段同步化。
在一些实施方案中,与尚未施用或接触所述化合物的一种或多种细胞相比,施用或接触所述化合物的所述一种或多种细胞具有提高的存活率。
在一些实施方案中,将所述基因组编辑系统和所述化合物同时施用到所述一种或多种细胞中。在一些实施方案中,将所述基因组编辑系统和所述化合物依次施用到所述一种或多种细胞中。在一些实施方案中,在所述化合物之前将所述基因组编辑系统施用到所述一种或多种细胞中。在一些实施方案中,在所述基因组编辑系统之前将所述化合物施用到所述一种或多种细胞中。
在一些实施方案中,所述一种或多种细胞为培养细胞。在一些实施方案中,所述一种或多种细胞为生物体内的体内细胞。在一些实施方案中,所述一种或多种细胞为来自生物体的离体细胞。
在一些实施方案中,所述生物体为哺乳动物。在一些实施方案中,所述生物体为人。
在一些实施方案中,所述基因组编辑系统和所述化合物通过相同途径施用。在一些实施方案中,所述基因组编辑系统和所述化合物通过不同途径施用。在一些实施方案中,通过静脉内施用所述基因组编辑系统,且通过口服施用所述化合物。
在一些实施方案中,所述基因组编辑系统选自基于兆核酸酶(meganuclease)的系统,基于锌指核酸酶(ZFN)的系统,基于转录激活因子样效应物的核酸酶(TALEN)系统,基于CRISPR的系统或基于NgAgo的系统。
在一些实施方案中,所述基因组编辑系统为基于CRISPR的系统。在一些实施方案中,基于CRISPR的系统为CRISPR-Cas系统或CRISPR-Cpf系统。
在一些实施方案中,基于CRISPR的系统为CRISPR-Cas系统,且其中所述CRISPR-Cas系统包括:(a)至少一种向导RNA元件,其包括:(i)包含与在一种或多种靶基因组区域处的核苷酸序列基本上互补的核苷酸序列的靶向物RNA或包含编码所述靶向物RNA的核苷酸序列的核酸;和(ii)包含能够与所述靶向物RNA杂交的核苷酸序列的激活物RNA或包含编码所述激活物RNA的核苷酸序列的核酸;和(b)包含Cas蛋白质的Cas蛋白质元件或包含编码所述Cas蛋白质的核苷酸序列的核酸。
在一些实施方案中,靶向物RNA和激活物RNA融合为单一分子。
在一些实施方案中,Cas蛋白质为II型Cas9蛋白质。在一些实施方案中,Cas9蛋白质为SaCas9,SpCas9,SpCas9n,Cas9-HF,Cas9-H840A,FokI-dCas9或D10A切口酶或其任意组合。
在一些实施方案中,基于CRISPR的系统为CRISPR-Cpf系统,且所述CRISPR-Cpf系统包括:(a)至少一种向导RNA元件,或包含编码所述向导RNA元件的核苷酸序列的核酸,所述向导RNA包含靶向物RNA,所述靶向物RNA包含与在一种或多种靶基因组区域处的核苷酸序列基本上互补的核苷酸序列;和(b)包含Cpf蛋白质的Cpf蛋白质元件,或包含编码所述Cpf蛋白质的核苷酸序列的核酸。
在一些实施方案中,所述基因组编辑系统通过一种或多种载体递送。
在一些实施方案中,所述一种或多种载体选自病毒载体,质粒或ssDNA。
在一些实施方案中,所述病毒载体选自逆转录病毒,慢病毒,腺病毒,腺相关和单纯疱疹病毒载体。
在一些实施方案中,所述基因组编辑系统通过合成RNA递送。
在一些实施方案中,所述基因组编辑系统通过纳米制剂递送。
在一些实施方案中,提供用于编辑一种或多种靶基因组区域的试剂盒或组合物。在一些实施方案中,所述试剂盒或组合物包括基因组编辑系统;和
由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”),式(III”’)表示的化合物或其药学上可接受的盐或共晶。
在一些实施方案中,所述试剂盒或组合物的化合物由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”),式(III”’)或其药学上可接受的盐或共晶表示,其中R1和R2各自为氢或氘。
在一些实施方案中,所述试剂盒或组合物的基因组编辑系统为基于兆核酸酶的系统,基于锌指核酸酶(ZFN)的系统,基于转录激活因子样效应物的核酸酶(TALEN)系统,基于CRISPR的系统或基于NgAgo的系统。在一些实施方案中,所述试剂盒或组合物的基因组编辑系统为基于CRISPR的系统。在一些实施方案中,所述试剂盒或组合物的基于CRISPR的系统为CRISPR-Cas系统或CRISPR-Cpf系统。
在一些实施方案中,所述试剂盒或组合物的基于CRISPR的系统为CRISPR-Cas系统,且其中所述CRISPR-Cas系统包括:(a)至少一种向导RNA元件,其包括:(i)包含与在一种或多种靶基因组区域处的核苷酸序列基本上互补的核苷酸序列的靶向物RNA或包含编码所述靶向物RNA的核苷酸序列的核酸;和(ii)包含能够与所述靶向物RNA杂交的核苷酸序列的激活物RNA或包含编码所述激活物RNA的核苷酸序列的核酸;和(b)包含Cas蛋白质的Cas蛋白质元件或包含编码所述Cas蛋白质的核苷酸序列的核酸。
在一些实施方案中,所述试剂盒或组合物的Cas蛋白质为II型Cas9蛋白质。在一些实施方案中,所述试剂盒或组合物的Cas9蛋白质为SaCas9,SpCas9,SpCas9n,Cas9-HF,Cas9-H840A,FokI-dCas9或D10A切口酶或其任意组合。
在一些实施方案中,所述试剂盒或组合物的基于CRISPR的系统为CRISPR-Cpf系统,且其中所述CRISPR-Cpf系统包括:(a)包含与在一种或多种靶基因组区域处的核苷酸序列基本上互补的核苷酸序列的靶向物RNA或包含编码所述靶向物RNA的核苷酸序列的核酸;和(b)包含Cpf蛋白质的Cpf蛋白质元件或包含编码所述Cpf蛋白质的核苷酸序列的核酸。
在一些实施方案中,所述试剂盒或组合物的基因组编辑系统包括在或包装在一种或多种载体中。在一些实施方案中,所述一种或多种载体选自病毒载体,质粒或ssDNA。在一些实施方案中,所述病毒载体选自逆转录病毒,慢病毒,腺病毒,腺相关和单纯疱疹病毒载体。
在一些实施方案中,所述试剂盒或组合物的化合物包含选自表1的化合物。
在一些实施方案中,所述试剂盒或组合物的化合物为共晶,其包括具有式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)的结构的化合物和选自己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸的共晶形成剂。
在一些实施方案中,所述试剂盒或组合物的化合物为共晶,其包括选自表1的化合物和(b)己二酸。
下面的详细描述中,本发明的其它特征,目的和优点是显而易见的。然而,应当理解,尽管指示了本发明的实施方案和方面,但是给出详细描述仅是出于示例性目的,而非限制。通过详细描述,本发明范围内的各种改变和变型对于本领域技术人员将变得显而易见。
在一些实施方案中,本公开提供用于例如通过纠正突变来编辑靶基因组的方法、组合物和试剂盒。这类方法、组合物和试剂盒可以通过使用DNA-PK抑制剂提高基因组编辑效率。
基因组编辑系统可以刺激或诱导DNA断裂,例如基因组(或靶基因组区域)中期望基因座处的DSB。DNA裂解的产生促使细胞酶通过易错的NHEJ途径或无错的HDR途径修复断裂位点。在NHEJ中,通过在一系列涉及Ku70/80异二聚体和DNA依赖性蛋白激酶(DNA-PK)的酶促过程中融合DNA断裂的两端来修复DNA损伤。修复机制牵涉两个DNA末端的系链和排列,切除,延伸和连接(Rouet et al.;Dexheimer T.DNA repair pathways andmechanisms.In:Mathews L,Cabarcas S,Hurt E,editors.DNA repair of cancer stemcells.Dordrecht:Springer;2013.p.19-32.),导致在断裂位点处形成小的插入或缺失突变(indels)。导入基因编码序列中的Indels可能导致过早的终止密码子或移码突变,其导致产生无功能的截短蛋白。对HDR途径的机制了解甚少,并且其牵涉一组不同的修复蛋白,例如Rad51,其可通过供体修复模板进行碱基插入或基因置换刺激链侵袭。因此,HDR允许导入外源DNA模板以获得基因组内DNA编辑的理想结果,并且可以为转化性疾病建模和治疗性基因组编辑以恢复基因功能提供强大的策略。
在两种DNA修复途径中,NHEJ发生的频率更高,且即使在神经元中也可以达到70%以上的效率(Swiech et al.,“In vivo interrogation of gene function in themammalian brain using CRISPR-Cas9,”Nat Biotechnol.2015Jan;33(1):102-62014)。然而,在S和G2阶段,当DNA复制完成且姐妹染色单体可以用作修复模板时,HDR基因校正以极低的频率发生(Heyer et al.,Regulation of homologous recombination ineukaryotes.Annual Review of Genetics44:113-139,2010)。由于NHEJ贯穿于竞争中的细胞周期发生,并且在有利性方面超过S和G2阶段的HDR,因此,通过HDR途径靶向插入保留了持续研究的挑战和焦点。
DNA蛋白激酶(DNA-PK)在不同DNA修复过程中起作用。DNA-PK通过活化非同源末端连接(NHEJ)途径参与DNA双链断裂修复。认为NHEJ通过三个步骤进行:DSB的识别,DNA加工以除去不可连接的末端或末端上的损伤的其它形式,和最终连接DNA末端。DSB的识别是通过使Ku异二聚体结合至不规则的(ragged)DNA末端,然后使DNA-依赖性蛋白激酶催化亚单位的两个分子(DNA-PKc或DNA-PK)募集至DSB相邻侧来进行的;这用于保护断裂的末端,直至募集另外的加工酶为止。近期数据支持如下推定:DNA-PKc使加工酶Artemis及其自身磷酸化,以制备用于另外的加工的DNA末端。在一些情况中,可能需要DNA聚合酶合成新的末端,然后进行连接步骤。认为DNA-PKc的自磷酸化诱导打开中心DNA结合腔的构象改变,从DNA中释放DNA-PKc,并且有利于最终的DNA末端再连接。
在一些实施方案中,本公开提供增强基因编辑的方法、组合物和试剂盒,特别是在基因组编辑系统中提高通过HDR途径修复DNA断裂的效率或抑制或阻抑通过NHEJ途径修复DNA断裂的效率,包括细胞中基于CRISPR的HDR修复。尽管不希望受到特定理论束缚,但是认为施用于细胞的基因组编辑系统与靶基因的核酸相互作用,导致或造成DNA断裂;这类DNA断裂通过几种修复途径修复,例如HDR,而施用于细胞的DNA-PK抑制剂抑制、阻断或阻抑NHEJ修复途径,且可以提高或促进HDR DNA修复途径的频率和效率。
基因组编辑系统与靶基因的核酸之间的相互作用可以是基因组编辑系统的至少一部分与靶基因的核酸的杂交,或基因组编辑系统对靶基因的核酸的任意其它识别。在一些实施方案中,这类相互作用为蛋白质-DNA相互作用或碱基对之间的杂交。
在一些实施方案中,本公开提供编辑细胞中一种或多种靶基因组区域的方法,通过对该细胞施用基因组编辑系统和DNA-PK抑制剂来进行。所述编辑可以同时或依次发生。所述一种或多种靶基因组区域的编辑包括细胞基因组的任意种类的遗传操作或改造。在一些实施方案中,一种或多种靶基因组区域的编辑可以包括细胞中基因组区域的插入、缺失或替代。基因组区域包含细胞中的遗传物质,例如DNA,RNA,多核苷酸和寡核苷酸。细胞中的基因组区域还包含细胞中包含的线粒体或叶绿体的基因组。
在一些实施方案中,插入、缺失或替代可以在编码或非编码基因组区域、在内含子或外显子区域或其任意组合中,包括其重叠或非重叠片段。如本文所用,“非编码区”是指不编码氨基酸序列的基因组区域。例如,非编码区包括内含子。编码区是指编码氨基酸序列的基因组区域。例如,编码区包括外显子。
在一些实施方案中,一种或多种靶基因组区域的编辑可发生在细胞基因组中的任何一个或多个靶区域中。例如,在一些实施方案中,一种或多种靶基因组区域的编辑可以出现在外显子,内含子,转录起始位点,启动子区,增强子区,沉默子区,绝缘子区,一个或多个靶基因组区域中,抗阻抑物,翻译后调节元件,聚腺苷酸化信号(例如最小的聚腺苷酸),保守区,转录因子结合位点或其任意组合中。
在一些实施方案中,与其中不给细胞施用DNA-PK抑制剂和基因组编辑系统的情况相比,给细胞施用DNA-PK抑制剂和基因组编辑系统导致基因组编辑效率提高。在一些实施方案中,与其中不给细胞施用DNA-PK抑制剂和基因组编辑系统的情况相比或与其中给细胞仅施用基因组编辑系统但不施用DNA-PK抑制剂的情况相比,提高的编辑效率为约1-倍,2-倍,3-倍,4-倍,5-倍,10-倍,15-倍,20-倍,25-倍,30-倍,40-倍,50-倍或100-倍。可以通过本领域公知的任意方法测定基因组编辑效率,例如,通过确定靶向多核苷酸整合的频率或通过测定靶向的诱变的频率的任何方法。靶向多核苷酸整合还可以导致基因组、染色体或细胞染色质中关注的区域中序列的改变或替代。靶向多核苷酸整合可以导致靶向突变,包括但不限于点突变(即单一碱基对转化成不同碱基对),取代(即多个碱基对转化成相同长度的不同序列),插入一个或多个碱基对,缺失一个或多个碱基对和上述序列改变的任意组合。
在一些实施方案中,编辑细胞中一种或多种靶基因组区域的方法牵涉向细胞施用基因组编辑系统和DNA-PK抑制剂。在一些实施方案中,细胞在S或G2细胞周期阶段同步化。细胞在S或G2细胞周期阶段同步化可以通过本领域已知的任意方法实现。作为非限制性实例,可以用于使细胞在S或G2细胞周期阶段同步化的活性剂包括阿非科林,dyroxyurea,洛伐他汀,含羞草氨酸,诺考达唑,胸苷或其任意组合。(参见Lin et al.,“Enhancedhomology-directed human genome engineering by controlled timing of CRISPR/Cas9delivery,”Elife.2014Dec 15;3)。在一些实施方案中,在基因编辑过程期间的任意时间施用用于细胞同步化的活性剂。在一些实施方案中,可以在对细胞施用基因组编辑系统和/或DNA-PK抑制剂之前、期间或之后使细胞在S或G2细胞周期阶段同步化。
在一些实施方案中,通过向细胞施用基因组编辑系统和DNA-PK抑制剂来编辑细胞中一种或多种靶基因组区域的方法,与其中不给细胞施用基因组编辑系统和DNA-PK抑制剂的情况或其中仅接触基因编辑系统或给细胞施用基因组编辑系统但不施用DNA-PK抑制剂的情况相比,导致细胞存活率提高。
在一些实施方案中,本文提供通过HDR途径修复一种或多种靶基因组区域中的DNA断裂的方法。向细胞施用基因组编辑系统和DNA-PK抑制剂导致基因组的靶区域的DNA断裂,且DNA断裂随后至少部分通过HDR途径修复。这些方法导致在一种或多种靶基因组区域中的HDR-介导的修复(例如HDR途径)的量增加,导致与其中不给细胞施用DNA-PK抑制剂和基因组编辑系统的情况相比,HDR-介导的修复的效率更高。在一些实施方案中,与其中不给细胞施用DNA-PK抑制剂和基因组编辑系统的情况相比或与其中仅给细胞施用基因组编辑系统但不施用DNA-PK抑制剂的情况相比,HDR途径介导的DNA断裂修复的效率为约1-倍,2-倍,3-倍,4-倍,5-倍,10-倍,15-倍,20-倍,25-倍,30-倍,40-倍,50-倍或100-倍。可以通过本领域已知的任意方法测定HDR途径介导的修复的效率,例如,通过确定靶向多核苷酸整合的频率或通过测定靶向的诱变的频率。
在一些实施方案中,本文的方法提供通过提高HDR途径的效率来修复DNA断裂的方法。
HDR途径可以是“典型的”或“可替代选择的”。“HDR”(同源介导修复)是指例如在细胞中双链断裂或DNA切口的修复期间发生的DNA修复的特殊形式。双链断裂的HDR通常基于核苷酸序列同源性,使用“供体”分子对“靶标”分子(例如经历双链断裂的分子)进行模板修复,并可能导致遗传信息从供体转移至靶标。双链断裂的典型HDR通常基于BRCA2和RAD51,并且典型地使用dsDNA供体分子。非典型的或“可替代选择的”HDR为受BRCA2,RAD51和/或功能相关基因抑制的HDR机制。可替代选择的HDR可以使用ssDNA或切口的dsDNA供体分子。参见,例如,WO2014172458。
在一些实施方案中,通过向细胞施用基因组编辑系统和DNA-PK抑制剂通过HDR途径修复一种或多种靶基因组区域中DNA断裂的方法,与其中不给细胞施用基因组编辑系统和DNA-PK抑制剂的情况相比或与其中给细胞仅施用基因编辑系统但不施用DNA-PK抑制剂的情况相比,导致细胞存活率提高。
在一些实施方案中,本文提供抑制或阻抑细胞中一种或多种靶基因组区域内的DNA断裂的NHEJ-介导的修复的方法。在一些实施方案中,抑制或阻抑NHEJ-介导的DNA断裂的修复通过抑制或阻抑NHEJ途径来进行。NHEJ途径可以为传统的(“典型的”)或可替代选择的NHEJ途径(alt-NHEJ或微同源介导的末端连接(MMEJ))。通过向细胞施用基因组编辑系统和DNA-PK抑制剂抑制细胞中的NHEJ途径或alt-NHEJ途径。
传统的NHEJ修复途径为DNA双链断裂修复途径,其中双链断裂的末端被连接而没有广泛的同源性。传统的NHEJ修复使用几种因子,包括KU70/80异二聚体(KU),XRCC4,连接酶IV和DNA蛋白激酶催化亚单位(DNA-PKc)。Alt-NHEJ为修复双链断裂的另一种途径。Alt-NHEJ在连接断裂末端之前的断裂端比对期间使用5-25碱基对微同源序列。Alt-NHEJ明显不依赖于KU70/80异二聚体(KU),XRCC4,连接酶IV,DNA蛋白激酶催化亚单位(DNA-PKc),RAD52和ERCC1。参见,Bennardo et al.,“Alternative-NHEJ is a Mechanistically DistinctPathway of Mammalian Chromosome Break Repair,”PLOS Genetics,2008年6月27日。
在一些实施方案中,与尚未接受基因组编辑系统和DNA-PK抑制剂的细胞相比或与其中细胞接受基因组编辑系统但未接受DNA-PK抑制剂的情况相比,通过经向细胞施用基因组编辑系统和DNA-PK抑制剂抑制或阻抑NHEJ途径来进行的抑制或阻抑细胞中一种或多种靶基因组区域内NHEJ-介导的通过NHEJ途径修复DNA断裂的方法导致抑制或阻抑NHEJ-介导的DNA断裂修复的效率提高。在一些实施方案中,与其中不给细胞施用DNA-PK抑制剂和基因组编辑系统的情况相比或与其中给细胞仅施用基因组编辑系统但不施用DNA-PK抑制剂的情况相比,通过使细胞与DNA-PK抑制剂和基因组编辑系统接触来抑制或阻抑通过NHEJ途径修复DNA断裂的效率提高约1-倍,2-倍,3-倍,4-倍,5-倍,10-倍,15-倍,20-倍,25-倍,30-倍,40-倍,50-倍或100-倍。可以通过本领域已知的任意方法测定抑制或阻抑通过NHEJ途径修复DNA断裂的效率,例如,通过确定靶向多核苷酸整合频率或通过测定靶向的诱变的频率。
在一些实施方案中,与其中基因组编辑系统和DNA-PK抑制剂不接触或不施用于细胞的情况相比或与其中仅基因编辑系统接触或施用于细胞但DNA-PK抑制剂不接触或施用于细胞的情况相比,通过经向细胞施用基因组编辑系统和DNA-PK抑制剂抑制或阻抑NHEJ途径来进行的抑制或阻抑细胞中一种或多种靶基因组区域内NHEJ-介导的DNA断裂修复的方法导致细胞存活率提高。
DNA断裂可以为双链断裂(DSB)或两个单链断裂(例如两个DNA切口)。DSB可以钝端化或具有5’或3’突出端,条件是链各自间隔过远裂解,突出端持续彼此退火并且作为两个切口存在,而不是一个DSB。
在一些实施方案中,本文提供修饰一种或多种基因(靶基因)和/或相应或下游蛋白质的表达的方法,通过向细胞施用基因组编辑系统和DNA-PK抑制剂来进行。在一些实施方案中,例如,所述基因组编辑系统可以在细胞的靶基因的靶基因组区域中创建插入,缺失,替代,修饰或破坏,导致修饰的靶基因的表达。在一些实施方案中,插入,缺失,替代,修饰或破坏可导致特定蛋白质或蛋白质组或下游蛋白质的靶向表达。在一些实施方案中所述基因组编辑系统可以在非编码区或编码区中创建插入、缺失或替代。在一些实施方案中,所述基因组编辑系统可以在启动子区,增强子区和/或任何其它基因调控元件,包括外显子,内含子,转录起始位点,沉默子区,绝缘子区,抗阻抑物,翻译后调节元件,聚腺苷酸化信号(例如最小聚腺苷酸),保守区,转录因子结合位点或其任意组合中产生创建插入,缺失,替代,修饰或破坏。在一些实施方案中,所述基因组编辑系统可以同时或依次在超过一个靶区域中创建插入,缺失,替代,修饰或破坏。在一些实施方案中,向细胞施用基因组编辑系统和DNA-PK抑制剂可以允许在细胞中靶向修饰的基因表达。这类靶向修饰的基因表达可以导致特异性蛋白质及其下游蛋白质的表达。
在一些实施方案中,与其中未对细胞施用DNA-PK抑制剂和基因组编辑系统的情况相比或与其中仅将基因组编辑系统施用于细胞但未施用DNA-PK抑制剂的情况相比,下游基因和/或蛋白质的表达提高至少10%,20%,30%,40%,50%,60%,70%,80%,90%,1,1.5-倍,2-倍,2.5-倍,3-倍,3.5-倍,4-倍,4.5-倍,5-倍或10-倍。
在一些实施方案中,与其中未对细胞施用DNA-PK抑制剂和基因组编辑系统的情况相比或与其中仅将基因组编辑系统施用于细胞但未施用DNA-PK抑制剂的情况相比,下游基因和/或蛋白质的基因表达降低至少10%,20%,30%,40%,50%,60%,70%,80%,90%,95%,96%,97%,98%或99%。
本文方法的细胞可以为任意的细胞。在一些实施方案中,所述细胞为脊椎动物细胞。在一实施方案中,所述脊椎动物细胞为哺乳动物细胞。在一些实施方案中,所述脊椎动物细胞为人体细胞。
所述细胞可以是处于任何发育阶段的任何种类的细胞。在一些实施方案中,该细胞可以为分化细胞,全能干细胞,多能干细胞,胚胎干细胞,胚胎生殖细胞,成人干细胞,前体细胞,诱导多能干细胞或其任意组合。分化的细胞为在组织中执行特定功能的专用细胞。全能干细胞为来自胚胎,胎儿或成人的未分化细胞,其可以长时间分裂,并具有分化为生物体的三个胚层中任何一个的任何细胞类型的能力。多能干细胞为来自胚胎,胎儿或成人的未分化的细胞,其可以长时间分裂,并具有分化成除胚外组织或胎盘外的生物体任何细胞类型的能力。胚胎干细胞为未分化的干细胞,其在胚胎的内部细胞团中发现,并且能够分化成三个胚层中任何一个的任何类型的细胞。胚胎生殖细胞为可以产生生殖细胞的胚胎细胞,例如精细胞或卵细胞。成人干细胞为未分化的细胞,其在分化的组织中发现,能够自我更新,并且可以分化成它所驻留的组织的任何细胞。前体细胞或先祖细胞为部分分化的细胞,其典型地仅可以分化成一种类型的细胞(例如单能细胞)。诱导型多能干细胞为从成人分化或部分分化的细胞中产生的多能干细胞种类。参见,例如,WO/2010/017562。
如本文所用,单数形式“一个,“一种”和“该”包括复数对应物,另有明确指示的除外。例如,术语“细胞”包括多种细胞,包括其混合物。例如,“一种或多种细胞”和“细胞”在本文中可以互换使用。类似地,“一种或多种靶基因组区域”和“靶基因组区域”在本文中可以互换使用。
术语“大约”和“约”在本文可互换使用。术语“大约”或“约”适用于一个或多个关注的值,其为与规定的参比值相似的值。在某些实施方案中,术语“大约”或“约”是指在任一方向(大于或小于)落入25%,20%,19%,18%,17%,16%,15%,14%,13%,12%,11%,10%,9%,8%,7%,6%,5%,4%,3%,2%,1%或以下的值,另有说明,否则在上下文中显而易见的除外(除非该数字超过可能值的100%)。
术语“多核苷酸”,“核苷酸”,“核苷酸序列”,“核酸”和“寡核苷酸”可以互换使用。它们是指任何长度的核苷酸的聚合形式,无论是脱氧核糖核苷酸(DNA)还是核糖核苷酸(RNA)或其类似物。多核苷酸可以具有任何三维结构,并且可以执行任何已知或未知的功能。以下是多核苷酸的非限制性实例:基因或基因片段的编码或非编码区,从连锁分析中定义的基因座(基因座),外显子,内含子,信使RNA(mRNA),转移RNA,核糖体RNA,干扰短RNA(siRNA),短发夹RNA(shRNA),微小RNA(miRNA),核酶,cDNA,重组多核苷酸,支链多核苷酸,质粒,载体,任何序列的分离DNA,任何序列的分离RNA,核酸探针和引物。多核苷酸可以包含一个或多个修饰的核苷酸,例如甲基化的核苷酸和核苷酸类似物。如果存在,则可以在聚合物组装之前或之后对核苷酸结构进行修饰。核苷酸的序列可以被非核苷酸组分打断。多核苷酸可在聚合后进一步被修饰,例如通过与标记组分缀合。术语“ssDNA”是指单链DNA分子。术语“ssODN”是指单链寡脱氧核苷酸。
本文涉及的术语“天然存在的核苷酸”包括脱氧核糖核苷酸和核糖核苷酸。本文所用的术语“修饰的核苷酸”包括具有修饰的或取代的糖基的核苷酸等。本文涉及的术语“寡核苷酸键”包括寡核苷酸键,例如硫代磷酸(phosphorothioate),二硫代磷酸(phosphorodithioate),硒代磷酸(phosphoroselerloate),二硒代磷酸(phosphorodiselenoate),硫代苯胺磷酸(phosphoroanilothioate),苯胺磷酸(phoshoraniladate),氨基磷酸(phosphoronmidate)等。如果期望,寡核苷酸可以包括用于检测的标记。
术语“合成RNA”是指改造的或非天然存在的RNA。
如本文所用,术语“野生型”是本领域技术人员理解的术语,并且表示作为与突变体或变体形式不同的天然存在时生物体,菌株,基因或特征的典型形式。
术语“非天然存在”或“改造的”可以互换使用,并且表示人为的介入。当提及核酸分子或多肽时,该术语是指该核酸分子或多肽至少基本上不含至少一种其它组分,它们与该组分在自然界中是自然缔合的,并且是如在自然界中所发现的。
“互补性”是指核酸通过传统的Watson-Crick或其它非传统类型与另一种核酸形成氢键的能力。互补性百分比表示可以形成氢键(例如Watson-Crick碱基配对)的核酸分子中具有第二核酸序列的残基百分比(例如,每10个中的5,6,7,8,9,10为50%,60%,70%,80%,90%和100%互补性)。“完全互补”是指核酸序列的所有连续残基将与第二核酸序列中相同数量的连续残基氢键键合。如本文所用,“基本上互补”是指在8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,30,35,40,45,50个或更多个核苷酸内为至少60%,65%,70%,75%,80%,85%,90%,95%,97%,98%,99%或100%的互补度或指在严格条件下杂交的两个核酸。
如本文所用,“表达”是指从DNA模板转录多核苷酸(例如翻译成mRNA或其它RNA转录物)的过程和/或转录的mRNA随后翻译成肽,多肽或蛋白质的过程。转录物和编码的多肽可以统称为“基因产物”。如果多核苷酸来源于基因组DNA,则表达可以包括在真核细胞中mRNA的剪接。
术语“多肽”,“肽”和“蛋白质”在本文中可以互换使用,以指任何长度的氨基酸的聚合物。该聚合物可以为直链或支链的,它可以包含修饰的氨基酸,并且可以被非氨基酸打断。该术语还包括已修饰的氨基酸聚合物;例如,二硫键形成,糖基化,脂质化,乙酰化,磷酸化或任何其它操作,例如与标记组分缀合。如本文所用,术语“氨基酸”包括天然和/或非天然或合成氨基酸,包括甘氨酸以及D或L旋光异构体和氨基酸类似物和肽模拟物。
如本文所用,术语“活性剂”用于表示化学化合物,小分子,化学化合物的混合物,生物大分子或由生物材料制成的提取物。
术语“受试者”,“个体”和“患者”在本文中可互换使用,是指脊椎动物,例如哺乳动物或人。哺乳动物包括但不限于鼠类,猿猴,人类,农场动物,运动动物和宠物。
如本文所用,“治疗”或“缓解”或“改善”可互换使用。这些术语是指获得有益或期望结果的方法,包括但不限于治疗有益性和/或预防有益性。所谓治疗有益性是指对一种或多种治疗中的疾病,病症或症状的任何治疗上相关的改善或作用。为了预防有益性,可以将组合物施用于处于发生特定疾病,病症或症状的风险中的受试者,或施用于报告疾病的一种或多种生理症状的受试者,不过,该疾病,病症或症状可能尚未表现出来。这些术语还表示在哺乳动物(例如,人)中的疾病,包括(a)抑制疾病,即遏制或预防其发展;(b)缓解疾病,即导致疾病状态消退;或(c)治愈疾病。
术语“有效量”或“治疗有效量”是指足以实现有益或期望结果的活性剂的量。治疗有效量可根据以下的一项或多项的不同而变化:待治疗的受试者和疾病状况,受试者的体重和年龄,疾病状况的严重程度,施用方式等,其可以由本领域技术人员便利地确定。该术语也适用于通过本文所述的成像方法的任意一种提供用于检测的图像的剂量。具体剂量可以根据以下一项或多项的不同而变化:所选的特定活性剂,遵循的给药方案,是否与其它化合物联合施用,施用时间,待成像的组织和其中进行的物理递送系统。
如本文所用,“施用”是指将基因组编辑系统和/或DNA-PK抑制剂接触,注射,分配,递送或施加至细胞或受试者。在一些实施方案中,施用为使基因组编辑系统和/或DNA-PK抑制剂与细胞接触。在一些实施方案中,施用为将基因组编辑系统和/或DNA-PK抑制剂递送至细胞。在一些实施方案中,施用为将基因组编辑系统和/或DNA-PK抑制剂施加于细胞。在一些实施方案中,施用为将基因组编辑系统和/或DNA-PK抑制剂注入细胞。施用可以在体内,离体或体外进行。可以同时或依次进行将基因组编辑系统和DNA-PK抑制剂施用于细胞。
本文所用的术语“获得性”是指与出生时存在的先天性疾病相反,在胎儿后发展的障碍或医学病症。先天性疾病可能是获得性疾病的先兆。
术语“先天性”或“遗传性”病症或疾病为出生时存在于受试者体内的受试者基因组中发现的遗传障碍。如本文所用,“基因组”包括细胞核中的所有遗传物质和细胞质,并且进一步包括线粒体基因组和核糖体基因组。先天性或遗传性可以在受试者一生中的任何时候表达,例如在出生或成年时。
术语“遗传性障碍”或“遗传性疾病”包括引起或可能引起疾病的受试者基因组中的遗传性或获得性突变。
术语“多态性”或“遗传变异”是指在遗传基因座处的基因的不同形式。
将“病毒载体”定义为重组产生的病毒或病毒颗粒,其包含在体内,离体或体外递送至宿主细胞的多核苷酸。病毒载体的实例包括逆转录病毒载体,腺病毒载体,腺相关病毒载体,腺病毒载体,慢病毒载体,单纯疱疹病毒载体和嵌合病毒载体等。在其中逆转录病毒载体介导基因转移的一些实施方案中,载体构建体是指包含逆转录病毒基因组或其部分的多核苷酸。
本公开的一些实施方案涉及包含一种或多种载体的载体系统或载体本身。可以设计载体以在原核或真核细胞中表达CRISPR转录物(例如核酸转录物,蛋白质或酶)。例如,CRISPR转录物可以在细菌细胞例如大肠杆菌(Escherichia coli),昆虫细胞(使用杆状病毒表达载体),酵母细胞或哺乳动物细胞中表达。
所述细胞可以是原代细胞,诱导型多能干细胞(iPSC),胚胎干细胞(hESC),成人干细胞,先祖细胞或细胞系。“原代细胞”是直接从活组织中取得并且置于体外生长的细胞。原代细胞几乎没有群体倍增,并且对于体外群体倍增具有有限的寿命。“干细胞”,“胚胎干细胞”和“诱导型多能干细胞”是能够自我更新并具有分化为具有专门功能的不同类型细胞的潜能的非专用和未分化细胞。“细胞系”包括衍生自一种细胞类型或相同类型的一组细胞的细胞培养物,它们可以无限期增殖。哺乳动物细胞系的非限制性实例可以包括CD34细胞,293细胞,HEK细胞,CHO细胞,BHK细胞,CV-1细胞,Jurkat细胞,HeLa细胞或其任何变体。
在一些实施方案中,载体能够使用哺乳动物表达载体驱动哺乳动物细胞中的一个或多个序列的表达。哺乳动物表达载体的实例包括pCDM8和pMT2PC。当用于哺乳动物细胞中时,表达载体的控制功能典型地由一种或多种调节元件提供。例如,常用的启动子衍生自多瘤,腺病毒2,巨细胞病毒,猿猴病毒40和本文公开的和本领域已知的其它启动子。其它启动子可以包括,例如EF1启动子或EF1α启动子。对于原核和真核细胞的其它适合的表达系统,参见,例如Sambrook et al.,MOLECULAR CLONING:A LABORATORY MANUAL.第2版的第16和17章,Cold Spring HarborLaboratory,Cold Spring HarborLaboratory Press,ColdSpring Harbor,N.Y.,1989。
如本文所用,术语“标记”或“标记的”是指掺入可检测的标记,例如通过掺入可被标记的抗生物素蛋白检测到的放射性标记的氨基酸或附着于生物素部分的多肽(例如可以通过光学或量热法检测到的包含荧光标记或酶活性的链霉抗生物素)。在某些情况下,标记或标记物也可以是治疗性的。标记多肽和糖蛋白的不同方法是本领域已知的并且可以使用。多肽标记的实例包括但不限于如下:放射性同位素或放射性核素(例如3H,14C,15N,35S,90Y,99Tc,111In,125I,131I),荧光标记(例如FITC,若丹明,镧系磷光体),酶标记(例如辣根过氧化物酶,p-半乳糖苷酶,荧光素酶,碱性磷酸酶),化学发光,生物素基团,被二级报道分子识别的预定多肽表位(例如亮氨酸拉链对序列,二次抗体的结合位点,金属结合结构域,表位标记)。在一些实施方案中,标记通过不同长度的间隔臂连接,以减少潜在的位阻。如本文所用,术语“药剂或药物”是指当适当地施用于患者时能够诱导期望的治疗效果的化学化合物或组合物。
如本文所用,“基本上纯的”是指目标种类为存在的主要种类(即,以摩尔浓度为基准,其比组合物中的任何其它单个种类更丰富)。在一些实施方案中,一种基本上纯化的级分为组合物,其中目标种类占存在的所有大分子种类的至少约50%(基于摩尔浓度)。
通常,基本上纯的组合物将包含大于约80%的该组合物中存在的所有大分子种类。在一些实施方案中,基本上纯的组合物包含大于约85%,90%,95%和99%的该组合物中存在的所有大分子种类。在一些实施方案中,将目标种类纯化为基本均一的(通过常规检测方法在组合物中未检测到污染物),其中组合物主要由单个大分子种类组成。
基因组编辑系统
可以使用不同类型的基因组工程系统。术语“基因组编辑系统”,“基因编辑系统”等在本文中可以互换使用,且是指编辑靶基因或其官能或表达的系统或技术。基因组编辑系统包含:至少一种核酸内切酶组分,其能够切割靶基因组区域(或靶序列);和至少一种基因组靶向元件,其携带核酸内切酶组分或使其靶向至靶基因组区域。基因组靶向元件的实例包括DNA-结合结构域(例如锌指DNA-结合蛋白或TALE DNA-结合结构域),向导RNA元件(例如CRISPR向导RNA)和向导DNA元件(例如NgAgo向导DNA)。可编程的基因组靶向和核酸内切酶元件可通过在特定基因组基因座处导入DNA断裂例如双链断裂(DSB)来进行精确的基因组编辑。随后,DSB向DSB位点募集用于非同源末端连接(NHEJ)或同源介导修复(HDR)的内源修复机制,以介导基因组编辑。“核酸内切酶组分”包含核酸内切酶或包含编码该核酸内切酶的核苷酸序列的核酸。
术语“核酸内切酶”是指能够催化DNA或RNA分子内核酸之间的键的水解(裂解)的任何野生型,突变,变体或工程酶。核酸内切酶可以在其靶基因组区域处识别并切割DNA或RNA分子。核酸内切酶的实例包括归巢核酸内切酶(homing endonuclease);限制酶,例如FokI;嵌合锌指核酸酶(ZFN),其由改造的锌指结构域与限制酶例如FokI的催化结构域融合得到;Cas酶和Cpf酶。在术语“核酸内切酶”中包含化学核酸内切酶,其中化学或肽切割器与核酸的聚合物或与识别特异性靶序列的另一种DNA缀合,由此将切割活性靶向特异性序列。化学核酸内切酶(enonuclease)的实例包括合成核酸酶,如邻二氮菲的缀合物,DNA裂解分子和形成三链体的寡核苷酸(TFO)。
所谓“变体”是指通过用不同的氨基酸替代亲代蛋白质的氨基酸序列中的至少一个残基而获得的重组蛋白质。
在一些实施方案中,核酸内切酶例如ZFN,TALEN和/或兆核酸酶包含切割结构域和/或切割半结构域。切割结构域可以与DNA结合结构域同源或异源。例如,可以使用锌指DNA结合结构域和来自核酸酶的切割结构域或兆核酸酶DNA结合结构域和来自不同核酸酶的切割结构域。异源切割结构域可以得自任何核酸内切酶或核酸外切酶。可以衍生切割结构域的示例性核酸内切酶包括但不限于限制核酸内切酶和归巢核酸内切酶。参见,例如,WO2013/130824。切割DNA的其它酶是已知的(例如S1核酸酶;绿豆核酸酶;胰腺DNase I;微球菌核酸酶;酵母HO核酸内切酶;也参见Linn et al.,(eds.)Nucleases,Cold SpringHarborLaboratory Press,1993)。这些酶中的一种或多种(或其功能片段)可以用作切割结构域和切割半结构域的来源。
切割半结构域可以衍生自如上所述的任何核酸酶或其部分,它们需要二聚化以用于切割活性。在一些实施方案中,如果融合蛋白包含切割半结构域,则需要两个融合蛋白进行切割。在一些实施方案中,可以使用包含两个切割半结构域的单一蛋白质。在一些实施方案中,两个切割半结构域可衍生自相同的核酸内切酶(或其功能片段)。在一些实施方案中,每个切割半结构域可以衍生自不同的核酸内切酶(或其功能片段)。此外,优选地彼此布置两个融合蛋白的靶位点,使得两个融合蛋白与它们各自的靶位点的结合彼此在空间取向上切割半结构域,这允许切割半结构域以形成功能性切割结构域,例如通过二聚化。因此,在某些实施方案中,靶位点的近边缘被5-50个核苷酸,5-8个核苷酸或15-18个核苷酸隔开。应当注意,任何整数个核苷酸或核苷酸对均可以插入两个靶位点之间(例如2-50个核苷酸对或以上)。在一些实施方案中,切割位点位于靶位点之间。
限制核酸内切酶(限制酶)存在于许多物种中,并且能够与DNA(在识别位点)进行序列特异性结合,并在结合位点处或其附近切割DNA。某些限制酶(例如IIS型)在从识别位点移出的位点切割DNA,并具有可分离的结合和切割结构域。例如,IIS型酶Fok I催化DNA的双链切割。参见,例如,美国专利5,356,802;5,436,150和5,487,994;以及Li et al.,(1992)Proc.Natl.Acad.Sci.USA 89:4275-4279;Li et al.,(1993)Proc.Natl.Acad.Sci.USA 90:2764-2768;Kim et al.,(1994a)Proc.Natl.Acad.Sci.USA91:883-887;Kim et al.,(1994b)J.Biol.Chem.269:31,978-31,982。
在一些实施方案中,核酸内切酶组分包含融合蛋白,所述融合蛋白包括来自至少一种IIS型限制酶的切割结构域(或切割半结构域)和一个或多个可以改造或不可以改造的锌指结合结构域。示例性的IIS型限制酶为FokI,其切割结构域可与结合结构域分离。该特定的酶作为二聚体具有活性。Bitinaite et al.,(1998)Proc.Natl.Acad.Sci.USA 95:10,570-10,575。在这种融合蛋白中使用的Fok I酶的一部分被视为切割半结构域。因此,对于使用锌指-或TALE-Fok I融合体的靶向双链裂解和/或靶向置换细胞序列,可以使用各自包含FokI裂解半结构域的两种融合蛋白来重构催化活性裂解结构域。或者,也可以使用包含锌指结合结构域和两个Fok I切割半结构域的单一多肽分子。
示例性的IIS型限制酶描述于国际公开号WO07/014275中,其整体并入本文。另外的限制酶也包含可分离的结合和切割结构域,并且这些是本公开考虑的。例如,参见,Roberts et al.,(2003)Nucleic Acids Res.31:418-420。
在某些实施方案中,切割结构域包含一个或多个改造的切割半结构域(也称为二聚化结构域突变体),其最小化或防止同型二聚化,例如在美国专利公开号20050064474和20060188987以及WO2013/130824中所述。形成专性异二聚体的Fok I的示例性改造的切割半结构域包括一对,其中第一切割半结构域包括Fok I的490和538位氨基酸残基上的突变,而第二切割半结构域包括氨基酸残基486和499上的突变。参见,例如美国专利公开号2008/0131962和2011/0201055。可以使任意适合的方法,例如通过如美国专利公开号20050064474和20080131962中所述的野生型切割半结构域(Fok I)的定点诱变来制备本文所述的改造的切割半结构域。
术语“编辑”是指任何种类的改造,改变,修饰或调节(在每种情况下,包括但不限于通过基因敲除,基因标记,基因破坏,基因突变,基因插入,基因缺失,基因激活,基因沉默或基因敲入)。
如本文所用,“遗传修饰”,“基因组编辑”,“基因组修饰”,“基因修饰”和“基因编辑”是指任何基因添加,缺失,敲除,敲入,标记,突变,激活,沉默,修饰和/或对细胞核苷酸的破坏。在本文上下文中,细胞可以是体外、体内或离体的。
所谓“靶基因组区域”,“靶基因”,“DNA靶标”,“DNA靶序列”,“靶序列”,“靶核苷酸序列”,“靶位点”,“靶标”,“关注的位点”,“识别位点”,“多核苷酸识别位点”,“识别序列”,“切割位点”预期是指被基因组编辑系统识别和切割的多核苷酸序列。这些术语是指不同的DNA位置,优选为基因组位置,此时所述基因组编辑系统诱导DNA断裂(切割)。
上述编辑包括改造,改变,修饰和调节可以同时或依次进行。可以使用本领域已知的任何基因组编辑系统。在一些实施方案中,所述基因组编辑系统为基于兆核酸酶的系统,基于锌指核酸酶(ZFN)的系统,基于转录激活因子样效应物的核酸酶(TALEN)系统,基于CRISPR的系统或基于NgAgo的系统。
基于兆核酸酶,基于ZFN和基于TALEN的各自包含至少一个DNA结合结构域或包含编码该DNA结合结构域的核酸序列的核酸,并通过蛋白质-DNA相互作用实现靶基因组区域的特异性靶向或识别。基于CRISPR的系统包含至少一种向导RNA元件或包含编码向导所述RNA元件的核酸序列的核酸,并通过直接与靶基因组区域的DNA碱基配对实现靶基因组区域的特异性地靶向或识别。基于NgAgo的系统包含至少一个向导DNA元件或包含编码所述向导DNA元件的核酸序列的核酸,并通过直接与靶基因组区域的DNA碱基配对实现靶基因组区域的特异性靶向或识别。
在一些实施方案中,所述基因组编辑系统为基于兆核酸酶的系统。基于兆核酸酶的系统为使用具有大(>14bp)识别位点的核酸内切酶的核酸内切酶,并且其DNA结合结构域也负责靶序列的切割。兆核酸酶的DNA结合结构域可以具有12-45bp的双链DNA靶序列。在一些实施方案中,兆核酸酶为二聚化酶,其中每个兆核酸酶位于单体上或在单一多肽上包含两个结构域的单体酶。不仅野生型兆核酸酶,而且不同的兆核酸酶变体均已经通过蛋白质改造生成,以覆盖各种兆核酸酶变体,以覆盖无数独特的序列组合。在一些实施方案中,也可以使用具有由兆核酸酶A的半位点和蛋白质B的半位点组成的识别位点的嵌合兆核酸酶。此类嵌合兆核酸酶的具体实例包括I-DmoI和I-CreI的蛋白质结构域。兆核酸酶的实例包括来自LAGLIDADG家族的归巢核酸内切酶。
LAGLIDADG兆核酸酶可以为I-SceI,I-ChuI,I-CreI,I-CsmI,PI-SceI,PI-TliI,PI-MtuI,I-CeuI,I-SceII,I-SceIII,HO,PI-CivI,PI-CtrI,PI-AaeI,PI-BsuI,PI-DhaI,PI-DraI,PI-MavI,PI-MchI,PI-MfuI,PI-MflI,PI-MgaI,PI-MgoI,PI-MinI,PI-MkaI,PI-MleI,PI-MmaI,PI-MshI,PI-MsmI,PI-MthI,PI-MtuI,PI-MxeI,PI-NpuI,PI-PfuI,PI-RmaI,PI-SpbI,PI-SspI,PI-FacI,PI-MjaI,PI-PhoI,PI-TagI,PI-ThyI,PI-TkoI,PI-TspI或I-MsoI;或可以为其功能性突变体或其变体,无论是同型二聚体,异二聚体,还是单体。在一些实施方案中,LAGLIDADG兆核酸酶为I-CreI衍生物。在一些实施方案中,LAGLIDADG兆核酸酶与天然I-CreI LAGLIDADG兆核酸酶共享至少80%相似性。在一些实施方案中,LAGLIDADG兆核酸酶与天然I-CreI LAGLIDADG兆核酸酶的残基1-152共享至少80%相似性。在一些实施方案中,LAGLIDADG兆核酸酶可以由与彼此连接的天然I-CreI LAGLIDADG兆核酸酶的残基1-152共享至少80%相似性的两个单体与或不与接头肽组成。
“LAGLIDADG兆核酸酶”是指来自LAGLIDADG家族的归巢核酸内切酶,如Stoddardet al.,(Stoddard,2005年)所定义的,或包含多肽的改造变体,所述多肽与所述天然归巢核酸内切酶共享至少80%,85%,90%,95%,97.5%,99%或以上的同一性或相似性。这类改造的LAGLIDADG兆核酸酶可以衍生自单体或二聚化兆核酸酶。当衍生自二聚化兆核酸酶时,这类改造的LAGLIDADG兆核酸酶可以为单链或二聚化核酸内切酶。
所谓“I-CreI”预期为天然野生型I-CreI兆核酸酶,其具有pdb登录代码1g9y的序列。兆核酸酶的DNA识别和切割功能通常在单个结构域中交织在一起。与兆核酸酶不同,基于ZFN和TALEN的系统的DNA结合结构域与核酸内切酶的切割功能不同。基于ZFN的系统包含:至少一种锌指蛋白或其变体或包含编码所述锌指蛋白或其变体的核苷酸序列的核酸作为其DNA结合结构域;以及核酸内切酶元件,例如锌指核酸酶(ZFN)或Fok1切割结构域。锌指(zinc finder)蛋白(ZFP)为非天然存在的,即其经过改造以结合至所选择的靶位点。参见,例如,Beerli et al.,(2002)Nature Biotechnol.20:135-141;Pabo et al.,(2001)Ann.Rev.Biochem.70:313-340;Isalan et al.,(2001)Nature Biotechnol.19:656-660;Segal et al.,(2001)Curr.Opin.Biotechnol.12:632-637;Choo et al.,(2000)Curr.Opin.Struct Biol.10:411-416;美国专利6,453,242;6,534,261;6,599,692;6,503,717;6,689,558;7,030,215;6,794,136;7,067,317;7,262,054;7,070,934;7,361,635;7,253,273;和美国专利公布号2005/0064474;2007/0218528;2005/0267061。
与天然存在的锌指蛋白相比,改造的锌指结合结构域可以具有新的结合特异性。改造的方法包括但不限于合理设计和不同类型的选择。合理的设计包括,例如,使用包含三联体(或四联体)核苷酸序列和单个锌指氨基酸序列的数据库,其中每个三联体或四联体核苷酸序列与结合特定三联体或四联体的序列锌指的一个或多个氨基酸序列相关联。参见,例如,共同拥有的美国专利6,453,242和6,534,261,其全部内容通过引用并入本文。
不同的选择方法可以与本文的方法一起使用。在美国专利5,789,538;5,925,523;6,007,988;6,013,453;6,410,248;6,140,466;6,200,759;和6,242,568;以及WO98/37186;WO98/53057;WO00/27878;WO01/88197和GB2,338,237中公开了示例性的选择方法,包括噬菌体展示和双杂交系统。此外,例如在WO02/077227中描述了对锌指结合结构域的结合特异性的增强。此外,如这些和其它参考文献中所公开的,可以使用任意适合的接头序列(例如,长度为5个或更多个氨基酸的接头)使锌指结构域和/或多指锌指蛋白彼此连接。关于长度为6个或更多个氨基酸的示例性接头序列,另外,参见,美国专利号6,479,626;6,903,185;以及7,153,949。本文所述的蛋白质可以包括蛋白质的各个锌指之间的适合接头的任意组合。靶位点的选择;ZFP以及用于设计和构建融合蛋白(和编码它们的多核苷酸)的方法是本领域技术人员已知的,并在如下文献中详细描述:美国专利6,140,0815;789,538;6,453,242;6,534,261;5,925,523;6,007,988;6,013,453;6,200,759;WO95/19431;WO96/06166;WO98/53057;WO98/54311;WO00/27878;WO01/60970;WO01/88197;WO02/099084;WO98/53058;WO98/53059;WO98/53060;WO02/016536和WO03/016496。
此外,如这些和其它参考文献中所公开的,可以使用任意适合的接头序列,包括长度为5个或更多个氨基酸的接头,使锌指结构域和/或多指锌指蛋白彼此连接。关于长度为6个或更多个氨基酸的示例性接头序列,参见,例如美国专利6,479,626;6,903,185;和7,153,949。本文所述的蛋白质可以包括蛋白质的各个锌指之间的适合接头的任意组合。
基于转录激活因子样效应物的核酸酶(TALEN)系统是指基因组编辑系统,其使用一种或多种转录激活因子样效应物(TALE)-DNA结合结构域和核酸内切酶元件,例如Fok1切割结构域。TALE-DNA结合结构域包含一个或多个TALE重复单元,它们各自具有30-38(例如31,32,33,34,35或36)氨基酸长度。TALE-DNA结合结构域可以使用全长TALE蛋白质或其片段或其变体。TALE-DNA结合结构域可以通过接头与核酸内切酶结构域融合或与之连接。
术语“基于CRISPR的系统”,“基于CRISPR的基因编辑系统”,“CRISPR-基因组编辑”,“CRISPR-基因编辑”,“基于CRISPR-核酸内切酶的基因组编辑”等在本文中可以互换使用,且统称为包含一个或多个向导RNA元件和一个或多个RNA-向导核酸内切酶元件的基因组编辑系统。向导RNA元件包括包含与在一种或多种靶基因组区域处的核苷酸序列基本上互补的核苷酸序列的靶向物RNA或包含编码所述靶向物RNA的核苷酸序列的核酸。RNA-向导的核酸内切酶元件包含通过向导RNA元件向导或达到靶基因组区域的核酸内切酶;或包含编码这类核酸内切酶的核苷酸序列的核酸。这类基于CRISPR的基因编辑系统的实例包括基于CRISPR的系统为CRISPR-Cas系统或CRISPR-Cpf系统。
如本文所用,术语“向导RNA元件”,“向导RNA”,“gRNA”,“gRNA分子”和“合成的向导RNA”可以互换使用,且是指多核苷酸序列,其包含与靶核酸序列杂交的靶向物RNA或包含编码所述靶向物RNA的核苷酸序列的核酸。gRNA的靶向物RNA包含靶向结构域,其包括与靶基因组区域处的核苷酸序列基本上互补的核苷酸序列。措词“基本上互补”是指在8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,30,35,40,45,50个或更多核苷酸区内至少为60%,65%,70%,75%,80%,85%,90%,95%,97%,98%,99%或100%的互补程度,或是指在严格条件下杂交的两种核酸。
向导RNA元件可以进一步包含能够与所述靶向物RNA杂交的激活物RNA或包含编码所述激活物RNA的核苷酸序列的核酸。激活物RNA和靶向物RNA可以为单独的或通过接头环序列融合为单一核酸,以形成单一gRNA分子。gRNA分子可以包含多个结构域。例如,这类gRNA例如从5’-3’包括:靶向结构域(其与靶核酸互补);第一互补结构域;连接结构域;第二互补结构域(其与第一互补结构域互补);近端结构域;和任选的尾结构域。参见WO2015048557。
“第一互补结构域”与第二互补结构域具有实质性的互补性,并且可以在至少某些生理条件下形成双链体区(duplexed region)。
“连接结构域”用于将单分子gRNA的第一互补结构域与第二互补结构域连接。连接结构域可以以共价或非共价方式连接第一和第二互补结构域。
“近端结构域”可以是3-25个核苷酸长度或5-20个核苷酸长度。近端结构域可以与天然存在的近端结构域共享同源性或衍生自天然存在的近端结构域。
“尾结构域”可以不存在或为1,2,3,4,5,6,7,8,9或10个核苷酸长度。尾结构域可以包括彼此互补的序列并且在至少一些生理学条件下形成双链体区。
向导RNA元件可以与RNA向导的核酸内切酶元件的核酸内切酶,例如Cas核酸内切酶形成复合物(“gRNA/核酸酶复合物”)。gRNA/核酸酶复合物的实例为如下所述关于基于CRISR的系统的CRISPR复合物。在一些实施方案中,CRISPR复合物包含与靶向物RNA复合的RNA向导的核酸内切酶系统的核酸内切酶。在一些实施方案中,CRISPR复合物包含与靶向物RNA和激活物RNA复合的RNA向导的核酸内切酶系统的核酸内切酶。
靶向物RNA的靶向结构域促进gRNA/核酸酶复合物特异性靶向或归巢至靶核苷酸序列。在一些实施方案中,靶向结构域可以为10-30bp,例如15-25bp,18-22bp或20bp。
用于设计gRNA的方法为本领域公知的,包括用于筛选,设计和验证靶结构域的方法。参见,例如,WO2015048577,Mali et al.,2013SCIENCE 339(6121):823-826;Hsu etal.,2013NATBIOTECHNOL,31(9):827-32;Fu et al.,2014NATBTOTECHNOL,doi:10.1038/nbt.2808.PubMed PMID:24463574;Heigwer et al.,2014NAT METHODS11(2):122-3.doi:l0.1038/nmeth.2812.PubMed PMID:24481216;Bae et al.,2014BIOTNFORMATICS PubMedPMID:24463181;Xiao A et al.,2014BIOINFORMATICS Pub Med PMID:24389662。
在一些实施方案中,可以使用RNA-向导的核酸内切酶,例如Cas酶或蛋白质(例如II型Cas9蛋白质)或Cpf酶或蛋白质(例如Cpf1蛋白质)。在一些实施方案中,还可以使用这样的Cas或Cpf酶或蛋白质的修饰形式。
在一些实施方案中,基于CRISPR的系统为CRISPR-Cas系统。所述CRISPR-Cas系统包括:(a)至少一种向导RNA元件或包含编码所述向导RNA元件的核苷酸序列的核酸;所述向导RNA元件包含靶向物RNA(其包含与一种或多种靶基因组区域处的核苷酸序列基本上互补的核苷酸序列),和激活物RNA(其包含能够与所述靶向物RNA杂交的核苷酸序列);和(b)包含Cas蛋白质的Cas蛋白质元件或包含编码所述Cas蛋白质的核苷酸序列的核酸。所述靶向物RNA和激活物RNA可以为单独的或融合成单一RNA。
在一些实施方案中,基于CRISPR的系统包括1类CRISPR和/或2类CRISPR系统。1类系统使用几种Cas蛋白质与作为靶向物RNA的CRISPR RNA(crRNA)以构建功能性核酸内切酶。2类CRISPR系统使用单一Cas蛋白质和作为靶向物RNA的crRNA。2类CRISPR系统(包括基于II型Cas9的系统)包含单一Cas蛋白质以介导裂解,而不是1类系统使用的多亚单位复合物。基于CRISPR的系统还包括II类V型CRISPR系统,其使用Cpf1蛋白质和作为靶向物RNA的crRNA。
Cas蛋白质为CRISPR-相关(Cas)双链核酸酶。在一些实施方案中,CRISPR-Cas系统包含Cas9蛋白质。在一些实施方案中,Cas9蛋白质为SaCas9,SpCas9,SpCas9n,Cas9-HF,Cas9-H840A,FokI-dCas9或D10A切口酶。术语“Cas蛋白质”,例如Cas9蛋白质包括野生型Cas蛋白质或其功能性衍生物(例如具有核酸酶活性的野生型Cas蛋白质的截短的形式或变体)。
在一些实施方案中,可以使用来自非酿脓链球菌(S.pyogenes)和S.thermophiles的种类的Cas9蛋白质。本文中可以得到并且使用另外的Cas9蛋白质种类,包括:Acidovoraxavenae,胸膜炎肺炎放线杆菌(Actinobacillus pleuropneumoniae),Actinobacillussuccinogenes,猪放线杆菌(Actinobacillus suis),放线菌属(Actinomyces sp.),cycliphilus denitrificans,Aminomonas paucivorans,蜡状芽孢杆菌(Bacilluscereus);史氏芽芽胞杆菌(Bacillus smithii),苏云金芽孢杆菌(Bacillusthuringiensis),拟杆菌属(Bacteroides sp.),Blastopirellula marina,短根瘤菌属(Bradyrhizobium sp.),Brevibacillus laterosporus,结肠弯曲杆菌(Campylobactercoli),空肠弯曲杆菌(Campylobacter jejuni),红嘴鸥弯曲杆菌(Campylobacter lari),Candidatus Puniceispirillum,解纤维素梭菌(Clostridium cellulolyticum),Clostridium perfingens,拥挤棒杆菌(Corynebacterium accolens),Corynebacteriumdolichum,马氏棒状杆菌(Corynebacterium matruchotii),Dinoroseobacter shibae,细长真杆菌(Eubacterium dolichum),gamma proteobacterium,Gluconacetobacterdiazotrophicus,Haemoplzilus parainfluenzae,Haemophilus sputorum,Helicobactercanadensis,Helicohacter cinaedi,鼬螺杆菌(Helicobacter mustelae),llyobacterpolytropus,金氏金氏杆菌(Kingella kingae),卷曲乳杆菌(lactobacillus crispatus),绵羊李斯特杆菌(listeria ivanovii),单核细胞增生利斯特菌(listeriamonocytogenes),李斯特氏菌科细菌(listeriaceae bacterium),甲基孢囊菌属(methylocystis sp.),丝孢酵母甲基窦菌(methylosinus trichosporium),羞怯动弯杆菌(Mobiluncus mulieris),Neisseria bacilliformis,灰色奈瑟菌(Neisseria cinerea),浅黄奈瑟球菌(Neisseria flavescens),乳酰胺奈瑟球菌(Neisseria lactamica),奈瑟球菌属(Neisseria sp.),Neisseria wadsworthii,亚硝化单胞菌属(Nitrosomonas sp.),Parvibaculum lavamentivorans,多杀巴斯德菌(Pasteurella multocida),Phascolarctobacterium succinatutells,Ralstonia syzygii,Rhodopseudomonaspalustris,小红卵菌属(Rhodovulum sp.),米氏西蒙斯菌(Simonsiella muelleri),假平胞菌属(Sphingomonas sp.),Sporolactobacillus vineae,路邓葡萄球菌(Staphylococcus lugdunensis),链球菌属(Streptococcus sp.),Subdoligranulum sp.,Tistrella mobilis,密螺旋体属(Treponema sp.)或Verminephrobacter eiseniae。
在一些实施方案中,基于CRISPR的系统的一种或多种元件来源于I型,II型或III型CRISPR系统。
在一些实施方案中,基于CRISPR的系统的一种或多种元件来源于特定生物体,包含内源性CRISPR系统,例如酿脓链球菌(Streptococcus pyogenes),金黄色葡萄球菌(Staphylococcus aureus),土拉热弗朗西丝菌(Francisella tularensis),普里沃菌属(Prevotella sp),氨基酸球菌属(Acidaminococcus sp.)和毛螺菌科属(Lachnospiraceaesp)。通常,基于CRISPR的系统的特征在于在靶序列的靶基因组区域或位点处促进CRISPR复合物形成(上下文中也称作内源性CRISPR系统中的原间隔基(protospacer))。在上下文中CRISPR复合物的形成过程中,“靶序列”是指向导序列被设计为具有实质互补性的序列,其中靶序列与向导序列之间的杂交促进了CRISPR复合物形成。完全互补不一定是必不可少的,只要存在足够的互补性以引起杂交并促进CRISPR复合物形成即可。靶序列可以包含任何多核苷酸,例如DNA或RNA多核苷酸。在一些实施方案中,靶序列位于细胞的细胞核或细胞质中。在一些实施方案中,靶序列可能在真核细胞的细胞器内,例如线粒体或叶绿体。
可用于重组为包含靶序列的靶基因座的序列或模板称作“编辑模板”或“编辑多核苷酸”或“编辑序列”。外源模板多核苷酸可以称作编辑模板或供体模板。在一些实施方案中,可以使用合成或生物来源的单链DNA和双链DNA。作为非限制性实例,适合的编辑模板包括ssODN,dsODN,PCR产物,质粒和病毒,包括AAV,腺病毒,逆转录病毒,慢病毒等。其它编辑模板也是可能的。在一些实施方案中,重组为同源重组。
在一些实施方案中,基于CRISPR的系统为CRISPR-Cas9系统。CRISPR-Cas9系统的靶向物RNA包含CRISPR靶向RNA(crRNA),且CRISPR-Cas 9系统的激活物RNA包含反式激活CRISPR RNA(tracRNA)。CRISPR-Cas9系统的Cas蛋白质元件使用Cas9蛋白质。crRNA和tracrRNA可以是单独的或通过接头环序列合并成单一RNA构建体。这种合并的RNA构建体称作单一-向导RNA(sgRNA;或向导RNA)。
关于CRISPR-Cas系统,其组分和此类组分的递送的一般信息,包括方法,材料,递送媒介物,载体,颗粒,AAV及其制备方法和使用,包括其量和制剂可以在如下文献中找到:美国专利8,999,641,8,993,233,8,945,839,8,932,814,8,906,616,8,895,308,8,889,418,8,889,356,8,871,445,8,865,406,8,795,965,8,771,945和8,697,359;美国专利公开号US2014-0310830,US2014-0287938A1,US2014-0273234A1,US2014-0273232A1,US2014-0273231,US2014-0256046A1,US2014-0248702A1,US2014-0242700A1,US2014-0242699A1,US2014-0242664A1,US2014-0234972A1,US2014-0227787A1,US2014-0189896A1,US2014-0186958,US2014-0186919A1,US2014-0186843A1,US2014-0179770A1和US2014-0179006A1,US2014-0170753;欧洲专利EP2784162B1和EP2771468B1;欧洲专利申请EP2771468(EP13818570.7),EP2764103(EP13824232.6)和EP2784162(EP14170383.5);和PCT专利申请PCT专利申请公开号WO2014/093661,WO2014/093694,WO2014/093595,WO2014/093718,WO2014/093709,WO2014/093622,WO2014/093635,WO2014/093655,WO2014/093712,WO2014/093701,WO2014/018423,WO2014/204723,WO2014/204724,WO2014/204725,WO2014/204726,WO2014/204727,WO2014/204728,WO2014/204729和WO2016/028682。
在一些实施方案中,基于CRISPR的系统为CRISPR-Cpf系统。所述“CRISPR-Cpf系统”包括:(a)至少一种向导RNA元件或包含编码所述向导RNA元件的核苷酸序列的核酸,所述向导RNA包含靶向物RNA,所述靶向物RNA具有与靶核酸的基因座处的核苷酸序列互补的核苷酸;和(b)Cpf蛋白质元件或包含编码所述Cpf蛋白质元件的核苷酸序列的核酸。
Cpf蛋白质元件的实例包括Cpf1核酸酶,例如Francisella Cpf1(FnCpf1)及其任何变体。参见,例如,Zetsche et al.,“Cpf1 is single RNA-guided endonuclease of aclass 2CRISPR-Cas system,”Cell,163(3):759-71页;和Fonfara et al.,“The CRISPR-associated DNA-cleaving enzyme Cpf1 also processes precursor CRISPR RNA,”Nature 532(7600):517-21页。Cpf1的优选PAM为5’-TTN,其在基因组位置和GC-含量方面均与Cas9(3’-NGG)不同。CRISPR-Cpf系统可以不使用激活物RNA(tracrRNA)。Cpf1及其向导RNA通常都比其SpCas9对应物小。Cpf1基因座包含混合的α/β结构域,RuvC-I,随后为螺旋区,RuvC-II和一个锌指状结构域。Cpf1蛋白质具有类似于Cas9的RuvC结构域的RuvC样核酸内切酶结构域。此外,Cpf1不具有HNH核酸内切酶结构域,并且Cpf1的N-末端不具有Cas9的α-螺旋识别叶。Cpf1基因座编码Cas1,Cas2和Cas4蛋白更类似于来自II型系统的I型和III型。Cpf1家族蛋白可以在许多细菌物种中发现。
不受特定理论的束缚,CRISPR-Cpf系统采用Cpf1-crRNA复合物,该复合物通过鉴定与原间隔物相邻的基序5’-YTN-3’(其中“Y”为嘧啶且“N”为任意核碱基)或5’-TTN-3来切割靶DNA或RNA,与Cas9靶向的富含G的PAM相反。鉴定PAM后,Cpf1导入4或5个核苷酸突出端的粘性末端样DNA双链断裂。
在一些实施方案中,所述基因组编辑系统为基于NgAgo的系统。基于NgAgo的系统包含至少一种向导DNA元件或包含编码所述向导DNA元件的核酸序列的核酸;和DNA-向导核酸内切酶。基于NgAgo的系统使用DNA作为向导元件。其工作原理与CRISPR-Cas9技术类似,但其向导元件为向导DNA(dDNA)的片段,而不是CRISPR-Cas9技术中的gRNA。DNA-向导核酸内切酶的实例为来自Natronobacterium gregoryi的Argonaute核酸内切酶(NgAgo)。参见,例如,Feng Gao et al.,“DNA-guided genome editing using the Natronobacteriumgregoryi Argonaute,”Nature Biotechnology,(2016):doi:10.1038/nbt.3547。
所谓“接头”,“肽接头”,“肽连接基”或“肽间隔基”旨在表示允许融合蛋白中不同单体连接并使正确构象适应所述融合蛋白的活性且不会改变任何一种单体的活性的肽序列。肽接头可以具有1,2,3,4,5,10,15,20,30,40至50个氨基酸的不同大小作为非限制性指示范围或该范围内的任何中间值。
DNA-PK抑制剂
在一些实施方案中,使用由结构式(I)表示的化合物:
或其药学上可接受的盐或共晶。
m和n独立地为1或2。
X为O或NR;其中R为H或C1-C4烷基。R还可以为2H(D或氘)。如本文所用,术语“氘”,“2H”和“D”可以互换使用。
R1为C1-C4烷基。
R2为
5-或6-元芳族环或包含一个或两个选自N,O和S的杂原子的杂芳族环,其中所述芳族或杂芳族环可以被0,1或2个取代基R3取代,取代基R3独立地选自CN,卤素,NO2,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基和C(=O)NHR1’,其中R1’为C1-C4烷基;或其中连接至所述芳族或杂芳族环的相邻碳原子的两个R3基团可以形成可以包含选自O,N和S的杂原子的稠合5-元环。
或者,R2可以为COOR4,其中R4为C1-C4-烷基或苄基。环A选自:
W为N或CR3’;且Z为O或S;其中R3’为H(或2H)或C1-C4烷基。
在实施方案中,A为在实施方案中,R1为甲基。
在实施方案中,R2为:
其中#表示R2连接至式(I)的化合物的其余部分的位置;且o为0,1或2。
在实施方案中,m和n的每一个为2。
在实施方案中,R2为:
在实施方案中,R2为:
在实施方案中,m和n的每一个为2,R1为甲基,R2为COOR4,且R4为C1-C4-烷基或苄基。
在实施方案中,o为0,1或2,且R3各自独立地选自CN,卤素,NO2,C1-C2-烷基,C1-C4-卤代烷基,C1-C2-烷氧基,C1-C2-卤代烷氧基和C(=O)NHR1’,其中R1’为C1-C2烷基。
在实施方案中,连接至所述杂芳族环的相邻碳原子的两个R3基团可以形成可以包含选自O,N和S的杂原子的稠合5-元环。
在实施方案中,使用结构式(I)的化合物的药学上可接受的盐。
在实施方案中,使用包括结构式(I)的化合物的共晶。
在实施方案中,使用包括结构式(I)的化合物和共晶形成剂(CCF)的共晶。在实施方案中,CCF为己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸。在实施方案中,CCF为己二酸。
在实施方案中,共晶形成剂(CCF)与结构式(I)的化合物之比为约2:1。在实施方案中,共晶形成剂(CCF)与结构式(I)的化合物之比为约1:2。在实施方案中,共晶包括为(结构式(I)的化合物)p:(CCF)q之比的结构式(I)的化合物和CCF。在实施方案中,p为约1,且q为约0.4至约2.1。在实施方案中,p为约1,且q为约0.9至约3.1。在实施方案中,p为约2,且q为约1。在实施方案中,p为约1,且q为约2。式(I))p:(CCF)q。在实施方案中,p为约1,且q为约0.4至约2.1。在实施方案中,p为约1,且q为约0.9至约3.1。在实施方案中,p为约2,且q为约1。在实施方案中,p为约1,且q为约2。在实施方案中,CCF为己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸。在实施方案中,CCF为己二酸。在实施方案中,CCF为己二酸。
在实施方案中,使用由结构式(II)表示的式(II)的化合物,
或其药学上可接受的盐或共晶。
在实施方案中,R1为甲基。
在实施方案中,Y为O或NR;其中R为H或C1-C4烷基。
在实施方案中,R2为:
其中#表示R2连接至式(II)的化合物的其余部分的位置;且o为0,1或2。
在实施方案中,m和n的每一个为2。
在实施方案中,m和n的每一个为2,且R2为:
在实施方案中,m和n的每一个为2,且R2为:
在实施方案中,m和n的每一个为2,R1为甲基,R2为COOR4,且R4为C1-C4-烷基或苄基。
在实施方案中,o为0,1或2,且R3各自独立地选自CN,卤素,NO2,C1-C2-烷基,C1-C4-卤代烷基,C1-C2-烷氧基,C1-C2-卤代烷氧基和C(=O)NHR1’,其中R1’为C1-C2烷基。
在实施方案中,环A选自
在另外的实施方案中,环A为
在一些实施方案中,环A为
在实施方案中,环A为
在实施方案中,环A为
在实施方案中,连接至所述杂芳族环的相邻碳原子的两个R3基团可以形成可以包含选自O,N和S的杂原子的稠合5-元环。
在实施方案中,使用结构式(II)的化合物的药学上可接受的盐。
在实施方案中,使用包括结构式(II)的化合物的共晶。
在实施方案中,使用包括结构式(II)的化合物和共晶形成剂(CCF)的共晶。在实施方案中,CCF为己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸。在实施方案中,CCF为己二酸。
在实施方案中,共晶形成剂(CCF)与结构式(II)的化合物之比为约2:1。在实施方案中,共晶形成剂(CCF)与结构式(II)的化合物之比为约1:2。在实施方案中,共晶包括为(结构式(II)的化合物)p:(CCF)q之比的结构式(II)的化合物和CCF。在实施方案中,p为约1,且q为约0.4至约2.1。在实施方案中,p为约1,且q为约0.9至约3.1。在实施方案中,p为约2,且q为约1。在实施方案中,p为约1,且q为约2。在实施方案中,CCF为己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸。在实施方案中,CCF为己二酸。在实施方案中,CCF为己二酸。
在实施方案中,使用由结构式(II’)表示的式(I)的化合物,
或其药学上可接受的盐或共晶。
在实施方案中,R1为甲基。
在实施方案中,Y为O或NR;其中R为H或C1-C4烷基。
在实施方案中,R2为:
其中#表示R2连接至式(II’)的化合物的其余部分的位置;且o为0,1或2。
在实施方案中,m和n的每一个为2。
在实施方案中,m和n的每一个为2,且R2为:
在实施方案中,m和n的每一个为2,且R2为:
在实施方案中,m和n的每一个为2,R1为甲基,R2为COOR4,且R4为C1-C4-烷基或苄基。
在实施方案中,o为0,1或2,且R3各自独立地选自CN,卤素,NO2,C1-C2-烷基,C1-C4-卤代烷基,C1-C2-烷氧基,C1-C2-卤代烷氧基和C(=O)NHR1’,其中R1’为C1-C2烷基。
在实施方案中,环A选自/>
在另外的实施方案中,环A为
在一些实施方案中,环A为
在实施方案中,环A为
在实施方案中,环A为
在实施方案中,连接至所述杂芳族环的相邻碳原子的两个R3基团可以形成可以包含选自O,N和S的杂原子的稠合5-元环。
在实施方案中,使用结构式(II’)的化合物的药学上可接受的盐。
在实施方案中,使用包括结构式(II’)的化合物的共晶。
在实施方案中,使用包括结构式(II’)的化合物和共晶形成剂(CCF)的共晶。
在实施方案中,共晶形成剂(CCF)与化合物II’之比为约2:1。在实施方案中,共晶形成剂(CCF)与化合物II’之比为约1:2。在实施方案中,共晶包括为(化合物II’)p:(CCF)q之比的化合物II’和CCF。在实施方案中,p为约1,且q为约0.4至约2.1。在实施方案中,p为约1,且q为约0.9至约3.1。在实施方案中,p为约2,且q为约1。在实施方案中,p为约1,且q为约2。在实施方案中,CCF为己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸。在实施方案中,CCF为己二酸。在实施方案中,CCF为己二酸。
在实施方案中,使用由结构式(II”)表示的式(I)的化合物,
或其药学上可接受的盐或共晶。
在实施方案中,R1为甲基。
在实施方案中,R2为:
其中#表示R2连接至式(II”)的化合物的其余部分的位置;且o为0,1或2。
在实施方案中,m和n的每一个为2。
在实施方案中,m和n的每一个为2,且R2为:
在实施方案中,m和n的每一个为2,且R2为:
在实施方案中,m和n的每一个为2,R1为甲基,R2为COOR4,且R4为C1-C4-烷基或苄基。
在实施方案中,o为0,1或2,且R3各自独立地选自CN,卤素,NO2,C1-C2-烷基,C1-C4-卤代烷基,C1-C2-烷氧基,C1-C2-卤代烷氧基和C(=O)NHR1’,其中R1’为C1-C2烷基。
在实施方案中,连接至所述杂芳族环的相邻碳原子的两个R3基团可以形成可以包含选自O,N和S的杂原子的稠合5-元环。
在实施方案中,环A选自
在另外的实施方案中,环A为
在一些实施方案中,环A为/>
在实施方案中,环A为
在实施方案中,环A为
在实施方案中,使用结构式(II”)的化合物的药学上可接受的盐。
在实施方案中,使用包括结构式(II”)的化合物的共晶。
在实施方案中,使用包括结构式(II”)的化合物和共晶形成剂(CCF)的共晶。
在实施方案中,共晶形成剂(CCF)与化合物II”之比为约2:1。在实施方案中,共晶形成剂(CCF)与化合物II”之比为约1:2。在实施方案中,共晶包括为(结构式II”的化合物)p:(CCF)q之比的化合物II”和CCF。在实施方案中,p为约1,且q为约0.4至约2.1。在实施方案中,p为约1,且q为约0.9至约3.1。在实施方案中,p为约2,且q为约1。在实施方案中,p为约1,且q为约2。在实施方案中,CCF为己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸。在实施方案中,CCF为己二酸。在实施方案中,CCF为己二酸。
在实施方案中,使用由结构式(II”’)表示的式(I)的化合物,
或其药学上可接受的盐或共晶。
在实施方案中,R1为甲基。
在实施方案中,R2为:
其中#表示R2连接至式(II’”)的化合物的其余部分的位置;且o为0,1或2。
在实施方案中,m和的每一个n为2。
在实施方案中,m和n的每一个为2,且R2为:
在实施方案中,m和n的每一个为2,且R2为:
在实施方案中,m和n的每一个为2,R1为甲基,R2为COOR4,且R4为C1-C4-烷基或苄基。
在实施方案中,m和n的每一个为2,Y为价键,R1为甲基,R2为COOR4,且R4为C1-C4-烷基或苄基。
在实施方案中,o为0,1或2,且R3各自独立地选自CN,卤素,NO2,C1-C2-烷基,C1-C4-卤代烷基,C1-C2-烷氧基,C1-C2-卤代烷氧基和C(=O)NHR1’,其中R1’为C1-C2烷基。
在实施方案中,连接至所述杂芳族环的相邻碳原子的两个R3基团可以形成可以包含选自O,N和S的杂原子的稠合5-元环。
在实施方案中,环A选自
在另外的实施方案中,环A为
在一些实施方案中,环A为
在实施方案中,环A为
在实施方案中,环A为/>
在实施方案中,使用结构式(II’”)的化合物的药学上可接受的盐。
在实施方案中,使用包括结构式(II’”)的化合物的共晶。
在实施方案中,使用包括结构式(II’”)的化合物和共晶形成剂(CCF)的共晶。
在实施方案中,共晶形成剂(CCF)与化合物II’”之比为约2:1。在实施方案中,共晶形成剂(CCF)与化合物II’”之比为约1:2。在实施方案中,共晶包括为(化合物II”’)p:(CCF)q之比的化合物II”’和CCF。在实施方案中,p为约1,且q为约0.4至约2.1。在实施方案中,p为约1,且q为约0.9至约3.1。在实施方案中,p为约2,且q为约1。在实施方案中,p为约1,且q为约2。在实施方案中,CCF为己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸。在实施方案中,CCF为己二酸。在实施方案中,CCF为己二酸。
在实施方案中,使用由结构式(III)表示的式(I)的化合物,
或其药学上可接受的盐或共晶。
在实施方案中,R2为:
其中#表示R2连接至式(III)的化合物的其余部分的位置;且o为0,1或2。
在实施方案中,Y为价键,X为O,且R2为:
在实施方案中,Y为价键,X为O,且R2为:/>
在实施方案中,Y为NH,X为O,且R2为:
在实施方案中,Y为NH,X为O,且R2为:
在实施方案中,Y为价键,X为O,R2为COOR4,且R4为C1-C4-烷基或苄基。
在实施方案中,Y为NH,X为O,R2为COOR4,且R4为C1-C4-烷基或苄基。
在实施方案中,o为0,1或2,且R3各自独立地选自CN,卤素,NO2,C1-C2-烷基,C1-C4-卤代烷基,C1-C2-烷氧基,C1-C2-卤代烷氧基和C(=O)NHR1’,其中R1’为C1-C2烷基。
在实施方案中,连接至所述杂芳族环的相邻碳原子的两个R3基团可以形成可以包含选自O,N和S的杂原子的稠合5-元环。
在实施方案中,使用结构式(III)的化合物的药学上可接受的盐。
在实施方案中,使用包括结构式(III)的化合物的共晶。
在实施方案中,使用包括结构式(III)的化合物和共晶形成剂(CCF)的共晶。
在实施方案中,共晶形成剂(CCF)与化合物III之比为约2:1。在实施方案中,共晶形成剂(CCF)与化合物III之比为约1:2。在实施方案中,共晶包括为(化合物III)p:(CCF)q之比的化合物III和CCF。在实施方案中,p为约1,且q为约0.4至约2.1。在实施方案中,p为约1,且q为约0.9至约3.1。在实施方案中,p为约2,且q为约1。在实施方案中,p为约1,且q为约2。在实施方案中,CCF为己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸。在实施方案中,CCF为己二酸。在实施方案中,CCF为己二酸。
在实施方案中,使用由结构式(III’)表示的式(I)的化合物,
或其药学上可接受的盐或共晶。
在实施方案中,R2为:
其中#表示R2连接至式(III’)的化合物的其余部分的位置;且o为0,1或2。
在实施方案中,Y为价键,X为O,且R2为:
在实施方案中,Y为价键,X为O,且R2为:
在实施方案中,Y为NH,X为O,且R2为:
在实施方案中,Y为NH,X为O,且R2为:
在实施方案中,Y为价键,X为O,R2为COOR4,且R4为C1-C4-烷基或苄基。
在实施方案中,Y为NH,X为O,R2为COOR4,且R4为C1-C4-烷基或苄基。
在实施方案中,o为0,1或2,且R3各自独立地选自CN,卤素,NO2,C1-C2-烷基,C1-C4-卤代烷基,C1-C2-烷氧基,C1-C2-卤代烷氧基和C(=O)NHR1’,其中R1’为C1-C2烷基。
在实施方案中,连接至所述杂芳族环的相邻碳原子的两个R3基团可以形成可以包含选自O,N和S的杂原子的稠合5-元环。
在实施方案中,使用结构式(III’)的药学上可接受的盐。
在实施方案中,使用包括结构式(III’)的化合物的共晶。
在实施方案中,使用包括结构式(III’)的化合物和共晶形成剂(CCF)的共晶。
在实施方案中,共晶形成剂(CCF)与化合物III’之比为约2:1。在实施方案中,共晶形成剂(CCF)与化合物III’之比为约1:2。在实施方案中,共晶包括为(化合物III’)p:(CCF)q之比的化合物III’和CCF。在实施方案中,p为约1,且q为约0.4至约2.1。在实施方案中,p为约1,且q为约0.9至约3.1。在实施方案中,p为约2,且q为约1。在实施方案中,p为约1,且q为约2。在实施方案中,CCF为己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸。在实施方案中,CCF为己二酸。在实施方案中,CCF为己二酸。
在实施方案中,使用由结构式(III”)表示的式(I)的化合物,
或其药学上可接受的盐或共晶。
在实施方案中,R2为:
其中#表示R2连接至式(III”)的化合物的其余部分的位置;且o为0,1或2。
在实施方案中,Y为价键,X为O,且R2为:
在实施方案中,Y为价键,X为O,且R2为:/>
在实施方案中,Y为NH,X为O,且R2为:
在实施方案中,Y为NH,X为O,且R2为:
在实施方案中,Y为价键,X为O,R2为COOR4,且R4为C1-C4-烷基或苄基。
在实施方案中,Y为NH,X为O,R2为COOR4,且R4为C1-C4-烷基或苄基。
在实施方案中,o为0,1或2,且R3各自独立地选自CN,卤素,NO2,C1-C2-烷基,C1-C4-卤代烷基,C1-C2-烷氧基,C1-C2-卤代烷氧基和C(=O)NHR1’,其中R1’为C1-C2烷基。
在实施方案中,连接至所述杂芳族环的相邻碳原子的两个R3基团可以形成可以包含选自O,N和S的杂原子的稠合5-元环。
在实施方案中,使用结构式(III”)的化合物的药学上可接受的盐。
在实施方案中,使用包括结构式(III”)的化合物的共晶。
在实施方案中,使用包括结构式(III”)的化合物和共晶形成剂(CCF)的共晶。
在实施方案中,使用由结构式(III’”)表示的式(I)的化合物,
或其药学上可接受的盐或共晶。
在实施方案中,R2为:
其中#表示R2连接至式(III’”)的化合物的其余部分的位置;且o为0,1或2。
在实施方案中,Y为价键,X为O,且R2为:
在实施方案中,Y为价键,X为O,且R2为:
在实施方案中,Y为NH,X为O,且R2为:
在实施方案中,Y为NH,X为O,且R2为:
在实施方案中,Y为价键,X为O,R2为COOR4,且R4为C1-C4-烷基或苄基。
在实施方案中,Y为NH,X为O,R2为COOR4,且R4为C1-C4-烷基或苄基。
在实施方案中,o为0,1或2,且R3各自独立地选自CN,卤素,NO2,C1-C2-烷基,C1-C4-卤代烷基,C1-C2-烷氧基,C1-C2-卤代烷氧基和C(=O)NHR1’,其中R1’为C1-C2烷基。
在实施方案中,连接至所述杂芳族环的相邻碳原子的两个R3基团可以形成可以包含选自O,N和S的杂原子的稠合5-元环。
在实施方案中,使用结构式(III’”)的化合物的药学上可接受的盐。
在实施方案中,使用包括结构式(III’”)的化合物的共晶。
在实施方案中,使用包括结构式(III’”)的化合物和共晶形成剂(CCF)的共晶。
在实施方案中,使用选自表1中的化合物编号1-37(上文)的式(I)的化合物或其药学上可接受的盐或其共晶。
在实施方案中,使用任意化合物编号1-37的药学上可接受的盐。
在实施方案中,使用包括任意化合物编号1-37的共晶。
在实施方案中,使用包括任意化合物编号1-37和共晶形成剂(CCF)的共晶。在实施方案中,CCF为己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸。在实施方案中,CCF为己二酸。
在一些实施方案中,所述化合物为选自表1的化合物或其药学上可接受的盐或共晶:
表1
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如本文所述,本文公开的化合物可任选地被一个或多个取代基取代,例如以上一般性示例或以特定类别,亚类和种类为典型。将理解的是,短语“任选取代的”与短语“取代或未取代的”可互换使用。通常,术语“取代的”,无论是否以术语“任选地”开头均是指用指定取代基的基团取代给定结构中的一个或多个氢基团。除非另有说明,否则任选取代的基团可在该基团的各个可取代位置上具有取代基。当给定结构中的多于一个位置可以被选自指定组的多于一个的取代基取代时,该取代基在各个位置上可以相同或不同。
在化学上可行或化学上稳定的情况下,本文所述的分子基团为未取代或取代的(即“任选取代的”)。如本文所述,当术语“任选取代的”在列表之前时,所述术语是指该列表中所有随后的可取代基团。例如,如果基团X为“卤素;任选取代的烷基或苯基”,则X可以为任选取代的烷基或任选取代的苯基。同样,如果术语“任选的”在列表之后,则除非另有说明,否则所述术语还指先前列表中的所有可取代基团。例如:如果X为卤素,C1-4烷基或苯基,其中X为任选地被Jx取代,则C1-4烷基和苯基均可以任选地被Jx取代。正如本领域普通技术人员显而易见的,由于它们不是可取代的基团,所以不包括诸如H,卤素,NO2,CN,NH2,OH或OCF3这样的基团。正如本领域技术人员同样显而易见的是,可以通过用取代基替代氢原子来任选地取代含有NH基的杂芳基或杂环。
在实施方案中,基团(例如C1-4烷基;C3-5环烷基;杂环基,例如氧杂环丁烷基,四氢呋喃基,四氢吡喃基或吗啉基;芳基,例如苯基;或杂芳基)未被取代。
在实施方案中,基团(例如C1-4烷基;C3-5环烷基;杂环基,例如氧杂环丁烷基,四氢呋喃基,四氢吡喃基或吗啉基;芳基,例如苯基;或杂芳基)被取代。在实施方案中,当化合价和化学稳定性允许时,基团包含1,2,3,4,5或6个取代基。
在本公开中预想的取代基的组合优选是导致形成稳定或化学上可行的化合物的那些。如本文所用,术语“稳定的”是指在经受允许用于其所公开的一种或多种目的的生产,检测以及优选地其回收,纯化和使用的条件时基本不改变的化合物。在实施方案中,稳定的化合物或化学上切实可行的化合物为在没有水分或其它化学反应条件下保持在40℃或以下的温度下至少1周不会发生明显改变的化合物。
术语“约”与数值x连接时是指,例如,x+/-10%。
如本文所用,术语“烷基”或“烷基基团”是指完全饱和的直链(即无支链)或支链,取代或未取代的烃链。除非另有指定,否则烷基具有1-8个碳原子(表示为“C1-8烷基”)。在实施方案中,烷基具有1-4碳原子(表示为“C1-4烷基”)。在实施方案中,描述为“C0-4烷基”的分子实体包括共价键(例如“C0烷基”)或如本文所述的C1-4烷基链。烷基的实例包括甲基,乙基,丙基,丁基,异丙基,异丁基,仲丁基和叔丁基。
如本文所用,术语“杂环”,“杂环基”,“杂环烷基”或“杂环化合物”是指单环,双环或三环环系统,其中该系统中的至少一个环包含一个或多个杂原子,其相同或不同,并且其为完全饱和的或其包含一个或多个不饱和单元,但其不是芳族的并且其具有连接至分子其余部分的单一点。在一些实施方案中,“杂环”,“杂环基”,“杂环烷基”或“杂环化合物”基团具有3-14个环成员,其中一个或多个环成员为杂原子,其独立地选自氧,硫,氮或磷,并且系统中的每个环包含3-8个环成员。杂环的实例包括但不限于如下单环:2-四氢呋喃基,3-四氢呋喃基,2-四氢噻吩基,3四氢噻吩基,2-吗啉代,3-吗啉代,4-吗啉代,2-硫吗啉代,3-硫吗啉代,4-硫吗啉代,1-吡咯烷基,2-吡咯烷基,3-吡咯烷基,1-四氢哌嗪基,2-四氢哌嗪基,3-四氢哌嗪基,1-哌啶基,2-哌啶基,3-哌啶基,1-吡唑啉基,3-吡唑啉基,4-吡唑啉基,5-吡唑啉基,1-哌啶基,2-哌啶基,3-哌啶基,4-哌啶基,2-噻唑烷基,3-噻唑烷基,4噻唑烷基,1-咪唑烷基,2-咪唑烷基,4-咪唑烷基,5-咪唑烷基;和如下双环:3-lH-苯并咪唑-2-酮,3-(l-烷基)-苯并咪唑-2-酮,二氢吲哚基,四氢喹啉基,四氢异喹啉基,苯并硫杂戊环(benzothiolane),苯并二噻烷和1,3-二氢-咪唑-2-酮。
如本文所用,术语“杂原子”是指氧,硫,氮或磷的一个或多个,包括氮,硫或磷的任意氧化形式;任意碱性氮的季铵化形式;或杂环的可取代的氮,例如N(如在3,4-二氢-2H-吡咯基中),ΝΗ(如在吡咯烷基中)或NR+(如在N-取代的吡咯烷基中)。
如本文所用,术语“不饱和的”是指部分具有一个或多个不饱和单元。
如本文所用,术语“烷氧基”或“烷硫基”是指如上述所定义的通过氧(“烷氧基”)或硫原子(“烷硫基”)连接至主碳链的烷基。
如本文所用,术语“卤代烷基”,“卤代烯基”和“卤代烷氧基”是指就烷基,烯基或烷氧基而言,其可以被一个或多个卤原子取代。术语“卤素”是指F,CI,Br或I。
如本文所用,单独使用或作为在“芳烷基”,“芳烷氧基”或“芳氧基烷基”中的较大部分组成部分使用的术语“芳基”是指单环,双环或三环碳环系统,其具有总计6-14个环成员,其中所述环系统具有与分子其余部分的单一连接点,该系统中的至少一个环为芳族的,且其中该系统中的每个环包含4-7个环成员。术语“芳基”可以与术语“芳基环”互换使用。芳基环的实例包括苯基,萘基和蒽。
如本文所用,单独使用或作为在“杂芳烷基”或“杂芳烷氧基”中的较大部分组成部分使用的术语“杂芳基”是指单环,双环和三环环系统,其具有总计5-14个环成员,其中所述环系统具有与分子的其余部分的单一连接点,该系统中的至少一个环为芳族的,该系统中的至少一个环包含一个或多个独立地选自氮,氧,硫或磷的杂原子,且其中该系统中的每个环包含4-7个环成员。术语“杂芳基”可以与术语“杂芳基环”或术语“杂芳族化合物”互换使用。杂芳基环的另外的实例包括如下单环:2呋喃基,3-呋喃基,N-咪唑基,2-咪唑基,4-咪唑基,5-咪唑基,3-异噁唑基,4-异噁唑基,5-异噁唑基,2-噁唑基,4-噁唑基,5-噁唑基,N-吡咯基,2-吡咯基,3-吡咯基,2-吡啶基,3-吡啶基,4-吡啶基,2-嘧啶基,4-嘧啶基,5-嘧啶基,哒嗪基(例如3哒嗪基),2-噻唑基,4-噻唑基,5-噻唑基,四唑基(例如5-四唑基),三唑基(例如2-三唑基和5-三唑基),2-噻吩基,3-噻吩基,吡唑基(例如2-吡唑基),异噻唑基,1,2,3-噁二唑基,1,2,5-噁二唑基,1,2,4-噁二唑基,1,2,3-三唑基,1,2,3-噻二唑基,1,3,4-噻二唑基,1,2,5-噻二唑基,吡嗪基,1,3,5-三嗪基;和如下双环:苯并咪唑基,苯并呋喃基,苯并噻吩基,吲哚基(例如2-吲哚基),嘌呤基,喹啉基(例如2-喹啉基,3-喹啉基,4-喹啉基)和异喹啉基(例如1-异喹啉基,3-异喹啉基或4-异喹啉基)。
除非另有描述或说明,否则本文所述结构可包括该结构的所有异构体(例如对映体,非对映体和几何(或构象))形式;例如,每个不对称中心的R和S构型,(Z)和(E)双键异构体和(Z)和(E)构象异构体。因此,本发明化合物的单一立体化学异构体以及对映体,非对映体和几何(或构象)混合物在本公开的范围内。通常通过使用阴影线或粗体价键定义的用立体化学中心拉出的化合物为立体化学纯的,但绝对立体化学仍不确定。这样的化合物可以具有R或S构型。在确定了绝对构型的那些情况下,手性中心在图中标记为(R)或(S)。
除非另有说明,否则本文公开的化合物的所有互变异构形式均在此类公开的范围内。另外,除非另有说明,否则本文描述的结构还旨在包括仅在一个或多个同位素富集的原子存在下不同的化合物。例如,具有当前结构的化合物,除了用氘或氚替代氢或用富含13C-或14C-的碳替代碳之外,都在本公开的范围内。例如,此类化合物可用作分析工具,生物学测定中的探针或具有改善的治疗特性的DNA-PK抑制剂。
药学上可接受的盐
还应理解,本文公开的某些化合物可以以游离形式或适当时以其药学上可接受的衍生物存在。药学上可接受的衍生物包括但不限于药学上可接受的前药,盐,酯,此类酯的盐或任何其它加合物或衍生物,其在向有需要的患者施用时能够直接或间接提供本文另外描述的化合物或其代谢物或其残余物。
如本文所用,术语“药学上可接受的盐”是指在合理的医学判断范围内的那些盐,其适用于与人类和低等动物的组织接触而没有过度的毒性,刺激性,过敏反应等。
药学上可接受的盐是本领域众所周知的。例如,S.M.Berge et al.,在J.Pharmaceutical Sciences,66:1-19,1977中详细描述了药学上可接受的盐,涉及药学上可接受的盐的该文献通过引用并入本文。本文公开的化合物的药学上可接受的盐包括衍生自适合的无机和有机酸和碱的那些。药学上可接受的无毒性酸加成盐的实例为与无机酸(例如盐酸,氢溴酸,磷酸,硫酸和高氯酸)或有机酸(例如乙酸,草酸,马来酸,酒石酸,柠檬酸,琥珀酸或丙二酸)或通过使用本领域中使用的其它方法例如离子交换形成的氨基盐。其它药学上可接受的盐包括藻酸盐,抗坏血酸盐,天冬氨酸盐,苯磺酸盐,硫酸氢盐,硼酸盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,环戊烷丙酸盐,二葡糖酸盐,十二烷基硫酸盐,乙磺酸盐,甲酸盐,葡庚糖酸盐,甘油磷酸盐,葡糖酸盐,半硫酸盐,庚酸盐,己酸盐,氢碘酸盐,2-羟基-乙磺酸盐,乳糖酸盐,乳酸盐,月桂酸盐,月桂基硫酸盐,苹果酸盐,丙二酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,硝酸盐,油酸盐,草酸盐,棕榈酸盐,双羟萘酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,磷酸盐,苦味酸盐,新戊酸酯,丙酸盐,硬脂酸盐,硫酸盐,酒石酸盐,硫氰酸盐,对甲苯磺酸盐,十一烷酸盐,戊酸盐等。更进一步的示例性盐包括己二酸盐,苯甲酸盐,柠檬酸盐,富马酸盐,马来酸盐或琥珀酸盐。衍生自适当碱的盐包括碱金属,碱土金属,铵和N+(C1-4烷基)4盐。
本公开还包括本文公开的化合物的任何碱性含氮基团的季铵化。通过这种季铵化可以得到水溶性或油溶性或可分散性的产物。代表性的碱金属或碱土金属盐包括钠,锂,钾,钙,镁等。其它药学上可接受的盐在适当时包括使用抗衡离子例如卤离子,氢氧根,羧酸根,硫酸根,磷酸根,硝酸根,C1-8磺酸根和芳基磺酸根形成的无毒性铵,季铵和胺阳离子。
共晶
在实施方案中,使用包括如本文所述的化合物(例如由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物)和共晶形成剂(CCF)的共晶。
在实施方案中,由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物和CCF均为固态(例如结晶)。在实施方案中,由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物和CCF通过非共价键合(例如通过氢键合)。
在实施方案中,由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物和CCF(例如己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸)的共晶在室温下为固体。在实施方案中,由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物和CCF(例如己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸)的共晶通过非共价键相互作用。在实施方案中,由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物和CCF(例如己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸)之间的非共价键相互作用包括氢键合和/或范德华相互作用。
在实施方案中,共晶形成剂(CCF)为己二酸,柠檬酸,富马酸,马来酸,琥珀酸或苯甲酸。
在实施方案中,共晶为国际公开号WO2015/058067中所述的共晶,其通过引用整体并入本文。
在实施方案中,共晶包括(5)-N-甲基-8-(l-((2’-甲基-[4,5’-联嘧啶]-6-基)氨基)丙-2-基)喹啉-4-甲酰胺。在实施方案中,所述化合物为(+)对映体。在实施方案中,所述化合物为(-)对映体。
在实施方案中,共晶包括(5)-N-甲基-8-(l-((2’-甲基-46’-二氘代-[4,5’-联嘧啶]-6-基)氨基)丙-2-基)喹啉-4-甲酰胺。在实施方案中,所述化合物为(+)对映体。在实施方案中,所述化合物为(-)对映体。
在实施方案中,使用包括由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物(例如化合物编号1-37中的任意一个)和作为CCF的柠檬酸的共晶。
在实施方案中,本发明的特征在于包括由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物(例如化合物编号1-37中的任意一个)和作为CCF的富马酸的共晶。
在实施方案中,使用包括由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物(例如化合物编号1-37中的任意一个)和作为的CCF的马来酸的共晶。
在实施方案中,使用包括由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物(例如化合物编号1-37中的任意一个)和作为CCF的琥珀酸的共晶。
在实施方案中,使用包括由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物(例如化合物编号1-37中的任意一个)和作为CCF的苯甲酸的共晶。
在实施方案中,使用包括由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物(例如化合物编号1-37中的任意一个)和作为CCF的己二酸的共晶。
在一些实施方案中,使用共晶,其中当与其它材料混合时,例如,由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物(例如化合物编号1-37中的任意一个)的游离形式或游离CCF,这类共晶包括由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物(例如化合物编号1-37中的任意一个)和上述CCF,为分离,纯化形式或混合物形式作为固体组合物。
在一些实施方案中,使用药学上可接受的组合物,其包含由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物(例如化合物编号1-37中的任意一个),第一种CCF(例如如本文所述)和一种或多种另外的游离CCF(它们可以与第一种CCF相同或不同)的共晶。在一些实施方案中,组合物包括由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物(例如化合物编号1-37中的任意一个),为己二酸的第一种CCF和另一种己二酸的共晶。在一些实施方案中,在这类组合物中由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物(例如化合物编号1-37中的任意一个)与CCF(例如包括第一种CCF(例如如本文所述)和一种或多种另外的游离CCF的总CCF)的总摩尔比为约1:0.55至约1:100。在一些实施方案中,在这类组合物中由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物(例如化合物编号1-37中的任意一个)与CCF的总摩尔比为约1:0.55至约1:50。在一些实施方案中,在这类组合物中由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物(例如化合物编号1-37中的任意一个)与CCF的总摩尔比为约1:0.55至约1:10。在一些实施方案中,在这类组合物中式I的化合物与CCF的总重量比为约85wt%:15wt%至约60wt%:40wt%。在一些实施方案中,由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物(例如化合物编号1-37中的任意一个)与CCF的总重量比为约70wt%:30wt%至约60wt%:40wt%。在一些实施方案中,由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物(例如化合物编号1-37中的任意一个)与CCF的总重量比为约65wt%:35wt%。
用于提高基因组编辑效率的DNA-PK抑制剂
可以通过向细胞施用本文所述的一种或多种化合物(例如DNA-PK抑制剂)和基因组编辑系统提高靶向的基因组编辑效率。适用的基因组编辑系统包括,例如,基于兆核酸酶的系统,基于锌指核酸酶(ZFN)的系统,基于转录激活因子样效应物的核酸酶(TALEN)系统,基于CRISPR的系统或基于NgAgo的系统。发明的方法、组合物和试剂盒提供用于提高基因组编辑效率的DNA-PK抑制剂和/或基因组编辑系统。在一些实施方案中,将DNA PK抑制剂施用于细胞后,HDR基因组编辑效率提高。
在一些实施方案中,所述基因组编辑系统为基于CRISPR的基因组编辑系统。基于CRISPR的基因组编辑系统可以为CRISPR-Cas系统或其变体。CRISPR-Cas系统可以使用任意的Cas核酸内切酶,例如Cas 9核酸内切酶及其变体。Cas 9核酸内切酶的实例包括Cas9核酸内切酶或其变体,例如SaCas9,SpCas9,SpCas9n,Cas9-HF,Cas9-H840A,FokI-dCas9或CasD10A切口酶。Cas核酸内切酶可以为野生型,改造的,或切口酶突变体或其任意的变化形式。
在一些实施方案中,基于CRISPR的基因组编辑系统包括CRISPR序列,反式激活cr(tracr)序列,向导序列和Cas核酸内切酶或其任意组合。
在一些实施方案中,基于CRISPR的基因组编辑系统包括包含CRISPR序列的RNA(crRNA),包含反式激活cr(tracr)序列的RNA(tracrRNA)和Cas核酸内切酶或其任意组合。
在一些实施方案中,基于CRISPR的基因组编辑系统包括CRISPR序列序列,向导序列和Cas核酸内切酶或Cpf核酸内切酶或其任意组合。
在一些实施方案中,基于CRISPR的基因组编辑系统为CRISPR-Cpf系统。Cpf核酸酶为2类CRISPR-Cas系统核酸内切酶。Cpf为单一RNA-向导核酸内切酶。Cpf核酸酶可以为野生型,改造的,或切口酶突变体或其任意的变化形式。参见,例如,Zetsche et al.,“CPF1 issingle RNA-guided endonuclease of a Class 2CRISPR-Cas system,”Cell,163(3):759-71。在一些实施方案中,Cpf核酸酶为Cpf 1核酸内切酶。
在一些实施方案中,所述基因组编辑系统为基于兆核酸酶的系统。基于兆核酸酶的基因组编辑使用识别DNA大靶位点(例如典型地约>12bp)的序列特异性核酸内切酶。参见,例如,U.S.9,365,964。兆核酸酶可以切割独特的染色体序列,而不会影响整体基因组的完整性。在一些实施方案中,兆核酸酶可以为归巢核酸内切酶。在一些实施方案中,兆核酸酶可以为内含子核酸内切酶或内含肽核酸内切酶。归巢核酸内切酶可以属于LAGLIDADG家族。兆核酸酶可以为野生型,改造的或切口酶突变体。
在一些实施方案中,所述基因编辑系统为基于锌指核酸酶(ZFN)的系统。ZFN为基于DNA-结合结构域与DNA-裂解结构域之间的融合体的锌指人造限制酶。参见,例如,U.S.9,145,565。
在一些实施方案中,所述基因编辑系统为基于转录激活因子样效应物核酸酶(TALEN)。TALEN为改造的限制酶,其通过使TAL效应物DNA-结合结构域与DNA裂解结构域融合制成。参见,例如,U.S.9,181,535。
在一些实施方案中,所述基因编辑系统为基于Argonaute的系统。基于Argonaute的基因编辑系统包括Argonaute衍生的核酸内切酶和5’磷酸化ssDNA。在一些实施方案中,磷酸化ssDNA可以为10-40个核苷酸,15-30个核苷酸或18-30个核苷酸(例如约24个核苷酸)的长度。在一些实施方案中,Argonaute核酸内切酶可以为任意的核酸内切酶。在一些实施方案中,Argonaute核酸内切酶来源于Thermus thermophiles(TtAgo),激烈热球菌(Pyrococcus furiosus)(PfAgo)或Natronobacterium gregoryi(NgAgo)。在一些实施方案中,Natrobacterium gregoryi(NgAgo)为菌株2(即N.gregoryi SP2)。在一些实施方案中,Argonaute核酸内切酶为NgAgo。参见,例如,Gao et al.,“DNA-guided genome editingusing the Natronobacterium gregoryi Argonaute,”NatureBiotechnology,2016年5月。
DNA-PK抑制剂可以为任意的DNA-PK抑制剂。DNA-PK抑制剂可以为导致DNA-PK抑制的任意化合物或物质。DNA-PK抑制剂可以为化合物,小分子,抗体或核苷酸序列。在一些实施方案中,DNA-PK抑制剂为由结构式I或结构式II表示的化合物。在一些实施方案中,DNA-PK抑制剂为由结构式I’或结构式II’表示的化合物。在一些实施方案中,DNA-PK抑制剂为化合物编号1-37中的任何一个。在一些实施方案中,DNA-PK抑制剂为包括化合物编号1-37中的任何一个和己二酸的共晶。
在一些实施方案中,DNA-PK抑制剂为化合物编号1-37中的任何一个或其组合。
在一些实施方案中,任意的NHEJ抑制剂可以用于提高HDR基因组编辑效率。在一些实施方案中,NHEJ抑制剂为化合物编号1-37中的任何一个或其组合。
在一些实施方案中,NHEJ抑制剂可以为导致NHEJ抑制的任意化合物或物质。NHEJ抑制剂的实例包括DNA-PK抑制剂。NHEJ抑制剂可以为化合物,小分子,抗体或核苷酸序列。在一些实施方案中,NHEJ抑制剂为由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物其药学上可接受的盐或共晶。在一些实施方案中,NHEJ抑制剂为化合物编号1-37中的任何一个或其组合。
在一些实施方案中,与其中不向细胞施用DNA-PK抑制剂和基因组编辑系统的情况或与其中仅向细胞施用基因组编辑系统但不施用DNA-PK抑制剂的情况相比,提高的基因组编辑效率为约1-倍,2-倍,3-倍,4-倍,5-倍,10-倍,15-倍,20-倍,25-倍,30-倍,40-倍,50-倍或100-倍。
DNA-PK抑制剂、组合物及其试剂盒的用途
在一些实施方案中,本文提供用于使细胞对诱导DNA损伤的治疗剂或疾病状态敏感的方法,所述方法包括使细胞接触本文公开的一种或多种DNA-PK抑制剂的步骤,例如结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的那些或其药学上可接受的盐或共晶。
在一些实施方案中,本文提供用于增强治疗癌症的治疗方案的方法,所述方法包括向有此需要的个体施用本文公开的有效量的DNA-PK抑制剂的步骤,例如结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)的那些或其药学上可接受的盐或其共晶。在一个方面,治疗癌症的治疗方案包括放疗。
本文公开的NDA-PK抑制剂用于其中指示放疗增强这类治疗的治疗效果的情况。此外,放疗通常指示为治疗癌症中的手术的辅佐疗法。放疗在辅佐设置中的目标在于,当原发性肿瘤得到控制时,降低复发风险和增强无病存活。在几种疾病中指示辅佐放疗,包括如下所述的结肠癌,直肠癌,肺癌,胃食管癌和乳腺癌。
另一种抗癌化学治疗剂可与本文公开的DNA-PK抑制剂与或不与放疗一起用于治疗癌症治疗方案。本文公开的DNA-PK抑制剂与此类其它活性剂的组合可增强化疗方案。例如,本文公开的DNA-PK抑制剂可以与已知引起DNA链断裂的依托泊苷或博来霉素一起施用。
本文进一步公开了利用本文的DNA-PK抑制剂的放射增敏性肿瘤细胞。如本文所用,将可以“放射致敏”细胞的DNA-PK抑制剂定义为以治疗有效量施用于动物以提高细胞对电磁辐射的敏感性和/或促进治疗可通过电磁辐射(例如X-射线)治疗的疾病的分子,优选低分子量分子。可以用电磁辐射治疗的疾病包括赘生性疾病,良性和恶性肿瘤以及癌细胞。
本文进一步提供治疗动物癌症的方法,所述方法包括向动物施用本文公开的有效量的DNA-PK抑制剂,例如本发明的化合物。本发明还涉及抑制癌细胞生长的方法,所述方法包括生物系统中的细胞增殖,侵袭性和转移过程。所述方法包括使用本发明的化合物作为癌细胞生长的抑制剂。优选地,该方法用于抑制或减少活体动物例如哺乳动物中的癌细胞生长,侵袭性,转移或肿瘤发生率。本发明的化合物可以单独使用或与使用IR或一种或多种化疗剂组合使用,以治疗癌症或抑制癌细胞的生长。本发明的方法也易于适用于测定系统,例如测定癌细胞的生长及其特性,以及鉴定影响癌细胞生长的化合物。
瘤或肿瘤包括组织细胞的生长,其中细胞的增殖是不受控制的和进行性的。一些这样的生长是良性的,但另一些则被称为“恶性”,并可能导致生物体死亡。恶性肿瘤或“癌”与良性生长的区别在于,除了表现出侵袭性的细胞增殖外,它们还可以侵入周围组织并转移。此外,恶性肿瘤的特征在于它们表现出更大的分化缺失(更大的“去分化”)和它们相对于彼此及其周围组织的组织化。这种属性也称为“发育不全”。
可通过本发明治疗的肿瘤还包括实体瘤,即癌和肉瘤。癌包括源自上皮细胞的那些恶性肿瘤,其浸润(侵袭)周围组织并引起转移。腺癌是源自腺组织或形成可识别的腺结构的组织的癌。另一类广泛的癌症包括肉瘤,其是将细胞包埋在纤维状或均质物质(如胚胎结缔组织)中的肿瘤。本发明还能够治疗髓样或淋巴样系统的癌症,包括白血病,淋巴瘤和其它典型地不以肿瘤块形式存在,但分布在血管或淋巴网状系统中的癌症。
DNA-PK活性可以与不同形式的癌症相关,例如,成人肿瘤和儿科肿瘤,实体瘤/恶性肿瘤,粘液样和圆形细胞癌,局部晚期肿瘤,转移性癌症,人软组织肉瘤,包括尤因肉瘤,癌转移,包括淋巴结转移,鳞状细胞癌,尤其是头颈部鳞状细胞癌,食道鳞状细胞癌,口腔癌,血细胞恶性肿瘤,包括多发性骨髓瘤,白血病,包括急性淋巴细胞白血病,急性非淋巴细胞性白血病,慢性淋巴细胞白血病,慢性粒细胞白血病和毛细胞白血病,积液性淋巴瘤(基于体腔的淋巴瘤),胸腺淋巴瘤,肺癌,包括小细胞肺癌,皮肤T细胞淋巴瘤,霍奇金淋巴瘤,非霍奇金淋巴瘤,肾上腺皮质癌,ACTH产生性肿瘤,非小细胞癌,乳腺癌,包括小细胞癌和导管癌,胃肠道癌症,包括胃癌,结肠癌,结肠直肠癌,与结肠直肠癌相关的息肉,胰腺癌,肝癌,泌尿外科癌症,包括膀胱癌,包括原发性浅表膀胱肿瘤,膀胱浸润性移行细胞癌和肌肉浸润性膀胱癌,前列腺癌,女性生殖道恶性肿瘤,包括卵巢癌,原发性腹膜上皮肿瘤,宫颈癌,子宫内膜癌,阴道癌,外阴癌,子宫癌和卵巢滤泡中的实体瘤,男性生殖道恶性肿瘤,包括睾丸癌和阴茎癌,肾癌,包括肾细胞癌,脑癌,包括固有脑瘤,神经母细胞瘤,星形细胞瘤,神经胶质瘤,转移性肿瘤细胞侵入中枢神经系统,骨癌,包括骨瘤和骨肉瘤,皮肤癌,包括恶性黑素瘤,人体皮肤角质形成细胞的肿瘤进展,鳞状细胞癌,甲状腺癌,视网膜母细胞瘤,神经母细胞瘤,腹腔积液,恶性胸腔积液,间皮瘤,威尔姆氏肿瘤,胆囊癌,滋养细胞肿瘤,血管周皮细胞瘤和卡波西肉瘤。本发明包括增强对这些和其它形式的癌症的治疗的方法。
本发明提供抑制生物样品中的DNA-PK活性的方法,所述方法包括使生物样品与本发明的化合物或组合物接触。如本文所用,术语“生物样品”是指脱离活生物体之外的样品,并且包括但不限于细胞培养物或其提取物;获自哺乳动物的活检材料或其提取物;以及血液,唾液,尿液,粪便,精液,泪液或其它体液或其提取物。抑制生物样品中的激酶活性,特别是DNA-PK活性可用于本领域技术人员已知的多种目的。此类目的的实例包括但不限于生物样本存储和生物测定。在一个实施方案中,在生物样品中抑制DNA-PK活性的方法限于非治疗方法。
用于基因组编辑的用途
其中特定基因组区域被精确改变的基因组编辑保持巨大的治疗潜能。
在一些实施方案中,本文提供用于编辑一种或多种靶基因组区域,通过HDR途径修复一种或多种靶基因组区域中的DNA断裂,抑制或阻抑一种或多种靶基因组中的NHEJ介导的DNA断裂修复的方法和通过向细胞施用基因组编辑系统和DNA-PK抑制剂修饰一种或多种基因或蛋白质的表达的方法。
在一些实施方案中,本文提供修饰包含一种或多种基因或蛋白质的表达的方法,所述方法包括向包含一种或多种靶基因组区域的一种或多种细胞施用本文所述的基因组编辑系统和DNA-PK抑制剂,其中所述基因组编辑系统与靶基因一种或多种靶基因组区域的核酸相互作用,导致编辑一种或多种靶基因组区域,且其中该编辑修饰与靶基因相关的下游基因和/或的蛋白质的表达。
所述基因组编辑系统可以为任意的基因组编辑系统,其可以编辑细胞中的靶基因组区域。示例性的基因组编辑系统如上述详细描述,且可以包括,例如,基于兆核酸酶的系统,基于锌指核酸酶(ZFN)的系统,基于转录激活因子样效应物的核酸酶(TALEN)系统,基于CRISPR的系统或基于NgAgo的系统。
一种或多种靶基因组区域的编辑包括细胞基因组的任何种类的遗传操作或改造。一种或多种靶基因组区域的编辑可以包括通过一种或多种核酸内切酶在细胞中插入、缺失或替代基因组区域。基因组区域包含细胞中的遗传物质,例如DNA,RNA,多核苷酸和寡核苷酸。细胞中的基因组区域还包含细胞中包含的线粒体或叶绿体的基因组。
DNA-PK抑制剂可以为任意的DNA-PK抑制剂。DNA-PK抑制剂可以为导致DNA-PK抑制的任意化合物或物质。DNA-PK抑制剂可以为化合物,小分子,抗体或核苷酸序列。在一些实施方案中,DNA-PK抑制剂为由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物。在一些实施方案中,DNA-PK抑制剂为由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物。在一些实施方案中,DNA-PK抑制剂为化合物编号1-37中的任何一个。在一些实施方案中,DNA-PK抑制剂为包括化合物编号1-37中的任何一个和己二酸的共晶。在一些实施方案中,己二酸与化合物编号1-37中的任何一个之比为约5:0.5或其中间的任意之比。在一些实施方案中,己二酸与化合物编号1-37中的任何一个之比为约4:0.5或其中间的任意之比。在一些实施方案中,己二酸与化合物编号1-37中的任何一个之比为约3:0.5或其中间的任意之比。在一些实施方案中,己二酸与化合物编号1-37中的任何一个之比为约2:0.5或其中间的任意之比。在一些实施方案中,己二酸与化合物编号1-37中的任何一个之比为约2:1.0或其中间的任意之比。在一些实施方案中,NHEJ抑制剂为由结构式(I),式(II),式(II’),式(II”),式(II”’),式(III),式(III’),式(III”)或式(III”’)表示的化合物或其任意组合。
在一些实施方案中,本文提供了治疗患有需要编辑受试者细胞中一种或多种靶基因组区域的疾病或病症的受试者的方法,所述方法包括向一种或多种细胞施用基因组编辑系统和DNA-PK抑制剂。
在一些实施方案中,本文提供的方法用于修饰途径中的基因,RNA分子,蛋白质,一组蛋白质或下游蛋白质的表达。这种修饰可以用于治疗疾病,功能障碍,机体稳态异常,无论是获得性还是遗传性或因衰老过程所致。如本文所用,术语“修饰”或“改变”包括调节,增强,降低,提高,插入,缺失,敲除,敲入等。
本领域技术人员理解,获得性或遗传性或其它获得性的疾病涉及包括牵涉基因或蛋白质功能的体内平衡机制的失调。为此,本领域技术人员可以使用本文提供的方法来调节,修饰,增强,减少或提供受试者的其它基因功能。
可以通过本文提供的方法,例如通过特异性编辑(例如,替代,插入或缺失,其任意组合)任意外显子,内含子,转录起始位点,启动子区,增强子区,沉默子区,绝缘子区,抗阻遏物,翻译后调节元件,聚腺苷酸化信号(例如最小聚腺苷酸),保守区,转录因子结合位点可以任意地组合中的核酸序列来实现修饰细胞中基因和随后的蛋白质表达。
在一些实施方案中,本文提供的方法、试剂盒和组合物用于治疗患有癌症的受试者。治疗患有癌症或癌症相关病症的受试者的方法包含向该受试者的细胞施用DNA-PK抑制剂和基因组编辑系统。可以在体内或离体施用DNA-PK抑制剂和所述基因组编辑系统。
所述癌症可以为任何种类的癌症。癌症包括实体瘤,例如乳腺癌,卵巢癌,前列腺癌,肺癌,肾癌,胃癌,结肠癌,睾丸癌,头颈癌,胰腺癌,脑癌,黑素瘤和其它组织器官肿瘤以及血细胞癌,例如淋巴瘤和白血病,包括急性髓性白血病,慢性淋巴细胞性白血病,T细胞淋巴细胞性白血病和B细胞淋巴瘤。癌症可以包括黑素瘤,白血病,星形细胞瘤,胶质母细胞瘤,淋巴瘤,神经胶质瘤,霍奇金淋巴瘤,慢性淋巴细胞白血病和胰腺癌,乳腺癌,甲状腺癌,卵巢癌,子宫癌,睾丸癌,垂体癌,肾癌,胃癌,食道癌和直肠癌。
在一些实施方案中,本文提供的方法、试剂盒和组合物用于治疗患有如下癌症的任意一种或多种的受试者:急性淋巴细胞白血病(ALL),急性髓细胞性白血病,肾上腺皮质癌,与AIDS相关的癌症,与AIDS相关的淋巴瘤,肛门癌,阑尾肿瘤,星形细胞瘤,儿童小脑或脑基底细胞癌,胆管癌,肝外(见胆管上皮癌),膀胱癌,骨肿瘤,骨肉瘤/恶性纤维组织细胞瘤,脑干神经胶质瘤,脑癌,脑瘤,小脑星形细胞瘤,脑瘤,脑星形细胞瘤/恶性神经胶质瘤,脑瘤,室管膜瘤,脑瘤,髓母细胞瘤,脑瘤,幕上原始神经外胚瘤,脑瘤,视觉途径和下丘脑神经胶质瘤,乳腺癌,支气管腺瘤/类癌,伯基特淋巴瘤,类癌瘤,儿童期类癌瘤,未知的原发性胃肠道癌,原发性中枢神经系统淋巴瘤,儿童期小脑星形细胞瘤,儿童期中枢神经系统恶性神经胶质瘤,宫颈癌,儿童期癌,软骨肉瘤,慢性淋巴细胞白血病,慢性髓性白血病,慢性脊髓增生性病症,结肠癌,皮肤T细胞淋巴瘤,结缔组织增生性小圆细胞肿瘤,子宫内膜癌症,室管膜瘤,上皮血管内皮瘤(Epitheliod Hemangioendothelioma)(EHE),食管癌,Ewing肿瘤家族中的Ewing肉瘤,颅外胚细胞瘤,性腺外生殖细胞肿瘤,肝外胆管,眼癌,眼内黑素瘤,眼癌,视网膜母细胞瘤,胆囊癌,胃(胃部)癌,胃肠道类癌瘤,胃肠道间质瘤(GIST),胚细胞瘤:颅外,性腺外或卵巢,妊娠滋养细胞肿瘤,脑干神经胶质瘤,神经胶质瘤,儿童期星形细胞瘤,儿童期视觉途径和下丘脑神经胶质瘤,胃类癌,多毛细胞白血病,头颈癌,心脏肿瘤,肝细胞(肝)癌,何杰金氏淋巴瘤,下咽癌,儿童期下丘脑和视觉途径神经胶质瘤,眼内黑素瘤,胰岛细胞癌(内分泌胰腺),卡波西肉瘤,肾癌(肾细胞癌),喉癌,白血病,急性淋巴母细胞白血病(也称作急性淋巴细胞性白血病),急性髓性白血病(也称作急性髓性白血病),慢性淋巴细胞性白血病(也称作慢性淋巴细胞白血病),慢性髓性白血病(也称作慢性髓样白血病),多毛细胞白血病,唇和口腔癌,脂肪肉瘤,肝癌(原发性),肺癌,小细胞癌,肺癌,小细胞淋巴瘤,AIDS-相关淋巴瘤,伯基特淋巴瘤,皮肤T细胞淋巴瘤,霍金奇淋巴瘤,非霍金奇(所有淋巴瘤的旧分类,除外霍金奇)淋巴瘤,原发性中枢神经系统巨球蛋白血症,男性乳癌,骨恶化纤维组织细胞瘤/骨肉瘤,髓母细胞瘤,儿童期黑素瘤,眼内(眼)黑素瘤,Merkel细胞癌,间皮瘤,成人恶性间皮瘤,就要不可思议的原发性的儿童期转移性鳞状颈癌,口腔癌,多发性内分泌肿瘤综合征,多发性骨髓瘤/浆细胞肿瘤,蕈样真菌病,骨髓增生异常综合征,脊髓发育不良/骨髓组织增殖性疾病,髓性白血病,慢性髓样白血病,成人急性髓性白血病,儿童期多发性急性骨髓瘤(骨髓癌),骨髓增殖性疾病,慢性粘液瘤,鼻腔和鼻窦肿瘤,鼻咽癌,神经母细胞瘤,非霍奇金淋巴瘤,非小细胞肺癌,少突神经胶质瘤,口癌,口咽癌,骨肉瘤/骨恶性纤维组织细胞瘤,卵巢癌,卵巢上皮癌(表面上皮-间质瘤),卵巢生殖细胞肿瘤,卵巢低度潜在恶性肿瘤,胰腺癌,胰岛胰腺癌,鼻旁窦和鼻腔癌,甲状旁腺癌,阴茎癌,咽癌,嗜铬细胞瘤,松果体星形细胞瘤,松果体生殖细胞瘤,松果体母细胞瘤和幕上原始神经外胚瘤,垂体腺瘤,浆细胞瘤/多发性骨髓瘤,胸膜肺母细胞瘤,原发性中枢神经系统淋巴瘤,前列腺癌,直肠癌,肾细胞癌(肾癌),肾盂和输尿管癌,移行细胞癌,视网膜母细胞瘤,横纹肌肉瘤,涎腺癌,肉瘤,Ewing家族肿瘤,卡波西肉瘤软组织肉瘤,子宫肉瘤,Sézary综合征,皮肤癌(非黑素瘤),皮肤癌(黑素瘤),皮肤癌,Merkel细胞,小细胞肺癌,小肠癌,软组织肉瘤,鳞状细胞癌—参见皮肤癌(非黑素瘤),具有不可思议的原发性,转移性鳞状颈癌,胃癌,幕上原发性神经外胚层瘤,T细胞淋巴瘤,皮肤(皮真菌病和Sézary综合征),睾丸癌症,喉癌,胸腺瘤,胸腺瘤和胸腺癌,甲状腺癌,甲状腺癌,肾盂和输尿管的移行细胞癌,妊娠滋养细胞肿瘤,成年未知的基本位点癌,儿童期未知的基本位点癌,输尿管和肾盂移行细胞癌,尿道癌症,子宫癌,子宫内膜肿瘤,子宫肉瘤,阴道癌症,视觉途径和下丘脑神经胶质瘤,外阴癌,/>巨球蛋白血症或Wilms瘤(肾癌)。/>
在一些实施方案中,与癌症相关的示例性靶基因包括
ABL1,ABL2,ACSL3,AF15Q14,AF1Q,AF3p21,AF5q31,
AKAP9,A T1,AKT2,ALDH2,AL,AL017,APC,ARHGEF12,
ARHH,ARID1A,ARID2,ARNT,ASPSCR1,ASXL1,ATF1,
ATIC,ATM,ATRX,AXIN1,BAP1,BCL10,BCL11A,
BCL11B,BCL2,BCL3,BCL5,BCL6,BCL7A,BCL9,BCOR,
BCR,BHD,BIRC3,BLM,BMPRIA,BRAF,BRCAl,BRCA2,
BRD3,BRD4,BRIPI,BTG1,BUB1B,C12orf9,C15orf21,
C15orf55,C16orf75,C2orf44,CAMTA1,CANT1,CARD11,
CARS,CBFA2T1,CBFA2T3,C.BFB,CBL,CBLB,CBLC,
CCDC6,CCNB1IP1,CCND1,CCND2,CCND3,CCNE1,
CD273,CD274,CD74,CD79A,CD79B,CDH1,CDH11,
CDK12,CDK4,CDK6,CD N2A,CD N2a(pl4),CD N2C,CDX2,
CEBPA,CEPl,CHCHD7,CHEK2,CHIC2,CHNl,CIC,Cin A,
CLTC,CLTCL1,CMKOR1,CNOT3,COL1 Al,COPEB,
COX6C,CREB1,CREB3L1,CREB3L2,CREBBP,CRLF2,
CRTC3,CTNNB1,CYLD,D10S170,DAXX,DDB2,DDIT3,
DDX10,DDX5,DDX6,DEK,D1CER1,DNM2,DNMT3A,
DUX4,EBFI,ECT2L,EGFR,E1F4A2,ELF4,ELK4,ELKS,
ELL,ELN,EML4,EP300,EPS 15,ERBB2,ERCC2,ERCC3,
ERCC4,ERCC5,ERG,ETVl,ETV4,ETV5,ETV6,EVIl,
EWSR1,EXTl,EXT2,EZH2,EZR,FACL6,FAM22A,
FAM22B,FAM46C,1ANCA,EANCC,FANCD2,FANCE,
FANCF,FANCG,FBXOl 1,FBXW7,FCGR2B,FEV,FGFR1,
FGFRIOP,FGFR2,FGFR3,FTI,FIIIT,FIP1L1,FLU,
FLJ27352,FLT3,FNBP1,FOXL2,FOXOIA,FOX03A,FOXP1,
FSTL3,FUBP1,FUS,FVT1,GAS7,GATA1,GATA2,GATA3,
GMPS,GNA11,GNAQ,GNAS,GOLGA5,GOPC,GPC3,
GPHN,GRAF,H3F3A,IICMOGT-1,IIEAB,HERPUD1,
IIEY1,IIIPl,HIST1IT3B,IIIST1II4I,IILF,HLXB9,HMGA1,
HMGA2,HNRNPA2BI,HOOK3,HOXA11,HOXA13,HOXA9,
HOXC11,HOXC13,HOXD11,HOXD13,HRAS,IIRPT2,
HSPCA,HSPCB,IDHl,IDH2,IGH,IGK,IGL,IKZFl,IL2,
TL21R,IL6ST,IL7R,IRF4,IRTA1,ITK,JAK1,JAK2,
JAK3,JAZF1,JUN,KCNJ5,KDM5A,KDM5C,KDM6A,
KDR,KIAA1549,KIF5B,KIT,KLF4,KLK2,KRAS,KTN1,
LAF4,LASPl,LCK,LCP1,LCX,LHFP,LIFR,LMOl,LM02,
LPP,LRIG3,LYL1,MADH4,MAF,MAFB,MALT1,
MAML2,MAP2KL MAP2K2,ΜλΡ2K4,MAX,MDM2,MDM4,
MDS1,MDS2,MECTl,MED12,MEN1,MET,MITF,MKL1,
MLF1,MLIIl,MLL,MLL2,MLL3,MLLT1,MLLT10,
MLLT2,MLLT3,MLLT4,MLLT6,MLLT7,MN1,MPL,
MSF,MSH2,MSH6,MSI2,MSN,MTCP1,MUC1,MUTYH,
MYB,MYC,MYCL1,MYCN,MYD88,MYH11,MYH9,
MYST4,NACA,NBS1,NCOA1,NCOA2,NCOA4,NDRG1,
NF1,NF2,NFE2L2,NFIB,NFKB2,NIN,NKX2-1,NONO,
NOTCH I,NOTCH2,NPMl,NR4A3,NRAS,NSDl,NT5C2,
NTRKl,NTRK3,NUMAl,NUP214,NUP98,OLIG2,OMD,
P2RY8,PAFAH1B2,PALB 2,PAX3,PAX5,PAX7,PAX8,
PBRM1,PBX1,PCM1,PCSK7,PDE4DIP,PDGFB,PDGFRA,
PDGFRB,PERI,PIIF6,PHOX2B,PICALM,PIK3CA,PIK3R1,
PIM1,PLAG 1,PML,PMS1,PMS2,PMX1,PNUTL1,POT1,
POU2AF1,POU5F1,PPARG,PPP2R1A,PRCC,PRDM1,
PRDM16,PRF1,PRKAR1 A,PRO1073,PSIP2,PTCH,PTEN,
PTPN11,RAB5EP,RACl,RAD51L1,RAFl,RALGDS,
RANBP17,RAPIGDSI,RARA,RBI,RBM15,RECQL4,REL,
RET,RNF43,ROS1,RPL10,RPL22,RPL5,RPN1,
RUNDC2A,RUNX1,RUNXBP2,SBDS,SDC4,SDH5,SDHB,
SDHC,SDHD,SEPT6,SET,SETBP1,SETD2,SF3B1,SFPQ,SFRS3,SH2B3,SH3GL1,SIL,SLC34A2,SLC45A3,SMARCA4,SMARCB1,SMARCE1,SMO,SOCS1,SOX2,SRGAP3,SRSF2,SSI8,SS18L1,SSH3BP1,SSX1,SSX2,SSX4,STAT3,STK11,STL,SUFU,SIJZ12,SYK,TAF15,TALI,TAL2,TCEA1,TCF1,TCF12,TCF3,TCF7L2,TCL1A,TCL6,TERT,TET2,TFE3,TFEB,TFG,TFPT,TFRC,THRAP3,TIF1,TLX1,TLX 3,TMPRSS2,TNFAIP3,TNFRSF14,TNFRSF17,TNFRSF6,TOPI,TP53,TPM3,TPM4,TPR,TRA,TRAF7,TRB,TRD,TRIM27,TRIM33,TRIP11,TSC1,TSC2,TSHR,TTL,U2AF1,USP6,VHL,VTUA,WAS,WHSC1,WHSC1L1,WIF1,WRN,WT1,WTX,WWTR1,XPA,XPC,XPOl,YWHAE,ZNF145,ZNF198,ZNF278,ZNF331,ZNF384,ZNF521,ZNF9,ZRSR2或其任意组合。
在一些实施方案中,本文公开的方法用于治疗具有遗传障碍的受试者。治疗患有遗传性疾病或病症或遗传障碍的受试者的方法包含向受试者细胞施用DNA-PK抑制剂和基因组编辑系统。施用DNA-PK抑制剂和基因组编辑系统可以为体内或离体的。
所述遗传障碍可以因染色体区中的突变或复制导致(例如来自点突变,缺失,插入,移码,染色体复制或缺失)。所述遗传障碍可以为任意的遗传障碍。
在一些实施方案中,所述遗传障碍为22q11.2缺失综合征,Angelman综合征,卡纳万病,夏-马-图三氏病,色盲,猫叫样哭泣,唐氏综合征,杜兴肌营养不良,血色病,血友病,先天性睾丸发育不全综合征,神经纤维瘤病,苯丙酮尿症,多囊肾疾病,帕-魏二氏综合征,镰刀形细胞病,脊髓性肌萎缩,脊髓性肌萎缩,泰-萨克斯病,特纳综合征,血红蛋白病或其任意组合。
在一些实施方案中,所述遗传障碍为1p36缺失综合征,18p缺失综合征,21-羟化酶缺乏症,47XXX(三X综合征),47XXY(克氏(Klinefelter)综合征),5-ALA脱水酶缺乏卟啉症,ALA脱水酶缺乏,5-氨基酮戊酸脱水酶缺乏卟啉症,5p缺失综合征,猫叫样哭泣(AKA 5p-综合征),共济失调性毛细血管扩张(AKA A-T),α1抗胰蛋白酶缺乏症(AAT),铜蓝蛋白血症,II型软骨成长不全(ACG2),软骨发育不全(ACH),葡糖苷酰鞘氨醇酶缺乏,戈谢病(任意类型,例如1型,2型,3型),尖头并指(Apert),Apert综合征,尖头并指(任意类型,例如1型,2型,3型,5型),斐弗综合征,尖头,急性脑型Gaucher病,急性间歇性卟啉病,(AIP)ACY2缺乏,阿尔茨海默病(AD),Adelaide-型颅缝早闭,Muenke综合征,腺瘤结肠息肉,家族性多发性腺癌,结肠腺瘤息肉病,家族性多发性腺癌(ADP),腺苷酸琥珀酸裂解酶缺乏,肾上腺病症,肾上腺生殖综合征,肾上腺脑白质营养不良,雄激素不敏感综合征(AIS),黑尿病(AKU),ALA脱水酶卟啉症,ALA-D卟啉症,ALA脱水酶缺乏,Alagille综合征,白化病,黑尿病,黑尿病,亚历山大病,黑尿病,尿黑酸黄褐病,黑尿病,α-1蛋白酶抑制剂疾病,α-1相关肺气肿,α-半乳糖苷酶A缺乏,法布里病,综合征,亚历山大病(ALX),釉质形成不全,氨基乙酰丙酸脱水酶缺乏,酰化氨基酸水解酶2缺乏,卡纳万病,安德森-法布里病,雄激素不敏感综合征,贫血,遗传性铁粒幼红细胞性贫血,X-连锁铁粒幼细胞贫血和/或家族性贫血,弥漫性躯体性血管角化瘤,弥漫性血管角质瘤,拉-希二氏病,希-林二氏病,APC抵抗,Leiden型,因子VLeiden血栓形成倾向,Apert综合征,AR缺乏,雄激素不敏感综合征,夏-马-图三氏病(任意类型,例如CMT1,CMTX,CMT2,CMT4,严重早期发作CMT),蜘蛛脚样指,马凡综合征ARNSHL,非综合征性耳聋(常染色体隐性遗传,常染色体显性,x-连锁或线粒体),关节-眼病,遗传性进行性Stickler综合征(例如COL2A1,COL11A1,COL11A2,COL9A1),先天性多发性关节松弛,Ehlers-Danlos综合征(例如高运动性型,关节炎型,经典型,血管型,脊柱后凸型,皮肤松弛型)Asp缺乏,Aspa缺乏,天冬氨酸酰化酶缺乏,共济失调性毛细血管扩张,自闭症-痴呆症-共济失调-有目的手使用综合征,Rett综合征,常染色体显性少年ALS,常染色体显性遗传opitz G/BBB综合征,3型少年ALS的常染色体隐性形式,肌萎缩侧索硬化(任意类型;例如ALS1,ALS2,ALS3,ALS4,ALS5,ALS5,ALS6,ALS7,ALS8,ALS9,ALS10,ALS11,ALS12,ALS13,ALS14,ALS15,ALS16,ALS17,ALS18,ALS19,ALS20,ALS21,ALS22,FTDALS1,FTDALS2,FTDALS3,FTDALS4,FTDALS4,IBMPFD2),常染色体隐性遗传非综合征性听觉丧失,常染色体隐性遗传感觉神经听力损伤和甲状腺肿,家族性呆小聋哑症,亚历山大病(AxD),阿耶萨综合征,家族性肺动脉高压,己糖胺酶GM2神经节苷脂贮积病的B型变体,BANF-相关障碍,神经纤维瘤病(任意类型,例如NF1,NF2,神经鞘瘤病),Beare-Stevenson Cutis Gyrata综合征,良性阵发性腹膜炎,体质性贫血综合征,β地中海贫血,BH4缺乏,四氢生物喋呤缺乏,双侧听神经纤维瘤病,生物素酶缺乏,膀胱癌,出血障碍,因子V Leiden血栓形成倾向,Bloch-Sulzberger综合征,色素失调症,Bloom综合征,骨疾病,布尔尼维利病,结节性硬化症,脑疾病,朊病毒病,乳腺癌,Birt-Hogg-Dubé综合征,脆骨病,成骨不全,宽指综合征,鲁宾斯坦综合征,青铜色糖尿病,血色沉著病,青铜色肝硬变,延髓肌萎缩,X-连锁脊髓延髓肌肉萎缩症,伯-格二氏综合征,脂蛋白脂酶缺乏,家族性CADASIL综合征,CGD慢性肉芽肿病,躯干发育异常,癌症家族综合征,遗传性非息肉性结肠直肠癌,乳腺癌,膀胱癌,羧化酶缺乏,多发性迟发生物素酶缺乏,猫叫综合征,Caylor心面综合征,神经酰胺三己糖苷酶缺乏症,小脑视网膜血管瘤,家族性希林二氏病,大脑动脉病,CADASIL综合征,大脑常染色体显性动脉病,CADASIL综合征,脑萎缩性血氨过高,Rett综合征,脑苷脂沉积综合征,沙尔科病,CHARGE综合征,软骨营养不良,软骨营养不良综合征,具有感觉神经性聋的软骨营养不良,耳-脊髓-大骨骺发育异常(otospondylomegaepiphyseal dysplasia),软骨发生不全,舞蹈徐动症-自残-高尿酸血综合征,莱-萘二氏综合征,半乳糖血症,半乳糖血症,唇腭裂,Stickler综合征,具有死亡恐怖性侏儒症的分叶状颅,致死性发育不全(例如1型或2型),科-勒二氏综合征(CLS),Cockayne综合征,科-勒二氏综合征,II型和XI型胶原病,家族性非息肉病性,遗传性非息肉性结肠直肠癌,家族性结肠癌,家族性多发性腺癌,结直肠癌,完全HPRT缺乏,莱-萘二氏综合征,完全次黄嘌呤-鸟嘌呤-磷酸核糖基转移酶缺乏,压迫性神经障碍,具有易感压迫性麻痹的遗传性神经病,结缔组织病,圆锥动脉干异常面部综合征,Cooley贫血,β地中海贫血,铜贮积病,肝豆状核变性,铜转运疾病,门克斯病,粪卟啉症,遗传性粪卟啉病,粪卟啉原氧化酶缺乏,Cowden综合征,CPX缺乏,颅面关节变形,Crouzon综合征,颅面骨骨发育不良,Crouzon综合征,克罗恩病,纤维性狭窄,Crouzon综合征,克鲁宗综合征伴黑棘皮症,Crouzonodermoskeletal综合征,Crouzonodermoskeletal综合征,Cockayne综合征(CS),Cowden综合征,Curschmann-Batten-Steinert综合征,Beare-Stevenson的皮肤回旋综合征(cutis gyrata syndrome of Beare-Stevenson),Beare-Stevenson Cutis Gyrata综合征,D-甘油酸盐脱氢酶缺乏,高草酸尿,原发性斑点状干骺端综合征,脊椎干骺端发育不全,Strudwick型,阿尔茨海默型痴呆(DAT),遗传性高钙尿症,登特病,肌营养不良症(例如Duchenne和Becker型),具有甲状腺肿的聋,家族性呆小聋哑症,聋-色素性视网膜炎综合征,乌斯赫尔综合征,营养缺乏症,苯丙氨酸羟化酶,变性性神经疾病,德格罗契综合征1,德格罗契综合征,代-索二氏综合征,胆色素原合酶缺乏卟啉症,CADASIL综合征,脱髓鞘性脑白质营养不良症(demyelinogenic leukodystrophy),亚历山大病,Ehlers-Danlos综合征的Dermatosparactic型,皮肤脆裂症,遗传性发育性残疾,末梢遗传性运动神经病(dHMN),末梢遗传性运动神经病(例如DHMN-V),DHTR缺乏,雄激素不敏感综合征,弥漫性球体硬化,克拉伯病,狄乔治综合征,二氢睾甾酮受体缺乏,雄激素不敏感综合征,末梢遗传性运动神经病,营养不良性肌强直(1型或2型),远端脊髓性肌萎缩(任意类型,包括,例如1型,2型,3型,4型,5型,6型),Duchenne/Becker肌营养不良症,侏儒症(任意类型,例如软骨发育不全性,软骨发育不全,致死性发育不全),侏儒症-视网膜萎缩-耳聋综合征,Cockayne综合征,髓鞘增生性白细胞营养不良(dysmyelinogenic leukodystrophy),亚历山大病,营养不良性肌强直,营养不良性视网膜色点-成骨不全综合征,乌斯赫尔综合征,早发性家族性阿尔茨海默病(EOFAD),阿尔茨海默病(包括,例如1型,2型,3型或4型),Ekman-Lobstein病,成骨不全,卡陷性神经病变,具有易感遗传性神经病的遗传性神经病,红细胞生成性原卟啉病(EPP),成红细胞性贫血,β地中海贫血,红细胞肝性原卟啉症,红色5-氨基酮戊酸合成酶缺乏,X-连锁铁粒幼细胞贫血,眼癌,视网膜母细胞瘤FA—弗里德赖希共济失调,弗里德赖希共济失调症,FA,范科尼贫血,面部损伤和障碍,因子V Leiden血栓形成倾向,FALS,肌萎缩侧索硬化,家族性听神经瘤,家族性多发性腺癌,家族性Alzheimer病(FAD),家族性肌萎缩性侧索硬化,肌萎缩侧索硬化,家族性自主神经功能异常,家族性脂肪引起的高甘油三酯血症,脂蛋白脂酶缺乏,家族性血色病,血色沉著病,家族性LPL缺乏,脂蛋白脂酶缺乏,家族性非息肉病性结肠癌,遗传性非息肉性结肠直肠癌,家族性发作性多浆膜炎,家族性PCT,迟发性皮肤卟啉病,家族性压力敏感性神经病,具有易感压迫性麻痹的遗传性神经病,家族性原发性肺动脉高压(FPPH),家族性血管性脑白质病,CADASIL综合征,FAP,家族性多发性腺癌,FD,家族性自主神经功能异常,亚铁螯合酶缺乏,铁转运蛋白病(ferroportin disease),血色病(任意类型,例如1型,2A型,2B型,3型,4型,新生儿血色病,血浆铜绿蛋白血症,先天性转铁蛋白血症,gracile综合征),周期热综合征,家族性地中海热(FMF),FG综合征,FGFR3-伴随性头颅骨连接,星形细胞纤维蛋白样变性,亚历山大病,胰腺纤维囊性病变,福兰格病,fra(X)综合征,脆性X染色体综合征,骨脆症,成骨不全,FRAXA综合征,弗里德赖希共济失调症(FRDA),G6PD缺乏,半乳糖激酶缺乏病,半乳糖血症,半乳糖-1-磷酸尿苷酰基转移酶缺乏病,半乳糖血症,半乳糖神经酰胺酶缺乏病,克拉伯病,半乳糖酰基鞘氨醇脂沉积症,克拉伯病,半乳糖基脑苷酶缺乏,半乳糖鞘氨醇脂质沉积症,GALC缺乏,GALT缺乏,半乳糖血症,Gaucher-样病,假-戈谢病,GBA缺乏,遗传性脑疾病,遗传性肺气肿,遗传性血色素沉着病,血色沉著病,巨细胞性肝炎,新生儿血色病,GLA缺乏,胶质母细胞瘤,视网膜母细胞瘤,神经胶质瘤,视网膜母细胞瘤,球样细胞脑白质营养不良(GCL,GLD),克拉伯病,球样细胞脑白质营养不良,葡糖脑苷脂酶缺乏,脑醣苷沉着病,葡萄糖基脑苷脂贮积病,葡糖苷酰鞘氨醇酶缺乏,葡糖苷酰鞘氨醇酶β-葡萄糖苷酶缺乏,葡萄糖酰鞘氨醇脂沉积症,甘油酸尿症,高草酸尿,原发性甘氨酸脑病,非酮性高甘氨酸血症,羟基乙酸尿症,原发性高草酸尿,GM2神经节苷质病,泰-萨克斯病,甲状腺肿-聋综合征,家族性呆小聋哑症,Graefe-Usher综合征,乌斯赫尔综合征,格-斯二氏综合征,弹力纤维性假黄瘤,血色病,血色沉著病,视合网膜色素变性-耳聋-共济失调综合征,乌斯赫尔综合征,Harlequin型鱼鳞癣,Hb S病,软骨发育不良(HCH),遗传性粪卟啉病(HCP),头和脑畸形,听觉障碍和耳聋,儿童中的听觉问题,HEF2A,HEF2B,血卟啉病,卟啉症,血红素合成酶缺乏,血色沉著病,血红蛋白M病,高铁血红蛋白血症β-珠蛋白型,血红蛋白S病,血友病,肝红细胞生成型卟啉症(HEP),肝AGT缺乏,原发性高草酸尿,肝豆状核变性综合征,Wilson病,遗传性关节-眼病,Stickler综合征,遗传性异位沉积症,遗传性血色病(HHC),血色沉著病,遗传性出血性毛细血管扩张症(HHT),遗传性包涵体肌病,骨骼肌再生,遗传性铁负荷性贫血,X-连锁铁粒幼细胞贫血,遗传性运动感觉性神经病,遗传性运动神经病V型,末梢遗传性运动神经病,遗传性多发性外生骨疣,遗传性非息肉性结肠直肠癌,遗传性周期性发热综合征,遗传性结肠息肉,家族性多发性腺癌,遗传性肺气肿,活化蛋白C的遗传耐药性,因子V Leiden血栓形成倾向,遗传性感觉和自主神经病变III型,家族性自主神经功能异常,遗传性痉挛性截瘫,婴儿发作性升遗传性痉挛性瘫痪,遗传性脊髓性共济失调,弗里德赖希共济失调症,遗传性脊髓硬化,弗里德赖希共济失调症,镰状红细胞贫血,杂合型OSMED,Weissenbacher-Zweymüller综合征,杂合型耳-脊髓-大骨骺发育异常,Weissenbacher-Zweymüller综合征,HexA缺乏,泰-萨克斯病,己糖胺酶A缺乏,泰-萨克斯病,己糖胺酶α亚单位缺乏(任意变体,例如变体A,变体B),泰-萨克斯病,HFE-伴随血色沉著病,血色沉著病,HGPS,早衰,希-林二氏病,von Hippel-Lindau病,血色沉著病(HLAH),末梢遗传性运动神经病(HMN V),遗传性非息肉性结肠直肠癌(HNPCC),具有易感压迫性麻痹的遗传性神经病(HNPP),高胱氨酸尿,尿黑酸氧化酶缺乏,黑尿病,Homogentisic acidura,黑尿病,纯合子性迟发性卟啉症皮肤,肝红细胞生成型卟啉症,原发性高草酸尿(HP1),高草酸尿(HP2),高苯丙氨酸血症(HPA),HPRT-次黄嘌呤-鸟嘌呤-磷酸核糖基转移酶缺乏,Lesch-Nyhan综合征,HSAN III型,家族性自主神经功能异常,家族性自主神经功能异常(HSAN3),遗传性感觉性神经病(任意类型,例如HSN-1,HSN-II,HSN-III),家族性自主神经功能异常,人皮肤脆裂症,亨廷顿病,Hutchinson-Gilford早老综合征,早衰,雄激素增多症,因21-羟化酶缺乏症导致的非典型,高乳糜微粒血症,家族性脂蛋白脂酶缺乏症,具有酮酸中毒和白血球减少症的家族性血甘氨酸过多症,丙酸血症,高脂蛋白血症Ⅰ型,脂蛋白脂酶缺乏,家族性高草酸尿,原发性高苯丙氨酸血症,高苯丙氨酸血症,高苯丙氨酸血症,季肋部发育不全,季肋部发育不全,软骨形成不足,软骨发育不良,低色素性贫血,X-连锁铁粒幼细胞贫血,次黄嘌呤磷酸核糖基转移酶缺乏(HPRT)缺乏,莱-萘二氏综合征,婴儿迟发性升遗传性痉挛性瘫痪(IAHSP),ICF综合征,免疫缺陷,着丝粒不稳定性和面部异常综合征,特发性血色素沉着,血色沉著病3型,特发性新生儿血色病,新生儿血色沉著病,特发性肺动脉高压,免疫系统紊乱,X-连锁重症联合免疫缺陷,色素失调症,婴儿脑型Gaucher病,婴儿Gaucher病,婴儿迟发性升遗传性痉挛性瘫痪,不孕症,遗传性肺气肿,压迫性麻痹的遗传趋势,具有易感压迫性麻痹的遗传性神经病,Insley-Astley综合征,耳-脊髓-大骨骺发育异常,间歇性急性卟啉综合征,急性间歇性卟啉病,肠息肉病-皮肤色素沉着综合征,普-杰二氏综合征,色素失调症(IP),铁储存障碍,血色沉著病,具同形双着丝粒的15,具同形双着丝粒的15,分离型耳聋,非综合征性耳聋,杰克森-韦斯综合征,朱伯特综合征,青少年原发性侧索硬化症(JPLS),皮肤色素沉着,幼年痛风,舞蹈手足徐动症,精神发育迟滞综合征,莱-萘二氏综合征,青少年高尿酸血症综合征,莱-萘二氏综合征,杰克森-韦斯综合征(JWS),脊髓延髓肌肉萎缩症,Kennedy病,髓延髓肌肉萎缩症,Kennedy髓延髓肌肉萎缩症,髓延髓肌肉萎缩症,角苷脂组织细胞增多症,角苷脂沉积症,角苷脂贮积病,酮症性甘氨酸血症,丙酸血症,酮症性高甘氨酸血症,丙酸血症,肾病,原发性高草酸尿,Kniest发育不全,克拉伯病,库-韦病,脊髓性肌萎缩,腔隙性痴呆,CADASIL综合征,Langer-Saldino软骨成长不全,Langer-Saldino发育不良,迟发性阿尔茨海默病,迟发性克拉伯病(LOKD),克拉伯病,学习障碍,学习不能,口腔着色斑病,普-杰二氏综合征,莱-萘二氏综合征,脑白质营养不良症,罗森塔尔纤维的脑白质营养不良症具有,亚历山大病,海绵状脑白质营养不良症,Li-Fraumeni综合征(LFS),Li-Fraumeni综合征,脂肪酶D缺乏,脂蛋白脂酶缺乏,家族性LIPD缺乏,脂蛋白脂酶缺乏,家族性脑苷脂脂肪沉积,婴儿神经节苷脂脂肪沉积,泰-萨克斯病,类脂性组织细胞增生症(角苷脂型),脂蛋白脂酶缺乏,家族性肝病,半乳糖血症,LouGehrig病,路易斯·巴尔综合征,运动失调性毛细血管扩张症,Lynch综合征,遗传性非息肉性结肠直肠癌,赖氨酰羟化酶气氛,马至约病,脊髓小脑性共济失调(任意类型,例如SCA1,SCA2,SCA3,SCA 18,SCA20,SCA21,SCA23,SCA26,SCA28,SCA29),男性乳癌,乳腺癌,男性生殖性疾病,乳腺恶性肿瘤,乳腺癌,乳腺恶性肿瘤,乳腺癌,膀胱癌的恶性肿瘤,膀胱癌,乳腺癌,乳腺癌,马凡综合征,标志X染色体综合征,脆性X染色体综合征,Martin-Bell综合征,脆性X染色体综合征,麦-奥二氏综合征,McLeod综合征,MEDNIK综合征,地中海贫血,β地中海贫血,甲基眠尔通侏儒症,耳-脊髓-大骨骺发育异常,Menkea综合征,门克斯病,门克斯病,具有骨软骨异常的精神发育迟滞,科-勒二氏综合征,代谢性疾病,间向性侏儒II型,Kniest发育不全,变型骨发育不良II型,Kniest发育不全,高铁血红蛋白血症(任意类型,例如先天性β-珠蛋白型,先天性高铁血红蛋白血症II型),甲基丙二酸血症,马凡综合征(MFS),MHAM,考登综合征,Micro综合征,小头畸形,MMA,甲基丙二酸血症,门克斯病(AKA MK或MNK),单体性1p36综合征,运动神经元病,肌萎缩侧索硬化,肌萎缩侧索硬化,运动障碍,Mowat-Wilson综合征,黏多糖累积病(MPS I),粘液粘稠病,多发梗塞性痴呆,CADASIL综合征,迟发性多发性羧化酶缺乏,生物素酶缺乏,多发性错构瘤综合征,考登综合征,多发性神经纤维瘤病,肌营养不良症(任意类型,包括,例如Duchenne和Becker型),萎缩性肌强直,营养不良性肌强直,失养性肌强直病,Nance-Insley综合征,耳-脊髓-大骨骺发育异常,Nance-Sweeney软骨发育不全,耳-脊髓-大骨骺发育异常,NBIA1,泛酸激酶相关性神经退行性疾病,Neill-Dingwall综合征,Cockayne综合征,神经母细胞瘤,视网膜母细胞瘤,具有脑铁蓄积1型的神经变性,泛酸激酶相关性神经退行性疾病,神经病,神经肌肉性失常,末梢遗传性运动神经病,Niemann-Pick,Niemann-Pick病,诺亚克综合征,非酮性高甘氨酸血症,甘氨酸脑病,非神经原戈谢病,非苯酮尿酸高苯丙氨酸血症,四氢生物喋呤缺乏,非综合征性耳聋,努南综合征,Norrbottnian戈谢病,褐黄病,黑尿病,褐黄病性关节炎,黑尿病,Ogden综合征,成骨不全(OI),奥斯勒-韦伯-朗迪病,遗传性出血性毛细血管扩张症,OSMED,耳-脊髓-大骨骺发育异常,成骨不全,成骨不全,成骨不全,先天性骨硬化,耳-脊髓-大骨骺发育异常,耳-脊髓-大骨骺发育异常,耳-脊髓-大骨骺发育异常,草酸盐沉着症,原发性高草酸尿,原发性草酸尿,原发性高草酸尿,泛酸激酶相关性神经退行性疾病,Patau综合征(13三体),PBGD缺乏,急性间歇性卟啉病,PCC缺乏,丙酸血症,迟发性皮肤卟啉病(PCT),PDM病,家族性呆小聋哑症,周期性疾病,地中海热,家族性周期性腹膜炎,口周着色斑病综合征,普-杰二氏综合征,周围神经紊乱,家族性自主神经功能异常,周围神经纤维瘤病,腓肌萎缩,过氧化氢酶体丙氨酸:乙醛醛氨基转移酶缺乏,高草酸尿,原发性普-杰二氏综合征,苯丙氨酸羟化酶缺乏病,嗜铬细胞瘤,von Hippel-Lindau病,具有胎儿软骨发育不全的皮埃尔-罗班综合征,Weissenbacher-Zweymüller综合征,色素性肝硬变,血色沉著病,普-杰二氏综合征(PJS),泛酸激酶相关性神经退行性疾病(PKAN),PKU,苯丙酮尿,Plumboporphyria,ALA缺乏卟啉症,PMA,多囊肾病,多骨纤维发育不良,麦-奥二氏综合征,家族性多发性腺癌,错构瘤肠息肉病,息肉-和-斑点综合征,普-杰二氏综合征,卟啉胆素原合酶缺乏,ALA缺乏卟啉症,卟啉症,PPOX缺乏,多样性卟啉病,普-拉-威综合征,帕-魏二氏综合征,早老性和老年性痴呆,原发性纤毛运动障碍(PCD),原发性血色病,血色沉著病,原发性尿酸血症综合征,莱-萘二氏综合征,原发性老年性变性痴呆,前胶原型EDS VII突变,早衰,Hutchinson GilfordProgeria综合征,类早老综合征,Cockayne综合征,类早老侏儒症,Cockayne综合征,进行性舞蹈病,慢性遗传性(亨廷顿)亨廷顿病,具有正常巩膜的进行性变形性成骨不全,成骨不全(任意类型,例如I型,II型,III型,IV型,V型,VI型,VII型,VIII型),近端肌强直性营养障碍(PROMM),丙酸血症,丙酰辅酶A羧化酶缺乏,蛋白质C缺乏,蛋白质S缺乏,原卟啉症,卟啉原氧化酶缺乏,多样性卟啉病,近端肌强直性营养障碍,2型肌强直性营养障碍,近位肌强直肌病,假-戈谢病,弹力纤维性假黄瘤,鞘氨醇半乳糖苷脂沉积,克拉伯病,肺动脉高压,肺动脉高压,弹力纤维性假黄瘤(PXE),弹力纤维性假黄瘤,视网膜母细胞瘤(Rb),Recklinghausen病,复发性多浆膜炎,视网膜病,色素性视网膜炎-耳聋综合征,乌斯赫尔综合征,视网膜母细胞瘤,Rett综合征,RFALS 3型,Ricker综合征,Riley-Day综合征,家族性自主神经功能异常,鲁息-莱维综合征,鲁-塔二氏综合征(RSTS),Rett综合征(RTS),鲁-塔二氏综合征,鲁-塔二氏综合征,Sack-Barabas综合征,SADDAN病,Li和Fraumeni的肉瘤家族综合征,Li-Fraumeni综合征,SBLA综合征(肉瘤,乳腺,白血病和肾上腺综合征),Li-Fraumeni综合征,脊髓延髓肌肉萎缩症(SBMA),许旺细胞瘤,听觉双向神经纤维瘤病II型,施-詹二氏综合征,X-连锁重症联合免疫缺陷(SCIDX1),先天性SED,先天性椎体骨骺结构不良,SEDStrudwick,Strudwick型脊椎干骺端发育不全,先天性椎体骨骺结构不良(SEDc),脊椎干骺端发育不全(SEMD),Strudwick型SEMD,老年性痴呆,具有发育迟滞和黑棘皮症的严重软骨发育不全,SADDAN病,斯普林泽综合征,因PHF8基因中的突变导致的Siderius X-连锁精神发育迟滞综合征,骨骼-皮肤-脑综合征,皮肤色素沉着,脊髓性肌萎缩(SMA),脊椎-干骺端发育不良(SMED)(任意类型,例如Studwick型,1型),史-伦-奥三氏综合证,Smith Magenis综合征,南非遗传性卟啉病,婴儿发作性遗传性痉挛性麻痹,婴儿发作性遗传性痉挛性麻痹,语言和交流障碍,神经鞘脂贮积症,泰-萨克斯病,脊髓延髓肌肉萎缩症,脊髓性肌萎缩,脊髓性肌萎缩末梢V型,末梢遗传性运动神经病,远端上肢突出性脊髓性肌萎缩,末梢遗传性运动神经病,脊髓小脑性共济失调,先天性椎体骨骺结构不良,脊椎骺发育不全,胶原病(任意类型,例如II型和XI型),脊椎干骺端发育不全,脊椎干骺端结构不良(SMD),脊椎干骺端发育不全,中枢神经系统海绵状变性,脑海绵状变性,婴儿期白质海绵样变性,零星原发性肺动脉高压,SSB综合征,钢发综合征,门克斯病,Steinert病,营养不良性肌强直,Steinert肌强直性营养不良综合征,营养不良性肌强直,Stickler综合征,中风,CADASIL综合征,Strudwick综合征,亚急性神经元病性Gaucher病,瑞典遗传性卟啉病,急性间歇性卟啉病,急性间歇性卟啉病,瑞士干酪软骨发育不良,Kniest发育不全,泰-萨克斯病,TD-死亡恐怖性侏儒症,致死性发育不全,具有连续股骨和分叶状颅的TD,致死性发育不全2型,毛细血管扩张,小脑-眼皮肤,运动失调性毛细血管扩张症,睾丸女性化综合征,雄激素不敏感综合征,四氢生物喋呤缺乏,睾丸女性化综合征(TFM),雄激素不敏感综合征,中间型地中海贫血,β地中海贫血,重型珠蛋白生成障碍性贫血,β地中海贫血,致死性发育不全,因活化蛋白C的辅因子缺乏导致的血栓形成倾向,Leiden型,因子V Leiden血栓形成倾向,甲状腺病,椎间盘神经病(Tomaculous neuropathy),具有易感压迫性麻痹的遗传性神经病,完全HPRT缺乏,莱-萘二氏综合征,完全次黄嘌呤-鸟嘌呤磷酸核糖基转移酶缺乏症,莱-萘二氏综合征,下颌面骨发育不全,骨性脆弱性三联症(Trias fragilitis ossium),三X综合征,XXX综合征,三体性21三体性X,阿-肖二氏综合征,血色沉著病,泰-萨克斯病(TSD),复合型结节性硬化病(TSC),结节性硬化症,Turner样综合征,努南综合征,UDP-葡萄糖-4-表异构酶缺乏病,半乳糖血症,UDP葡萄糖4-表异构酶缺乏病,半乳糖血症,UDP葡萄糖己糖-1-磷酸尿甙基转化酶缺乏,半乳糖血症,分化不良型耳聋,非综合征性耳聋,UPS缺乏,急性间歇性卟啉病,膀胱癌,膀胱癌,UROD缺乏,尿卟啉原脱羧酶缺乏,尿卟啉原合酶缺乏,急性间歇性卟啉病,乌斯赫尔综合征,UTP己糖-1-磷酸尿甙基转化酶缺乏,半乳糖血症,范-贝二氏综合征阿-戴二氏综合征,软腭-心-面综合征,VHL综合征,von Hippel-Lindau病,视力障碍和失明,综合征,Von Bogaert-Bertrand病,von Hippel-Lindau病,von Recklenhausen-Applebaum病,血色沉著病,von Recklinghausen病,神经纤维瘤病I型,夫罗利克病,成骨不全,瓦登伯格综合征,Warburg Sjo Fledelius综合征,Micro综合征,Wilson病(WD),Weissenbacher-Zweymüller综合征,韦-霍二氏综合征,脊髓性肌萎缩,威廉斯综合征,Wilson病,肝豆状核变性,Wilson病,Wolf-Hirschhorn综合征,Wolff周期性疾病,Weissenbacher-Zweymüller综合征(WZS),着色性干皮病,X-连锁精神发育迟滞和巨大睾丸,脆性X染色体综合征,X-连锁原发性尿酸血症,莱-萘二氏综合征,X-连锁重症联合免疫缺陷,X-连锁铁粒幼细胞贫血,X-连锁脊柱-延髓肌肉萎缩,脊髓延髓肌肉萎缩症,X-连锁尿酸尿症酶缺陷,莱-萘二氏综合征,X-SCID,X-连锁重症联合免疫缺陷,X-连锁铁粒幼细胞贫血(XLSA),X-SCID,X-连锁重症联合免疫缺陷,X-连锁铁粒幼细胞贫血(XLSA),XSCID,X-连锁重症联合免疫缺陷,XXX综合征,三X综合征,XXXX综合征,XXXXX综合征,XXXXX,XXY综合征,XXY三体性,先天性睾丸发育不全综合征,XYY综合征,三核苷酸重复病症或其任意组合。
在实施方案中,通过施用DNA-PK抑制剂和基因组编辑系统使特异性转录后控制调节剂靶向活性方面的调节,改变,增强或减少。例如,特异性转录后控制调节剂可以包括PARN,PAN,CPSF,CstF,PAP,PABP,PAB2,CFI,CFII,RNA三磷酸酶,RNA谷丙酰转移酶,RNA甲基转移酶,SAM合酶,泛素结合酶E2R,SR蛋白SFRS1-SFR11,hnRNP蛋白(例如HNRNPA0,HNRNPA1,HNRNPA1L1,HNRNPA1L2,HNRNPA2,HNRNPA2B1,HNRNPAB,HNRNPB1,HNRNPC,HNRNPCL1,HNRNPD,HNRPDL,HNRNPF,HNRNHP1,HNRNPH2,HNRNPH3,HNRNPK,HNRNPL,HNRNPLL,HNRNPM,HNRNPR,HNRNPU,HNRNPUL1,HNRNPUL2,HNRNPUL3,ADAR,Mex67,Mtr2,Nab2,死箱解旋酶,elF4A,elF4B,elF4E,elF4G,GEF,GCN2,PKR,HRI,PERK,eEF1,eEF2,GCN,eRF3,ARE-特异性结合蛋白,EXRN1,DCP1,DCP2,RCK/p54,CPEB,eIF4E,microRNAS和siRNAs,DICER,Ago蛋白,无义介导的mRNA衰变蛋白,UPF3A,UPF3BeIF4A3,MLN51,Y14/MAGOH,MG-1,SMG-5,SMG-6,SMG-7或其任意组合。
在一些实施方案中,通过向细胞施用DNA-PK抑制剂和基因组编辑系统在活性方面调节,增强或减少与细胞周期相关的遗传途径。与细胞周期相关的示例性途径和基因包括ATM,PMS2,FAS-L,MRE11,MLH1,FasR,NBS1,MSH6,Trail-L,RAD50,MSH2,Trail-R,53BP1,RFC,TNF-Ct,P53,PCNA,TNF-R1,CHKE,MSH3,FADD,E2F1,MutS,同源物,TRADD,PML,MutL,同源物,R1P1,FANCD2,核酸外切酶,MyD88,SMC1,DNA,聚合酶,δ,IRAK,BLM1,(POLDl,POLD2,POLD3,NIL,BRCA1,和,POLD4,-基因,IKK,H2AX,编码,亚单位),NFKβ,ATR,拓扑异构酶,1,ΙκΒα,RPA,拓扑异构酶,2,IAP,ATRIP,RNAseHl,半胱天冬酶,3,RAD9,连接酶,1,半胱天冬酶,6,RAD1,DNA,聚合酶,1,半胱天冬酶,7,HUS,DNA,聚合酶,3,半胱天冬酶,8,RAD17,引物酶,半胱天冬酶,10,RFC,解链酶,HDAC1,CHK1,单链,结合,HDAC2,TLK1,蛋白质,细胞因子,C,CDC25,Bxl-xL,STAT3,STAT5,DFF45,Vcl-2,ENDO-G,PI3K,Akt,卡配因,Bad,Bax,遍在蛋白介导的蛋白水解,低氧症,细胞增殖,HIF-loc,MAPK,El,HERC1,TRAF6,HIF-Ιβ,MAPKK,E2,UBE2Q,MEKK1,Refl,MAPKKK,E3,UBE2R,COP!,HSP90,c-Met,UBLE1A,UBE2S,PIFH2,VEGF,HGF,UBLE1B,UBE2U,cIAP,PAS,ER,S1/2,UBLEIC,UBE2W,PIAS,ARNT,ATK,UBE2A,UBE2Z,SYVN,VHL,PKCs,UBE2B,AFC,LLC,N,NHLRC1,HLF,Paxilin,UBE2C,UBE1,AIRE,EPF,FAK,UBE2A,E6AP,MGRN1,VDU2,内收蛋白,UBE2E,UBE3B,BRCA1,SUMORESUME,PYK1,UBE2F,Smurf,FANCL,SENP1,RB,UBE2G1,Itch,MIDI,钙神经素,A,RBI,UBE2G2,HERC2,Cdc20,RACK1,Raf-1,UBE2I,HERC3,Cdhl,PTB,A-Raf,UBE2J1,HERC4,Apcl,Hur,B-raf,UBE2J2,UBE4A,Apc2,PHD2,MEK1/2,UBE2L3,UBE4B,Apc3,SSAT2,ERK1/2,UBE2L6,CHIP,Apc4,SSAT1,Ets,UBE2M,CYC4,Apc5,GSK3,Elkl,UBE2N,PPR19,Apc6,CBP,SAP1,UBE20,UIP5,Apc7,FOX04,cPLA2,WWPI,Mdm2,Apc8,FlH-1,WWP2,Parkin,Apc9,TRIP,12,Trim32,Ape,10,NEED4,Trim37,Ape,11,ARF-BP1,SIAH-1,Ape,12,EDD1,PML,Cell,survival,Cell,cycle,arrest,SMADI,P21,SMAD5,BAX,SAMD8,MDR,LEF1,DRAIL,IGFBP3,TCF3,GADD45,TCF4,P300,HAT1,PI3,Akt,GF1或其任意组合。
在一些实施方案中,通过向细胞施用DNA-PK抑制剂和基因组编辑系统在活性方面调节,增强或减少与血管生成相关的基因。与血管生成相关的示例性基因和遗传途径和血管生成相关病症包括VEGF,VEGFR2,SHC,E2F7,VEGFB,VEGFR3,PI3,VEGFC,Nrp l,PIP3,EGFDIP3,DAG,GRB2,SOS,Akt,PB,PKC,Ras,RAF1,DAG,eNOS,NO,ERK1,ER2,cPLA2,ME1,MEK2或其任意组合。
在一些实施方案中,通过向细胞施用DNA-PK抑制剂和基因组编辑系统在活性方面调节,增强或减少与线粒体功能相关的遗传途径和/或基因。与线粒体功能相关的示例性基因和遗传途径包括苹果酸脱氢酶氨基转移酶,水合酶,脱酰酶,脱氢酶,羧化酶,变位酶,脂肪酸氧化亮氨酸氧化异亮氨酸紊乱(酶途径氧化途径缺陷)氨基转移酶氨基转移酶,OCTN2支链支链,FATP1 -6氨基转移酶2,氨基转移酶2,CPT-1线粒体线粒体,CACT异丁酰基-CoA2-甲基丁酰基-CoA,CPT-II脱氢酶脱氢酶,SCAD(支链(支链,MCAD酮酸酮酸,VLCAD脱氢酶脱氢酶,ETF-DH复合物)复合物),α-ETF水合酶水合酶,β-ETF HMG-CoA裂解酶2-甲基-3-OH-SCHAD丁酰基-CoA,LCHAD脱氢酶,MTP 3-氧硫解酶,LKAT,DECR 1,HMGCS2,HMGCL或其任意组合。
在一些实施方案中,与DNA损伤或基因组不稳定性相关的遗传途径和/或基因在活性方面得到调节、增强或降低。与涉及DNA损伤和基因组不稳定性的途径和/或基因相关的示例性的基因和遗传途径包括53BP1,BLM,MBD2,DNA,连接酶,4,MDC1,H2AX,XLF,SMC1,53BP1,Rad50,P53,P53,Artemis,Rad27,TdT,APE1,PMS2,APE2,UvrA,RecA,MLH1,NEIL1,UvrB,SSB,MSH6,NEIL2,UvrC,Mrell,MSH2,NEIL3,XPC,Rad50,RFC,XRCC1,Rad23B,Nbsl,PCNA,PNKP,CEN2,CtIP,MSH3,Tdpl,DDB1,RPA,MutS,APTX,XPE,Rad51,MutL,DNA,聚合酶βCSA,Rad52,DNA聚合酶δ,CSB,Rad54,拓扑异构酶,1,DNA,TFT1H,BRCA1,拓扑异构酶,2,PCNA,XPB,BRCA2,RNAseHl,FEN1,XPD,Exol,连接酶1,RFC,XPA,BLM,DNA,聚合酶,1,PAR,1,RPA,Topllla,DNA,Ligl,XPG,GEN1,底漆酶,Lig3,ERCC1 Yenl解旋酶,UNG,XPF,Slxl,SSBs,MUTY DNA聚合酶δ,Slx4,SMUG DNA聚合酶ε,Mus8,MBD4,Emel,Dssl,ASH1L,SETD4,DQT1L,SETD5,EHMT1,SETD6,EHMT2,SETD7,EZH1,SETD8,EZH2,SETD9,MLL,SETDB1,MLL2,SETDB2,MLL3,SETMAR,MLL4,SMYD,1,MLL5,SMYD2,NSD,1,SMYD3,PRDM2,SMYD4,SET,SMYD5,SETBP1,SUV39H1,SETD 1A,SUV39H2,SETD 1B,SUV420H1,SETD2,SUV420 H2,SETD3或其任意组合。
在一些实施方案中,编码哺乳动物转录因子的基因得到调节,增强,减少或提供给细胞。示例性的人转录因子包括:AFF4,AFF3,AFF2,AFF1,AR,TFAP2B,TFAP2D,TFAP2C,TFAP2E,TFAP2A,JARID2,KDM5D,ARID4A,ARID4B,KDM5A,ARID3A,KDM5B,KDM5C,ARID5B,ARID3B,ARID2,ARID5A,ARID3C,ARID1A,ARID1B,HIF1A,NPAS1,NPAS3,NPAS4,MLXIPL,ARNTL2,MXD1,AHRR,TFE3,HES2,MNT,TCF3,SREBF1,TFAP4,TCFL5,LYL1,USF2,TFEC,AHR,MLX,MYF6,MYF5,SIM1,TFEB,HAND1,HES1,ID2,MYCL1,ID3,TCF21,MXI1,SOHLH2,MYOG,TWIST1,NEUROG3,BHLHE41,NEUROD4,MXD4,BHLHE23,TCF15,MAX,ID1,MYOD1,ARNTL,BHLHE40,MYCN,CLOCK,HEY2,MYC,ASCL1,TCF12,ARNT,HES6,FERD3L,MSGN1,USF1,TAL1,NEUROD1,TCF23,HEYL,HAND2,NEUROD6,HEY1,SOHLH1,MESP1,PTF1A,ATOH8,NPAS2,NEUROD2,NHLH1,ID4,ATOH1,ARNT2,HES3,MLXIP,ASCL3,KIAA2018,OLIG3,NHLH2,NEUROG2,MSC,HES7,ATOH7,BHLHA15,BHLHE22,NEUROG1,FIGLA,ASCL2,OLIG1,TAL2,MITF,SCXB,HELT,ASCL4,MESP2,HES4,SCXA,TCF4,HES5,SREBF2,BHLHA9,OLIG2,MXD3,TWIST2,LOC388553,C13orf38-SOHLH2,CEBPE,XBP1,BATF3,CREB5,CEBPG,ATF3,ATF7,CEBPB,CEBPD,CEBPA,CBFB,CAMTA2,CAMTA1,EBF4,EBF3,EBF1,EBF2,NR2F6,NR2F1,NR2F2,GRHL2,TFCP2L1,GRHL1,TFCP2,UBP1,GRHL3,YBX2,CSDE1,CSDA,YBX1,LIN28A,CARHSP1,CSDC2,LIN28B,NFIX,NFIC,NFIB,NFIA,CUX2,ONECUT2,CUX1,ONECUT1,SATB1,ONECUT3,SATB2,DMRT3,DMRT1,DMRTC2,DMRTA2,DMRTB1,DMRT2,DMRTA1,E2F2,E2F1,E2F3,TFDP2,E2F8,E2F5,E2F7,E2F6,TFDP3,TFDP1,E2F4,NR1H3,NR1H2,ETV1,ETV7,SPI1,ELF4,ETV2,ERF,ELF2,ELK3,ETV3,ELF1,SPDEF,ELK1,ETS1,EHF,ELF5,ETV6,SPIB,FLI1,GABPA,ERG,ETS2,ELK4,ELF3,FEV,SPIC,ETV4,ETV5,FOXN3,FOXC1,FOXJ2,FOXF1,FOXN1,FOXM1,FOXP1,FOXO3,FOXA2,FOXP2,FOXJ1,FOXP4,FOXF2,FOXN4,FOXK2,FOXO1,FOXH1,FOXQ1,FOXK1,FOXI1,FOXD4,FOXA3,FOXN2,FOXB1,FOXG1,FOXR1,FOXL1,FOXC2,FOXE1,FOXS1,FOXL2,FOXO4,FOXD4L1,FOXD4L4,FOXD2,FOXI2,FOXE3,FOXD3,FOXD4L3,FOXR2,FOXJ3,FOXO6,FOXB2,FOXD4L5,FOXD4L6,FOXD4L2,KIAA0415,FOXA1,FOXP3,GCM2,GCM1,NR3C1,GTF2IRD1,GTF2I,GTF2IRD2B,GTF2IRD2,SOX8,SOX30,PMS1,CIC,TCF7,TOX4,SOX10,HMGXB4,HBP1,TFAM,UBTF,WHSC1,SOX6,HMGXB3,BBX,TOX2,SOX4,SOX21,SOX9,SOX15,SOX5,SOX3,LEF1,HMG20A,SOX13,TCF7L2,SSRP1,TCF7L1,SOX17,SOX14,PINX1,SOX7,SOX11,SOX12,SOX2,SOX1,SRY,SOX18,UBTFL1,UBTFL2,TOX,HMGB1,HMGB2,PBRM1,
TOX3,SMARCE1,HMG20B,HMGB3,HMGA2,HMGA1,
ARX,HOXA11,MEOX1,DLX6,ISL1,HOXC8,BARX2,
ALX4,GSC2,DLX3,PITX1,HOXA9,HOXA10,LHX5,
LASS4,ZFHX4,SIX4,VSX1,ADNP,RHOXF1,MEIS3,PBX4,
DLX5,HOXA1,HOXA2,HOXA3,HOXA5,HOXA6,HOXA13,
EVX1,NOBOX,MEOX2,LHX2,LHX6,LHX3,TLX1,PITX3,
HOXB6,HNF1B,DLX4,SEBOX,VTN,PHOX2B,NKX3-2,
DBX1,NANOG,IRX4,CDX1,TLX2,DLX2,VAX2,PRRX1,
TGIF2,VSX2,NKX2-3,HOXB8,HOXB5,HOXB7,HOXB3,
HOXB1,MSX2,LHX4,HOXA7,HOXC13,HOXC11,HOXC12,
ESX1,BARHL1,NKX2-4,NKX2-2,SIX1,HOXD1,HOXD3,
HOXD9,HOXD10,HOXD11,HOXD13,MNX1,CDX4,BARX1,
RHOXF2,LHX1,GSC,MEIS2,RAX,EMX1,NKX2-8,
NKX2-1,HLX,LMX1B,SIX3,LBX1,PDX1,LASS5,ZFHX3,
BARHL2,LHX9,LASS2,MEIS1,DLX1,HMBOX1,ZEB1,
VAX1,NKX6-2,VENTX,HHEX,TGIF2LX,LASS3,ALX3,
HOXB13,IRX6,ISL2,PKNOX1,LHX8,LMX1A,EN1,MSX1,
NKX6-1,HESX1,PITX2,TLX3,EN2,UNCX,GBX1,NKX6-3,
ZHX1,HDX,PHOX2A,PKNOX2,CDX2,DRGX,NKX3-1,
PBX3,PRRX2,GBX2,SHOX2,GSX1,HOXD4,HOXD12,
EMX2,IRX1,IRX2,SIX2,HOXB9,HOPX,OTP,LASS6,
HOXC5,HOXB2,RAX2,EVX2,ZHX3,PROP1,ISX,HOXD8,
TGIF2LY,IRX5,SIX5,TGIF1,IRX3,ZHX2,LBX2,NKX2-6,
ALX1,GSX2,HOXC9,HOXC10,HOXB4,NKX2-5,SIX6,
MIXL1,DBX2,PBX1,SHOX,ARGFX,HMX3,HMX2,BSX,
HOXA4,DMBX1,HOXC6,HOXC4,RHOXF2B,PBX2,DUXA,
DPRX,LEUTX,,NOTO,HOMEZ,HMX1,DUX4L5,DUX4L2,
DUX4L3,DUX4L6,NKX1-1,HNF1A,HSF4,HSFY2,HSFX1,
HSFX2,HSFY1,HSF1,LCORL,LCOR,IRF6,IRF1,IRF3,
IRF5,IRF4,IRF8,IRF2,IRF7,IRF9,MBD3,BAZ2B,MBD4,
SETDB2,MBD1,MECP2,SETDB1,MBD2,BAZ2A,SMAD7,
SMAD5,SMAD9,SMAD6,SMAD4,SMAD3,SMAD1,SMAD2,
ZZZ3,RCOR1,CDC5L,MYBL2,DNAJC2,TADA2A,RCOR3,
MYB,TERF2,DMTF1,DNAJC1,NCOR1,TERF1,MIER3,
MYSM1,SNAPC4,RCOR2,TADA2B,MYBL1,TERF1P2,
NCOR2,CCDC79,SMARCC1,SMARCC2,TTF1,C11orf9,
NFYA,NFYC,NFYB,NRF1,NR4A3,NR4A1,NR4A2,ESR1,
NR0B2,NR0B1,PREB,EAF2,SPZ1,TP63,TP73,TP53,
PAX6,PAX7,PAX2,PAX4,PAX8,PAX1,PAX3,PAX5,
PAX9,SUB1,POU2F2,POU1F1,POU4F3,POU6F2,POU2F3,
POU2F1,POU4F2,POU4F1,POU6F1,POU3F2,POU3F1,
POU3F4,POU3F3,POU5F1,POU5F1B,PPARD,PPARG,
PPARA,PGR,PROX1,PROX2,NR2E1,NR5A2,NR2C1,
NR5A1,NR6A1,ESRRA,NR2C2,RFX3,RFX2,RFX4,RFX1,
RFX5,RFX7,RFX6,RFX8,NFATC3,NFKB2,NFATC4,
NFATC2,NFAT5,RELB,NFKB1,NFATC1,REL,RELA,
RORA,RORC,NR1D2,RORB,RUNX3,RUNX1,SP100,
SP140,GMEB2,SP110,AIRE,GMEB1,DEAF1,SP140L,
LOC729991-MEF2B,MEF2A,SRF,MEF2D,MEF2B,STAT1,
STAT5A,STAT4,STAT6,STAT3,STAT2,STAT5B,TBX21,
TBX5,TBX15,TBX18,TBX2,TBX4,TBX22,TBX3,TBR1,
TBX19,TBX6,EOMES,T,TBX20,TBX10,MGA,TBX1,
TEAD3,TEAD2,TEAD1,TEAD4,CREBL2,NFE2L3,
CREB3L3,FOSL2,NFE2L1,CREM,DBP,CREB3,HLF,
BACH2,ATF2,NFE2L2,ATF6,CREB1,ATF1,NFE2,FOSB,
ATF4,NRL,JUND,JDP2,CREB3L4,BATF,BACH1,
CREB3L1,NFIL3,TEF,BATF2,ATF5,FOS,JUNB,DDIT3,
FOSL1,JUN,MAF,CREB3L2,MAFA,MAFF,MAFG,
MAFK,MAFB,ATF6B,CRX,OTX1,OTX2,THAP3,
THAP10,THAP1,PRKRIR,THAP8,THAP9,THAP11,
THAP2,THAP6,THAP4,THAP5,THAP7,NR1H4,NR2E3,
RARB,HNF4A,VDR,ESRRB,THRA,NR1D1,RARA,ESR2,
NR1I3,NR1I2,THRB,NR3C2,HNF4G,RARG,RXRA,
ESRRG,RXRB,TSC22D1,TSC22D3,TSC22D4,TSC22D2,
TULP3,TULP2,TULP1,TULP4,TUB,ZBTB33,ZBTB32,
ZBTB11,MYNN,ZBTB25,PATZ1,ZBTB16,ZBTB24,BCL6,
ZBTB47,ZBTB17,ZBTB45,GZF1,ZBTB1,ZBTB46,ZBTB8A,
ZBTB7B,BCL6B,ZBTB49,ZBTB43,HIC2,ZBTB26,ZNF131,
ZNF295,ZBTB4,ZBTB34,ZBTB38,HIC1,ZBTB41,ZBTB7A,
ZNF238,ZBTB42,ZBTB2,ZBTB20,ZBTB40,ZBTB7C,
ZBTB37,ZBTB3,ZBTB6,ZBTB44,ZFP161,ZBTB12,ZBTB48,
ZBTB10,ZBED4,ZBED3,ZBED2,C11orf95,ZBED1,IKZF5,
ZNF821,ZNF451,ZNF195,ZFX,ZNF263,ZNF200,HIVEP2,
WIZ,ZNF582,SNAI2,ZFP64,IKZF2,ZIC2,ZNF800,
PRDM1,PRDM6,ZFP112,ZNF275,ZNF76,ZFAT,KLF6,
ZFY,ZXDC,GLI2,ZNF532,ZNF37A,ZNF510,ZNF506,
ZNF324,ZNF671,ZNF416,ZNF586,ZNF446,ZNF8,ZNF264,
REST,MECOM,ZNF213,ZNF343,ZNF302,ZNF268,ZNF10,
HIVEP1,ZNF184,MZF1,SALL4,ZNF516,KLF8,KLF5,
ZNF629,ZNF423,CTCF,ZNF500,ZNF174,SALL1,MAZ,
ZNF419,OVOL3,ZNF175,ZNF14,ZNF574,ZNF85,SP4,
ZKSCAN1,GLI3,GLIS3,KLF3,PRDM4,GLI1,PRDM13,
ZNF142,PRDM2,ZNF684,ZNF541,KLF7,PLAGL1,ZNF430,
KLF12,KLF9,ZNF410,BCL11A,EGR1,ZFP30,TSHZ3,
ZNF549,ZSCAN18,ZNF211,ZNF639,ZSCAN20,GTF3A,
ZNF205,ZNF644,EGR2,IKZF4,CTCFL,ZNF831,SNAI1,
ZNF576,ZNF45,TRERF1,ZNF391,RREB1,ZNF133,OVOL2,
ZNF436,PLAGL2,GLIS2,ZNF384,ZNF484,HIVEP3,
BCL11B,KLF2,ZNF780B,FEZF1,KLF16,ZSCAN10,
ZNF557,ZNF337,PRDM12,ZNF317,ZNF426,ZNF331,
ZNF236,ZNF341,ZNF227,ZNF141,ZNF304,ZSCAN5A,
ZNF132,ZNF20,EGR4,ZNF670,VEZF1,KLF4,ZFP37,
ZNF189,ZNF193,ZNF280D,PRDM5,ZNF740,ZIC5,
ZSCAN29,ZNF710,ZNF434,ZNF287,ZIM3,PRDM15,ZFP14,
ZNF787,ZNF473,ZNF614,PRDM16,ZNF697,ZNF687,OSR1,
ZNF514,ZNF660,ZNF300,RBAK,ZNF92,ZNF157,ZNF182,
ZNF41,ZNF711,PRDM14,ZNF7,ZNF214,ZNF215,SALL3,
ZNF827,ZNF547,ZNF773,ZNF776,ZNF256,ZSCAN1,
ZNF837,PRDM8,ZNF117,ZIC1,FEZF2,ZNF599,ZNF18,
KLF10,ZKSCAN2,ZNF689,ZIC3,ZNF19,ZSCAN12,ZNF276,
ZNF283,ZNF221,ZNF225,ZNF230,ZNF222,ZNF234,
ZNF233,ZNF235,ZNF362,ZNF208,ZNF714,ZNF394,
ZNF333,ZNF382,IKZF3,ZNF577,ZNF653,ZNF75A,GFI1,
ZNF281,ZNF496,ZNF2,ZNF513,ZNF148,KLF15,ZNF691,
ZNF589,PRDM9,ZNF12,SP8,OSR2,ZNF367,ZNF22,
GFI1B,ZNF219,SALL2,ZNF319,ZNF202,ZNF143,ZNF3,
ZSCAN21,ZNF606,SP2,ZNF91,ZNF23,ZNF226,ZNF229,
ZNF180,ZNF668,ZNF646,ZNF641,ZNF610,ZNF528,
ZNF701,ZNF526,ZNF146,ZNF444,ZNF83,ZNF558,ZNF232,
E4F1,ZNF597,INSM2,ZNF30,ZNF507,ZNF354A,ZEB2,
ZNF32,KLF13,ZFPM2,ZNF764,ZNF768,ZNF35,ZNF778,
ZNF212,ZNF282,PRDM10,SP7,SCRT1,ZNF16,ZNF296,
ZNF160,ZNF415,ZNF672,ZNF692,ZNF439,ZNF440,
ZNF581,ZNF524,ZNF562,ZNF561,ZNF584,ZNF274,ZIK1,
ZNF540,ZNF570,KLF17,ZNF217,ZNF57,ZNF556,ZNF554,
KLF11,HINFP,ZNF24,ZNF596,OVOL1,SP3,ZNF621,
ZNF680,BNC2,ZNF483,ZNF449,INSM1,ZNF417,ZNF791,
ZNF80,GLIS1,ZNF497,KLF14,ZNF266,ZIC4,ZNF408,
ZNF519,ZNF25,ZNF77,ZNF169,ZNF613,ZNF683,ZNF135,
ZSCAN2,ZNF575,ZNF491,ZNF620,ZNF619,ZNF354C,
ZNF114,ZNF366,ZNF454,ZNF543,ZNF354B,ZNF223,
ZNF713,ZNF852,ZNF552,ZFP42,ZNF664,EGR3,ZFPM1,
ZNF784,ZNF648,FIZ1,ZNF771,TSHZ1,ZNF48,ZNF816,
ZNF571,ZSCAN4,ZNF594,ZFP3,ZNF443,ZNF792,ZNF572,
ZNF707,ZNF746,ZNF322A,ZNF467,ZNF678,ZFP41,HKR1,
PLAG1,ZNF329,ZNF101,ZNF716,ZNF708,ZSCAN22,
ZNF662,ZNF320,ZNF623,ZNF530,ZNF285,ZFP1,WT1,
ZFP90,ZNF479,ZNF445,ZNF74,SP1,SNAI3,ZNF696,
IKZF1,ZNF267,ZNF566,ZNF224,ZNF529,ZNF284,ZNF749,
ZNF17,ZNF555,ZNF75D,ZNF501,ZNF197,ZNF396,ZFP91,
ZNF732,ZNF397,ZSCAN30,ZNF546,ZNF286A,ZKSCAN4,
ZNF70,ZNF643,ZNF642,ZSCAN23,ZNF490,ZNF626,
ZNF793,ZNF383,ZNF669,ZNF559,ZNF177,ZNF548,MTF1,
ZNF322B,ZNF563,ZNF292,ZNF567,SP6,ZNF573,ZNF527,
ZNF33A,ZNF600,ZKSCAN3,ZNF676,ZNF699,ZNF250,
ZNF79,ZNF681,ZNF766,ZNF107,ZNF471,ZNF836,ZNF493,
ZNF167,ZNF565,ZNF34,ZNF781,ZNF140,ZNF774,ZNF658,
ZNF765,ZNF124,ZNF569,ZNF777,ZNF775,ZNF799,
ZNF782,ZNF846,ZNF136,ZKSCAN5,ZNF502,ZFP62,
ZNF33B,ZNF512B,ZNF431,ZNF418,ZNF700,ZNF239,
ZSCAN16,ZFP28,ZNF705A,ZNF585A,ZNF138,ZNF429,
ZNF470,ZNF100,ZNF398,ZNF498,ZNF441,ZNF420,
ZNF763,ZNF679,ZNF682,ZNF772,ZNF257,ZNF785,
ZSCAN5B,ZNF165,ZNF655,ZNF98,ZNF786,ZNF517,
ZNF675,ZNF860,ZNF628,ZNF665,ZNF624,ZNF841,ZNF615,ZNF350,ZNF432,ZNF433,ZNF460,ZNF81,ZNF780A,ZNF461,ZNF181,LOC100287841,ZNF44,ZNF790,ZNF677,ZNF823,ZNF311,ZNF347,ZNF71,ZNF121,ZNF335,ZNF560,ZNF273,ZNF84,ZNF667,ZNF649,ZNF248,ZNF544,ZNF770,ZNF737,ZNF251,ZNF607,ZNF334,ZXDA,ZNF485,ZIM2,PEG3,ZNF192,ZNF442,ZNF813,ZNF26,ZNF69,ZNF583,ZNF568,ZXDB,ZNF480,ZNF587,ZNF808,ZNF43,ZNF28,ZNF627,ZNF789,ZNF536,ZNF534,ZNF652,ZNF521,ZNF358,ZFP2,SP5,ZNF814,ZNF551,ZNF805,ZSCAN5C,ZNF468,ZNF616,ZFP57,ZNF155,ZNF783,ZNF425,ZNF580,ZNF611,ZNF254,ZNF625,ZNF134,ZNF845,ZNF99,ZNF253,ZNF90,ZNF93,ZNF486,REPIN1,LOC100131539,ZNF705D,LOC100132396,ZNF705G,SCRT2,ZNF407,SP9,ZNF579,ZNF880,ZNF630,ZNF844,ZNF469,ZNF717,ZNF865,ZNF492,ZNF688,YY2,ZNF878,ZNF879,ZNF736,ZNF323,ZNF709,ZNF512,ZNF585B,ZNF154,ZNF324B,ZNF564,ZFP82,GLI4,ZNF674,ZNF345,ZNF550,KLF1,YY1,MYST2,ST18,L3MBTL4,MYT1L,MYT1,L3MBTL1,MTA3,GATA1,TRPS1,GATA3,GATA5,GATA4,GATA6,GATAD2B,GATAD1,GATA2,MTA1,ZGLP1,MTA2,RERE,C16orf5,LITAF,PIAS1,PIAS2,PIAS4,ZMIZ1,ZMIZ2,PIAS3,RNF138,NFX1,NFXL1或其任意组合。
在一些实施方案中,将细胞从一种细胞类型操纵(例如转化或分化)为另一种细胞类型。在一些实施方案中,胰腺细胞被操纵成β胰岛细胞。在一些实施方案中,成纤维细胞被操纵入iPS细胞中。在一些实施方案中,前脂肪细胞被操纵为棕色脂肪细胞。其它示例性细胞包括例如肌细胞,神经细胞,白细胞和淋巴细胞。
在一些实施方案中,所述细胞为患病或带有突变体的细胞。可以操纵这类细胞用于治疗疾病,例如,以便纠正突变或改变细胞表型,例如抑制癌细胞生长。例如,细胞与本文所述的一种或多种疾病或病症相关。
在一些实施方案中,操纵的细胞为正常细胞。
在一些实施方案中,操纵的细胞为干细胞或先祖细胞(例如iPS,胚胎,造血,脂肪,种系,肺或神经干细胞或先祖细胞)。在一些实施方案中,操纵的细胞可以为来自任意三层的细胞(即中胚层,内胚层或外胚层)。在一些实施方案中,操纵的细胞可以来自被操纵的细胞可以来自胚外组织,例如来自胎盘。
在一些实施方案中,操纵的细胞选自成纤维细胞,单核细胞前体,B细胞,外分泌细胞,胰腺先祖细胞,内分泌先祖细胞,成肝细胞,成肌细胞或前脂肪细胞。在一些实施方案中,细胞被操纵(例如转化或分化)为肌细胞,红系巨核细胞,嗜酸性粒细胞,iPS细胞,巨噬细胞,T细胞,胰岛β细胞,神经元,心肌细胞,血细胞,内分泌祖细胞,外分泌先祖细胞,导管细胞,腺泡细胞,α细胞,β细胞,δ细胞,PP细胞,肝细胞,胆管细胞,血管母细胞,中成血管细胞或褐色脂肪细胞。
在一些实施方案中,细胞为肌细胞,红系巨核细胞,嗜酸性粒细胞,iPS细胞,巨噬细胞,T细胞,胰岛β细胞,神经元,心肌细胞,血细胞,内分泌祖细胞,外分泌先祖细胞,导管细胞,腺泡细胞,α细胞,β细胞,δ细胞,PP细胞,肝细胞,胆管细胞,白色或棕色脂肪细胞。
在一些实施方案中,细胞为前体细胞,多能细胞,全能细胞,成人干细胞,内部细胞团细胞,胚胎干细胞或iPS细胞。
在一些实施方案中,操纵的细胞为癌细胞。在一些实施方案中,癌细胞可以为肺癌细胞,乳腺癌细胞,皮肤癌细胞,脑癌细胞,胰腺癌细胞,造血癌细胞,肝癌细胞,肾癌细胞,卵巢癌细胞,前列腺癌细胞,皮肤癌细胞。
在一些实施方案中,细胞为肌细胞,红系巨核细胞,嗜酸性粒细胞,iPS细胞,巨噬细胞,T细胞,胰岛β细胞,神经元,心肌细胞,血细胞,内分泌先祖细胞,外分泌先祖细胞,导管细胞,腺泡细胞,α细胞,β细胞,δ细胞,PP细胞,肝细胞,胆管细胞或白色或棕色脂肪细胞。
DNA-PK抑制剂和基因编辑系统对细胞的施用
可以通过本领域已知的任意方法向细胞施用基因组编辑系统和DNA-PK抑制剂。所述施用可以在体外、离体或体内。向细胞施用基因组编辑系统和DNA-PK抑制剂可以同时或依次进行。在一些实施方案中,所述施用导致DNA-PK抑制剂和所述基因组编辑系统组分进入细胞膜。在一些实施方案中,所述施用导致DNA-PK抑制剂和所述基因组编辑系统组分进入细胞核。在一些实施方案中,所述施用包括在DNA-PK抑制剂和基因组编辑系统存在下温育细胞。
可以通过本领域已知的任意方法向细胞施用所述基因组编辑系统。例如,可以使用本领域已知的任意核酸或蛋白质递送方法。该基因编辑系统通过编码该基因编辑系统组分的核酸施用(例如递送)至细胞中。可以通过病毒载体或非病毒载体将基因编辑系统施用于细胞。在一些实施方案中,使用病毒载体。病毒载体可以为逆转录病毒(例如鼠白血病,HIV或慢病毒)或DNA病毒(例如腺病毒,单纯疱疹和腺相关病毒)。在一些实施方案中,转染方法(例如非病毒递送方法)用于将所述基因组编辑系统导入细胞。转染方法包括使细胞接触质粒的DEAE-葡聚糖,磷酸钙,脂质体或电穿孔而进入细胞。非病毒递送的另外的方法包括电穿孔,脂转染,显微注射,生物弹药,病毒体,脂质体,免疫脂质体,聚阳离子或脂质:核酸缀合物,裸DNA,裸RNA,人工病毒体和试剂增强的对DNA的吸收。使用例如Sonitron2000系统(Rich-Mar)进行的超声操作也可以用于递送核酸。在一些实施方案中,一种或多种核酸作为mRNA递送。在一些实施方案中,带帽的mRNA用于提高翻译效率和/或mRNA稳定性。在一些实施方案中,使用ARCA(防反向帽类似物)帽或其变体。参见美国专利US7074596和US8153773。
在实施方案中,核酸内切酶(例如Cas,Cpf1等)和gRNA从DNA转录。
在实施方案中,核酸内切酶(例如Cas,Cpf1等)从DNA转录,且gRNA作为RNA提供。
在实施方案中,核酸内切酶(例如Cas,Cpf1等)和gRNA作为RNA提供。
在实施方案中,核酸内切酶(例如Cas,Cpf1等)作为蛋白质提供,且gRNA作为DNA提供。
在实施方案中,核酸内切酶(例如Cas,Cpf1等)作为蛋白质提供,且gRNA作为RNA提供。
另外的核酸递送系统包Amaxa Biosystems(Cologne,Germany),Maxcyte,Inc.(Rockville,Maryland),BTX Molecular Delivery Systems(Holliston,MA)和CopernicusTherapeutics Inc括提供的那些(参见,例如US6008336)。脂转染描述在例如美国专利5,049,386;4,946,787;和4,897,355中),且脂转染试剂以商品方式销售(例如TransfectamTM和LipofectinTM和LipofectamineTM RNAiMAX)。适合于多核苷酸的有效受体-识别脂转染的阳离子和中性脂质包括Feigner,WO91/17424,WO91/16024的那些。可以递送至细胞(立体施用)或靶组织(体内施用)。
脂质:核酸复合物包括靶向脂质体例如免疫脂质复合物的制备为本领域技术人员众所周知的(参见,例如Crystal,Science270:404-410(1995);Blaese et al.,CancerGene Ther.2:291-297(1995);Behr et al.,Bioconjugate Chem.5:382-389(1994);Remyet al.,Bioconjugate Chem.5:647-654(1994);Gao et al.,Gene Therapy2:710-722(1995);
另外的递送方法包括使用待递送的核酸包装入EnGeneIC递送媒介物(EDV)中。双特异性抗体将这些EDV特异性地递送至靶组织,其中抗体的一个臂对靶组织具有特异性,而另一臂对EDV具有特异性。抗体将EDV携带至靶细胞表面,且然后通过内吞作用将EDV带入细胞。进入细胞后,内容物释放(参见MacDiarmid et al.,(2009)Nature Biotechnology 27(7):643)Ahmad et al.,Cancer Res.52:4817-4820(1992);美国专利4,186,183,4,217,344,4,235,871,4,261,975,4,485,054,4,501,728,4,774,085,4,837,028和4,946,787)。
在一些实施方案中,转染可以是瞬时的,其中含有质粒的被转染的基因组编辑系统进入细胞核,但在复制期间掺入细胞基因组中。转染可以是稳定的,其中转染的质粒将整合到细胞的基因组区域中。
在一些实施方案中,其中使用瞬时表达,可以使用基于腺病毒的系统。基于腺病毒的载体能够以极高的转导效率存在于许多细胞类型中,且无需细胞分裂。使用这类载体,得到高滴度和水平表达。这种载体可以在相对简单系统中大量生产。腺相关病毒("AAV")载体还用于转导具有靶核酸的细胞,例如在体外生产核酸和肽和离体基因疗法中(参见,例如West et al.,Virology 160:38-47(1987);美国专利4,797,368;WO 93/24641;Kotin,Human Gene Therapy 5:793-801(1994);Muzyczka,J..Clin.Invest.94:1351(1994)。重组AAV载体的构建描述在多个出版物中,包括美国专利5,173,414;Tratschin et al.,Mol.Cell.Biol.5:3251-3260(1985);Tratschin,et al.,Mol Cell.Biol.4:2072-2081(1984);Hermonat&Muzyczka,PNAS 81:6466-6470(1984);和Samulski et al.,J.Virol63:03822-3828(1989)。
在一些实施方案中,通过在DNA-PK抑制剂和允许DNA-PK抑制剂进入细胞膜和/或细胞核的任意适合的培养基重组下培养分离的细胞对细胞施用DNA-PK抑制剂。
在一些实施方案中,在体外、体内或离体施用DNA-PK抑制剂。在一些实施方案中,使DNA-PK抑制剂接触细胞约5小时,10小时,15小时,20小时,21小时,22小时,23小时,24小时,25小时,30小时,35小时,40小时,45小时,50小时,55小时,60小时,65小时,70小时,85小时,90小时,100小时,125小时,150小时,200小时或其中间的任意时间期限。在一些实施方案中,使DNA-PK抑制剂接触细胞约1.5周,2.0周,2.5周,3.0周,3.5周,4周或其中间的任意时间期限。可以在改变细胞培养基的情况下再施用DNA-PK抑制剂。可以在导入基因组编辑系统组分之前、期间或之后使DNA-PK抑制剂接触细胞。
在一些实施方案中,以约0.1μM,0.25μM,0.5μM,0.75μM,1.0μM,1.25μM,1.50μM,1.75μM,2.0μM,2.5μM,3.0μM,3.5μM,4.0μM,4.5μM,5.0μM,5.5μM,6.0μM,6.5μM,7.0μM,7.5μM,8.0μM,8.5μM,9.0μM,9.5μM,10μM,10.5μM,11.0μM,11.5μM,12μM或其中间的任意浓度的浓度向细胞施用DNA-PK抑制剂。可以在施用过程期间改变DNA-PK抑制剂浓度。
在一些实施方案中,将基因编辑组分用一种或多种载体或以RNA,mRNA或在核酸内切酶组分的情况下作为纯化蛋白或mRNA(例如Cas9蛋白质)的形式递送入细胞。所述一种或多种载体可以包括病毒载体,质粒或ssDNA。病毒载体可以包括逆转录病毒,慢病毒,腺相关和单纯疱疹病毒载体或其任意组合。在一些实施方案中,通过RNA或合成RNA递送基因编辑组分。
在一些实施方案中,与其中不向细胞施用DNA-PK抑制剂的基线条件相比,向细胞施用DNA-PK抑制剂与基因组编辑系统导致同源介导修复基因编辑结果的量提高。在一些实施方案中,向细胞施用DNA-PK抑制剂与基因组编辑系统导致上靶或脱靶的indel(来自NHEJ)被抑制。在一些实施方案中,向细胞施用DNA-PK抑制剂与基因组编辑系统导致关注的基因表达提高或降低。向细胞施用DNA-PK抑制剂与基因组编辑系统导致对于细胞非内源性的基因表达。在一些实施方案中,向细胞施用DNA-PK抑制剂与基因组编辑系统导致来自细胞的基因完全或部分去除或修饰。在一些实施方案中,向细胞施用DNA-PK抑制剂与基因组编辑系统导致细胞中内含子和/或外显子的完全或部分去除或修饰。在一些实施方案中,向细胞施用DNA-PK抑制剂与基因组编辑系统导致细胞中非编码区的完全或部分去除或修饰。在一些实施方案中,向细胞施用DNA-PK抑制剂与基因组编辑系统导致细胞中的编码和/或非编码区的同时或依次、完全或部分去除或修饰。在一些实施方案中,向细胞施用DNA-PK抑制剂与基因组编辑系统导致细胞中编码和/或非编码区的同时或依次、完全或部分去除或修饰,包括染色体外的DNA或RNA。染色体外的DNA可以为线粒体DNA,叶绿体DNA,染色体外的环状DNA或病毒染色体外DNA。
在一些实施方案中,向细胞施用DNA-PK抑制剂与基因组编辑系统导致关注的基因的表达提高或表达降低。在一些实施方案中,与其中不向细胞施用DNA-PK抑制剂的基线条件相比,关注的基因表达提高或减少为约2.5%,5%,10%,20%,30%,40%,50%,60%,70%,80%,90%或在其之间。在一些实施方案中,与其中不向细胞施用DNA-PK抑制剂的基线条件相比,关注的基因提高或降低可以为约0.5-倍,1.0-倍,1.5-倍,2.0-倍,2.5-倍,3.0-倍,3.5-倍,4-倍,4.5-倍,5-倍或10-倍或在其之间。
在一些实施方案中,向细胞施用DNA-PK抑制剂与基因组编辑系统导致基因组编辑提高。在一些实施方案中,与其中不向细胞施用DNA-PK抑制剂的基线条件相比,基因组编辑提高可以为约2.5%,5%,10%,20%,30%,40%,50%,60%,70%,80%,90%或在其之间。在一些实施方案中,与其中不向细胞施用DNA-PK抑制剂的基线表达水平相比,基因组编辑提高可以为约0.5-倍,1.0-倍,1.5-倍,2.0-倍,2.5-倍,3.0-倍,3.5-倍,4-倍,4.5-倍,5-倍或10-倍或在其之间。
在一些实施方案中,与其中仅给细胞群施用基因编辑系统但不施用DNA-PK抑制剂的基线条件相比,向细胞施用DNA-PK抑制剂和基因编辑系统导致存活率更高。在一些实施方案中,导致细胞存活率更高的DNA-PK抑制剂为结构式I,结构式II或结构式II”的化合物。
在一些实施方案中,在施用DNA-PK抑制剂之前、之后或期间使细胞在S或G2细胞周期阶段同步化。在一些实施方案中,在施用基因编辑系统之前、之后或期间使细胞在S或G2细胞周期阶段同步化。可以通过本领域已知的任意方法实现细胞在S或G2细胞周期阶段同步化。作为非限制性实例,可以用于使细胞在S或G2细胞周期阶段同步化的活性剂包括阿非科林,dyroxyurea,洛伐他汀,含羞草氨酸,诺考达唑,胸苷或其任意组合。(参见,Lin etal.,Elife.2014Dec 15;32014)。在一些实施方案中,可以在基因编辑过程中的任意时间施用用于细胞同步化的活性剂。
在一些实施方案中,DNA-PK抑制剂和/或所述基因组编辑系统与使用说明书一起包括在容器、包装或分配器中。在一些实施方案中,DNA-PK抑制剂和/或所述基因组编辑系统与使用说明书一起包括在容器、包装或分配器中为试剂盒。
在一些实施方案中,DNA-PK抑制剂和/或所述基因组编辑系统与使用说明书一起包括在试剂盒中。该试剂盒可以包含任意的基因组编辑系统和/或DNA-PK抑制剂和使用说明书。在一些实施方案中,DNA-PK抑制剂为由结构式I,I’,II,II’,II”,II”’,III,III’表示的任意化合物或其任意组合。在一些实施方案中,所述基因组编辑系统选自基于兆核酸酶的系统,基于锌指核酸酶(ZFN)的系统,基于转录激活因子样效应物的核酸酶(TALEN)系统,基于CRISPR的系统或基于NgAgo的系统。所述基因组编辑系统可以以任意形式在试剂盒中提供,例如作为质粒,载体,DNA或RNA构建体。
在一些实施方案中,体内施用DNA-PK抑制剂和/或基因组编辑系统。配制DNA-PK抑制剂和基因编辑系统以使其与预期的施用途径相容。施用途径的实例包括肠胃外,例如静脉内,皮内,皮下,口服(例如吸入),透皮(即局部),跨粘膜和直肠施用。用于肠胃外,皮内或皮下应用的溶液或混悬液可以包括以下组分:无菌稀释剂,例如注射用水,盐溶液,不挥发油,聚乙二醇,甘油,丙二醇或其它合成溶剂;抗菌剂,例如苄醇或对羟基苯甲酸甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;螯合剂,例如乙二胺四乙酸(EDTA);缓冲剂,例如乙酸盐,柠檬酸盐或磷酸盐;以及张度调节剂,例如氯化钠或葡萄糖。可用酸或碱,例如盐酸或氢氧化钠调节pH。可以将肠胃外制剂封装入玻璃或塑料制成的安瓿,一次性注射器或多剂量小瓶中。
对于可注射用途,适合的载体包括无菌水溶液(在水溶性的情况下)或分散体以及用于临时制备无菌可注射溶液或分散液的无菌粉末。对于静脉内(IV)施用,适合的载体包括生理盐水,抑菌水,Cremophor ELTM(BASF,Parsippany,N.J.)或磷酸缓冲盐水(PBS)。在这样的注射和IV施用中,组合物是无菌的并且是流体,其程度为存在容易的可注射性。它们在生产和储存条件下是稳定的,并且可以抵抗诸如细菌和真菌等微生物的污染作用而保存。载体可以为溶剂或分散介质,其包含例如水,乙醇,多元醇(例如,甘油,丙二醇和液体聚乙二醇等)及其适合的混合物。例如,可以通过使用诸如卵磷脂这样的涂层,在分散液的情况下通过维持所需的粒径以及通过使用表面活性剂来维持适当的流动性。可以通过各种抗菌和抗真菌剂,例如对羟基苯甲酸酯,三氯叔丁醇,苯酚,抗坏血酸,硫柳汞等来预防微生物的作用。在一些实施方案中,组合物中包括等渗剂,例如糖,多元醇例如甘露糖醇,山梨醇,氯化钠。可通过在组合物中包括延迟吸收的试剂例如单硬脂酸铝和明胶来实现可注射组合物的延长吸收。
无菌注射溶液可以通过将所需量的活性剂根据需要与上述列举的一种或多种成分结合在适当的溶剂中,然后过滤灭菌来制备。通常,通过将活性剂掺入到无菌媒介物中来制备分散液,所述无菌媒介物包含基本分散介质和以上列举的那些所需的其它成分。在用于无菌注射溶液的无菌粉末的情况下,制备方法为真空干燥和冷冻干燥,其从其在先的无菌过滤溶液中产生活性成分和任何其它所需成分的粉末。
口服组合物通常包括惰性稀释剂或可食用载体。它们可以封装入明胶胶囊中或压成片剂。为了口服治疗施用的目的,可以将活性化合物与赋形剂混合并以片剂,药片或胶囊的形式使用。口服组合物也可以使用流体载体制备以用作漱口水,其中,将流体载体中的化合物口服施用,然后漱口并吐出或吞咽。药学上相容的粘合剂和/或佐剂材料可以作为组合物的一部分包括在内。片剂,丸剂,胶囊剂,锭剂等可以包含以下任何性质相似的成分或化合物:粘合剂,例如微晶纤维素,黄蓍树胶或明胶;赋形剂,例如淀粉或乳糖;崩解剂,例如海藻酸,Primogel或玉米淀粉;润滑剂,例如硬脂酸镁或Sterotes;助流剂,例如胶体二氧化硅;甜味剂,例如蔗糖或糖精;或矫味剂,例如薄荷,水杨酸甲酯或橙矫味剂。
为了通过吸入施用,将活性剂以气雾喷雾剂的形式从加压的容器或分配器中递送,所述容器或分配器包含适合的推进剂,例如气体,例如二氧化碳的;或雾化器。
全身施用也可以通过跨粘膜或透皮方式进行。对于跨粘膜或透皮施用,在制剂中使用适合于要渗透的屏障的渗透剂。此类渗透剂在本领域中通常是已知的,并且包括,例如对于跨粘膜施用而言包括洗涤剂,胆汁盐和夫西地酸衍生物。跨粘膜施用可以通过使用鼻喷雾剂或栓剂来完成。对于透皮施用,将活性化合物配制成软膏,药膏,凝胶或霜剂,如本领域通常已知的。
也可以将活性剂以栓剂的形式(例如,与常规栓剂基质如可可脂和其它甘油酯一起)或保留灌肠剂的形式制备以用于直肠递送。
在一些实施方案中,所述活性剂与载体一起制备,所述载体将保护化合物免于迅速从体内清除,例如持续/控释制剂,包括植入物和微囊化递送系统。可以使用可生物降解的生物相容性聚合物,例如乙烯乙酸乙烯酯,聚酸酐,聚乙醇酸,胶原蛋白,聚原酸酯和聚乳酸。这种制剂的制备方法对本领域技术人员而言是显而易见的。
例如,可以将活性剂包埋在例如通过凝聚技术或通过界面聚合制备的微胶囊中,例如,羟甲基纤维素或明胶微胶囊和聚-(甲基丙烯酸甲酯)微胶囊中,分别在胶体药物递送系统中(例如,脂质体,白蛋白微球,微乳,纳米粒和纳米囊)或粗乳剂中。
可以制备缓释制剂。缓释制剂的适合实例包括含有活性剂的固体疏水性聚合物的半透性基质,该基质为定型制品,例如薄膜或微胶囊的形式。持续释放基质的实例包括聚酯,水凝胶(例如,聚(2-羟基乙基-甲基丙烯酸酯)或聚(乙烯醇)),聚丙交酯(美国专利号3,773,919),L-谷氨酸和γ乙基-L-谷氨酸的共聚物,不可降解的乙烯-乙酸乙烯酯,可降解的乳酸-乙醇酸共聚物,例如LUPRON DEPOTTM(由乳酸-乙醇酸共聚物和醋酸亮丙瑞林组成的可注射微球)和聚-D-(-)-3-羟基丁酸。尽管诸如乙烯-乙酸乙烯酯和乳酸-乙醇酸这样的聚合物能够在100天内释放分子,但某些水凝胶却可以在较短的时间内释放蛋白质。
在一些实施方案中,对于所治疗的特定适应症,如果必要,该制剂还可以包含一种以上的活性化合物,例如,具有互补活性的不会彼此产生不利影响的那些活性化合物。或者或此外,该组合物可以包含增强其功能的活性剂,例如细胞毒性剂,细胞因子,化疗剂或生长抑制剂。这样的分子适合地以对于预期目的有效的量组合存在。
在一些实施方案中,在联合疗法中施用DNA-PK抑制剂和/或所述基因组编辑系统,即与用于治疗病理学情况或障碍,例如癌症或炎性疾病的不同形式的另外的活性剂合并,例如治疗剂。术语“组合形式”在本文上下文中是指基本上同时或依次地给予活性剂。如果依次给予,则在第二种化合物开始施用时,优选仍可以在治疗部位以有效浓度检测到两种化合物中的第一种。
基因组编辑筛选方法
本领域已知的任何方法都可用于筛选细胞的基因组编辑效率,包括NHEJ和/或HDR的效率。例如,筛选方法可以包括基于PCR的靶区扩增,然后对扩增的区域进行测序或深度测序以确认基因组编辑。PCR基因分型可以允许在刺激HDR中对化合物进行定量和排序。其它筛选方法可以包括下一代测序。参见,例如Bell et al.,“A high-throughputscreening strategy for detecting CRISPR-Cas9induced mutations using next-generation sequencing,”BMC Genomics,15:1002(2014)。
可以改造PCR引物以选择性地扩增未修饰的和修饰的遗传区域,从而根据遗传修饰状态的不同产生不同长度的扩增子。然后可以在凝胶上解析扩增子,并使用Bio-Imager通过光密度测定法估算HDR效率。或者,一种新的PCR技术,即快速数字液滴PCR(DDPCR)可用于同时测量基因组编辑样本中的HDR和NHEJ事件。参见,例如,Miyaoka et al.,“Systematic quantification of HDR and NHEJ reveals effectrs of locus,nucleaseand cell type on genome-editin,”Scientific Reports,6,2016。其它可用于筛选细胞进行基因组修饰的方法包括:Sanger测序,深度测序和RT-PCR。
在一些实施方案中,交通信号报道(TLR)构建体用于筛选细胞。TLR筛选包括在靶向基因组编辑时为表达荧光标记而改造的报道细胞。经过适当的靶向后,荧光标记被细胞表达。可以通过本领域已知的任何方法,例如流式细胞术分析来对适当靶向的细胞进行定量。参见,例如,Certo et al.,2011,“Tracking genome engineering outcome atindividual DNA breakpoints,”Nature Methods,8,671-676页(2011)。
本文引用的所有出版物和专利对比文件的相关部分通过引用并入本文,如同此类出版物或对比文件各自被具体地和单独地指示通过引用并入本文。引用出版物和专利对比文件并非意图承认任何相关现有技术,也不构成对其内容或日期的承认。现在已经通过书面描述的方式描述了本公开,本领域技术人员将认识到可以实施不同的实施方案,并且前述描述和下面的实施例出于示例的目的,而不是对所附权利要求的限制。
DNA-PK抑制剂在治疗/预防病症中的用途
在另一个实施方案中,本发明提供了药物组合物,其包含本文所述的任何式的化合物和药学上可接受的赋形剂。在另一个实施方案中,本发明提供包含表1的化合物的药物组合物。在另一个实施方案中,所述组合物还包含另外的治疗剂。
根据另一个实施方案,本发明提供了组合物,其包含本发明的化合物或其药学上可接受的衍生物和药学上可接受的载体、佐剂或媒介物。在一个实施方案中,本发明的组合物中化合物的量应使得可有效地可测定地抑制生物样品或患者中的DNA-PK。在另一个实施方案中,本发明的组合物中化合物的量使得可有效地可测定地抑制DNA-PK。在一个实施方案中,配制本发明的组合物以施用于需要这种组合物的患者。在另一个实施方案中,配制本发明的组合物用于口服施用于患者。
本发明化合物的制备
部分I:羟基喹喔啉酮中间体的制备
部分I中描述了用于制备官能化8-羟基-1-甲基喹喔啉-2(1H)-酮中间体的合成方法。使用这些中间体与部分II中适当选择的甲磺酸酯中间体,以便制备表A中的化合物。
8-羟基-1,3-二甲基-6-吗啉代喹喔啉-2(1H)-酮的合成:
步骤1:5-溴-1-氟-3-((4-甲氧基苄基)氧基)-2-硝基苯
将5-溴-1,3-二氟-2-硝基-苯(300g,1.261mol)和对-甲氧基苄醇(190g,1.375mol)溶于N,N-二甲基甲酰胺(1.8L)。向得到的溶液中添加碳酸铯(611g,1.875mol),将该混合物温热至70℃,搅拌16h。将该混合物冷却至室温,倾入到冷水(2L)中,导致黄色固体沉淀。将沉淀收集在布氏漏斗上,用水(2×500mL)冲洗。将沉淀溶于二氯甲烷(5L),用水(2×1L)和盐水(1L)洗涤,干燥(Na2SO4),通过硅胶垫(500g)过滤。用二氯甲烷(500mL)洗涤硅胶床,减压浓缩合并的滤液。将残余物与庚烷(2L)一起研磨,在50℃真空烘箱中干燥14h,得到5-溴-1-氟-3-((4-甲氧基苄基)氧基)-2-硝基苯(350g,72%收率),为黄色固体。1HNMR(300MHz,CDCl3)δ7.35-7.27(m,2H),7.08-6.99(m,2H),6.97-6.87(m,2H),5.11(s,2H),3.82(s,3H)。19F NMR(282MHz,CDCl3)δ-120.36。
步骤2:(5-溴-3-((4-甲氧基苄基)氧基)-2-硝基苯基)氨基乙酸甲酯
向5-溴-1-氟-3-[(4-甲氧基苯基)甲氧基]-2-硝基-苯(350g,0.914mol)和2-氨基乙酸甲酯(盐酸盐,173g,1.364mol)在N,N-二甲基甲酰胺(2L)中的混合物中添加三乙胺(350mL,2.511mol)。将得到的反应混合物温热至50℃,在该温度下搅拌54h。将该反应混合物冷却至环境温度,倾入到冷水(3L)中,导致浅棕色胶状材料形成。滗析水,将浅棕色胶状物质溶于二氯甲烷(5L),用水(1L)和盐水(1L)洗涤,干燥(Na2SO4)。使该溶液通过硅胶床过滤,用二氯甲烷(2×500mL)洗涤。减压浓缩合并的滤液。将残余物与甲基叔丁基醚(2L)一起研磨,在50℃真空烘箱中干燥12h,得到(5-溴-3-((4-甲氧基苄基)氧基)-2-硝基苯基)氨基乙酸甲酯(252g,62%),为黄色固体。
1H NMR(300MHz,CDCl3)δ7.40-7.30(m,2H),6.96-6.86(m,2H),6.63(t,J=4.9Hz,1H),6.58(d,J=1.8Hz,1H),6.40(d,J=1.8Hz,1H),5.07(s,2H),3.96(d,J=5.2Hz,2H),3.82(s,6H)。
步骤3:6-溴-8-((4-甲氧基苄基)氧基)-3,4-二氢喹喔啉-2(1H)-酮
向(5-溴-3-((4-甲氧基苄基)氧基)-2-硝基苯基)氨基乙酸甲酯(52g,112.5mmol)在四氢呋喃(700mL)和甲醇(400mL)中的溶液中添加钯[7g,3%w/w,在活性木碳上,还原的,70%水湿润糊状物(ESCAT 2931),1.076mmol]。给该反应混合物抽真空5分钟,然后放入氢气气氛(球囊)中16h。通过C盐过滤该反应混合物,用甲醇(2×200mL)洗涤床。减压浓缩合并的滤液。将由此得到的残余物与二氯甲烷(400mL)一起共沸,与甲基叔丁基醚一起研磨,得到6-溴-8-((4-甲氧基苄基)氧基)-3,4-二氢喹喔啉-2(1H)-酮(39g,93%),为黄褐色固体。1H NMR(300MHz,DMSO-d6)δ9.42(s,1H),7.56-7.29(m,2H),7.02-6.81(m,2H),6.60(d,J=1.9Hz,1H),6.49(d,J=1.7Hz,1H),6.19(s,1H),5.05(s,2H),3.75(s,3H),3.70(s,2H)。
步骤4:6-溴-8-((4-甲氧基苄基)氧基)喹喔啉-2(1H)-酮
将6-溴-8-[(4-甲氧基苯基)甲氧基]-3,4-二氢-1H-喹喔啉-2-酮(178g,0.485mmol)溶于氯仿(6.0L)。向得到的溶液中添加二氧化锰(IV)(400g,4.601mol)。将得到的反应混合物温热至55℃,搅拌4h。将该反应混合物冷却至环境温度,通过硅胶床过滤。用40%乙酸乙酯的二氯甲烷溶液(4×500mL)洗涤床。减压浓缩合并的滤液。将得到的残余物与乙酸乙酯/甲基叔丁基醚(1:2之比,3L)一起研磨,在50℃真空烘箱中干燥14h,得到6-溴-8-((4-甲氧基苄基)氧基)喹喔啉-2(1H)-酮(125g,71%),为黄褐色固体。1H NMR(300MHz,DMSO-d6)δ12.06(s,1H),8.19(s,1H),7.67-7.33(m,4H),7.03-6.85(m,2H),5.26(s,2H),3.75(s,3H)。
步骤5:6-溴-8-((4-甲氧基苄基)氧基)-1-甲基喹喔啉-2(1H)-酮
向6-溴-8-((4-甲氧基苄基)氧基)喹喔啉-2(1H)-酮(125g,0.343mmol)在N,N-二甲基甲酰胺(4.0L)中的溶液中添加碘甲烷(110mL,1.767mol)。用冰浴将得到的混合物冷却至0℃,逐步添加氢化钠(35g的60%w/w,0.875mmol),历时20分钟。将得到的反应混合物搅拌≤3℃30分钟,此时HPLC-分析揭示出约85:15之比的N-甲基化和O-甲基化产物。将该反应混合物倾入到冷水(4.0L)中,导致黄色沉淀形成。将该固体收集在布氏漏斗上,用水(2×1.0L)冲洗,在50℃在对流烘箱中干燥4h。将沉淀(85:15之比)混悬于20%的甲基叔丁基醚(3.0L)的乙酸乙酯溶液中,回流1h,冷却至环境温度。将混合物通过中孔烧结漏斗过滤,在50℃在真空烘箱中干燥5h,得到期望的N-甲基化产物(120g),纯度96%。将该产物再次混悬于20%甲基叔丁基醚的乙酸乙酯溶液(3.0L),回流1h,如上所述过滤和真空干燥,得到6-溴-8-((4-甲氧基苄基)氧基)-1-甲基喹喔啉-2(1H)-酮(90g),纯度99%,为黄色固体。另外,减压浓缩滤液,通过硅胶色谱法纯化残余物(330g Isco金柱,线性梯度,0%→60%乙酸乙酯/二氯甲烷),又得到一批期望的产物3(13g,99%纯度)。1H NMR(300MHz,CDCl3)δ8.26(s,1H),7.63(d,J=2.2Hz,1H),7.40-7.29(m,2H),7.26(s,1H),7.05-6.83(m,2H),5.05(s,2H),3.84(d,J=1.7Hz,6H)。ESI-MS m/z计算值374.03,实测值375.05(M+1)。
步骤6:8-((4-甲氧基苄基)氧基)-1-甲基-6-吗啉代喹喔啉-2(1H)-酮
将6-溴-8-[(4-甲氧基苯基)甲氧基]-1-甲基-喹喔啉-2-酮(103g,270.9mmol)和吗啉(36mL,412.8mmol)在二噁烷(2.0L)中的混合物通过使氮气经过该溶液起泡脱氧10分钟。依次添加乙酸钯(II)(1.3g,5.790mmol),RuPhos(5.5g,11.79mmol)和碳酸铯(200g,613.8mmol)。将该反应混合物用氮气流再脱氧10分钟。将得到的反应混合物温热至80℃,搅拌14h。将该反应混合物冷却至环境温度,减压浓缩以除去二噁烷。添加冷水(2.5L),形成黄色沉淀。将沉淀收集在布氏漏斗上,用水(500mL)洗涤,在对流烤箱中干燥。通过硅胶色谱法纯化残余物(4×330g柱,线性梯度,0%→10%甲醇/二氯甲烷),得到8-((4-甲氧基苄基)氧基)-1-甲基-6-吗啉代喹喔啉-2(1H)-酮(68g,66%),为黄色固体。1H NMR(300MHz,CDCl3)δ8.25(s,1H),7.41-7.28(m,2H),7.03-6.89(m,3H),6.82(d,J=2.7Hz,1H),5.05(s,2H),3.93-3.87(m,4H),3.86(s,3H),3.84(s,3H),3.46-2.82(m,4H)。ESI-MS m/z计算值381.17,实测值382.21(M+1)。
步骤7:8-羟基-1-甲基-6-吗啉代喹喔啉-2(1H)-酮
将8-((4-甲氧基苄基)氧基)-1-甲基-6-吗啉代喹喔啉-2(1H)-酮(13.90g,36.44mmol)溶于二氯甲烷(250mL)。添加三氟乙酸(31.0mL,402mmol),将得到的深棕色溶液在室温搅拌3h。真空蒸发溶剂,将剩余的残余物溶于二氯甲烷,用硅胶垫过滤。首先用二氯甲烷洗脱垫以洗脱高Rf杂质,弃去。将洗脱液切换至丙酮,导致洗脱黄-橙色带。收集该带,浓缩至干,得到8-羟基-1-甲基-6-吗啉代喹喔啉-2(1H)-酮(8.89g,50%收率)。1H NMR(300MHz DMSO-d6)δ10.23(s,1H),8.11(s,1H),6.77(d,J=3.1Hz,2H),3.84(s,3H),3.81-3.70(m,4H),3.19-2.99(m,4H)。
8-羟基-1,3-二甲基-6-吗啉代喹喔啉-2(1H)-酮的合成:
步骤1:5-氟-3-[(4-甲氧基苯基)甲氧基]-2-硝基-苯胺
向(4-甲氧基苯基)甲醇(4.17g,30.18mmol)在四氢呋喃(52.4mL)中的溶液中添加氢化钠(60%的矿物油分散液;1.28g,32.00mmol)。将得到的混合物搅拌10分钟,用3,5-二氟-2-硝基-苯胺(5g,28.72mmol)处理,再搅拌1h。将该混合物谨慎地分配在乙酸乙酯与水之间,滴加1N盐酸,直至红色消散为黄色/橙色。收集有机层,干燥(Na2SO4),过滤并浓缩。将粗残余物通过硅胶色谱法纯化(330g ISCO柱,使用0-25%乙酸乙酯/庚烷的线性梯度),得到5-氟-3-[(4-甲氧基苯基)甲氧基]-2-硝基-苯胺,为黄-橙色固体。
步骤2:3-[(4-甲氧基苯基)甲氧基]-5-吗啉代-2-硝基-苯胺
将5-氟-3-[(4-甲氧基苯基)甲氧基]-2-硝基-苯胺(4.64g,15.88mmol)和吗啉(7.0mL,80.27mmol)在二甲亚砜(13.6mL)中的溶液加热至100℃2.5h。使该混合物分配在乙酸乙酯与水之间。分离各相,再用乙酸乙酯萃取水相。将有机相干燥(Na2SO4),过滤并浓缩,得到3-[(4-甲氧基苯基)甲氧基]-5-吗啉代-2-硝基-苯胺(5.70g,100%收率),为橙色固体,将其未经进一步操作使用。ESI-MS m/z计算值359.15,实测值360.17(M+1)。
步骤3:3-[(4-甲氧基苯基)甲氧基]-5-吗啉代-苯-1,2-二胺
将3-[(4-甲氧基苯基)甲氧基]-5-吗啉代-2-硝基-苯胺(5.66g,15.75mmol),氯化铵(1.53g,28.60mmol),锌(5.59g,85.46mmol)和2%TPGS-750-M在水(31mL)中的混合物搅拌过夜。添加C盐以吸附水,随后添加乙酸乙酯。将该混合物过滤,再用乙酸乙酯冲洗C盐垫。将合并的滤液浓缩,将粗残余物通过硅胶色谱法纯化(330g硅胶柱;0-5%甲醇/二氯甲烷的线性梯度),得到3-[(4-甲氧基苯基)甲氧基]-5-吗啉代-苯-1,2-二胺(3.41g,66%收率),为红色固体。ESI-MS m/z计算值329.17,实测值330.19(M+1)。
步骤4:8-[(4-甲氧基苯基)甲氧基]-3-甲基-6-吗啉代-1H-喹喔啉-2-酮
将3-[(4-甲氧基苯基)甲氧基]-5-吗啉代-苯-1,2-二胺(315mg,0.956mmol),丙酮酸乙酯(212μL,1.908mmol)和甲醇(3.0mL)的混合物在密封小瓶中在65℃加热2小时。固体从反应混合物中沉淀。将该反应冷却至室温,添加水,并将混合物搅拌30分钟。将固体通过过滤收集,用水洗涤,并真空干燥过夜,得到产物的区域异构体混合物(365mg,1.7:1之比,有利于上述方案中所示的期望的化合物)。通过SFC纯化得到的混合物,得到期望的异构体8-((4-甲氧基苯基)甲氧基)-3-甲基-6-吗啉代-1H-喹喔啉-2-酮(110mg)和不期望的异构体5-((4-甲氧基苄基)氧基)-3-甲基-7-吗啉代喹喔啉-2(1H)-酮(64mg)。
8-((4-甲氧基苄基)氧基)-3-甲基-6-吗啉代喹喔啉-2(1H)-酮的数据:
1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),7.55-7.46(m,2H),6.98(d,J=2.3Hz,1H),6.95-6.89(m,2H),6.72(d,J=2.3Hz,1H),5.21(s,2H),3.74(m,7H),3.10(m,4H),2.78(q,J=7.4Hz,2H),1.23-1.14(t,3H)。ESI-MS m/z计算值381.17,实测值382.17(M+1)。
5-((4-甲氧基苄基)氧基)-3-甲基-7-吗啉代喹喔啉-2(1H)-酮的数据:
1H NMR(400MHz,DMSO-d6)δ11.96(s,1H),7.49-7.38(m,2H),7.00-6.90(m,2H),6.60(d,J=2.4Hz,1H),6.21(d,J=2.4Hz,1H),5.17(s,2H),3.75(m,7H),3.18(m,4H),2.69(q,J=7.4Hz,2H),1.17(t,J=7.4Hz,3H)。ESI-MS m/z计算值381.17,实测值382.17(M+1)。
步骤5:8-((4-甲氧基苄基)氧基)-1,3-二甲基-6-吗啉代喹喔啉-2(1H)-酮
用碘甲烷(21μL,0.337mmol)处理8-[(4-甲氧基苯基)甲氧基]-3-甲基-6-吗啉代-1H-喹喔啉-2-酮(110mg,0.274mmol),碳酸钾(183mg,1.324mmol)和丙酮(3.0mL)的混合物。密封得到的反应混合物,在60℃搅拌过夜。使该混合物分配在乙酸乙酯与水之间。分离各相,再用乙酸乙酯萃取水相。将有机相干燥(Na2SO4),过滤并浓缩。将粗残余物通过硅胶色谱法纯化(4g硅胶柱;0-10%甲醇/二氯甲烷的线性梯度),得到8-((4-甲氧基苄基)氧基)-1,3-二甲基-6-吗啉代喹喔啉-2(1H)-酮(94mg,82%)。1H NMR(400MHz,DMSO-d6)δ7.48-7.41(m,2H),7.04(d,J=2.7Hz,1H),6.99-6.94(m,2H),6.79(d,J=2.6Hz,1H),5.15(s,2H),3.76(m,10H),3.16(m,4H),2.38(s,3H)。ESI-MS m/z计算值395.18,实测值396.26(M+1)。
步骤6:8-羟基-1,3-二甲基-6-吗啉代喹喔啉-2(1H)-酮
用三氟乙酸处理8-[(4-甲氧基苯基)甲氧基]-1,3-二甲基-6-吗啉代-喹喔啉-2-酮(88mg,0.177mmol)在二氯甲烷(5.0mL)中搅拌的溶液。将得到的溶液在室温搅拌1小时。浓缩该反应混合物,将粗残余物未经进一步纯化使用。ESI-MS m/z计算值275.13,实测值276.14(M+1)。
1-乙基-8-羟基-6-吗啉代喹喔啉-2(1H)-酮的合成:
步骤1:8-((4-甲氧基苄基)氧基)-6-吗啉代喹喔啉-2(1H)-酮
向3-[(4-甲氧基苯基)甲氧基]-5-吗啉代-苯-1,2-二胺(7.51g,22.80mmol)在甲醇(877mL)中的溶液中添加乙醛酸乙酯(9.3mL的50%w/v甲苯溶液,45.55mmol)。密封得到的溶液,在65℃加热2小时。固体从反应混合物中沉淀。将该反应冷却至室温,添加水。将固体通过过滤收集,用水洗涤,与异丙醇一起研磨,真空干燥,得到产物的区域异构体混合物(6.34g)。通过SFC[IB制备柱,采用40%乙醇(5mM氨)]纯化得到的混合物,得到期望的区域异构体8-[(4-甲氧基苯基)甲氧基]-6-吗啉代-1H-喹喔啉-2-酮(3.48g)和不期望的区域异构体5-[(4-甲氧基苯基)甲氧基]-7-吗啉代-1H-喹喔啉-2-酮(2.35g)。
8-[(4-甲氧基苯基)甲氧基]-6-吗啉代-1H-喹喔啉-2-酮的数据:
1H NMR(400MHz,DMSO-d6)δ11.80(s,1H),8.12(s,1H),7.55-7.47(m,2H),7.06(d,J=2.4Hz,1H),6.96-6.89(m,2H),6.76(d,J=2.3Hz,1H),5.23(s,2H),3.76(m,7H),3.12(m,4H)。ESI-MS m/z计算值367.15,实测值368.09(M+1)。
5-[(4-甲氧基苯基)甲氧基]-7-吗啉代-1H-喹喔啉-2-酮的数据:
1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),7.72(s,1H),7.46-7.37(m,2H),7.02-6.92(m,2H),6.63(d,J=2.3Hz,1H),6.19(d,J=2.3Hz,1H),5.14(s,2H),3.77(m,7H),3.24(m,4H)。ESI-MS m/z计算值367.15,实测值368.09(M+1)。
步骤2:1-乙基-8-[(4-甲氧基苯基)甲氧基]-6-吗啉代-喹喔啉-2-酮
向8-[(4-甲氧基苯基)甲氧基]-6-吗啉代-1H-喹喔啉-2-酮(150mg,0.408mmol)在丙酮(4.3mL)中的溶液中添加碳酸钾(273mg,1.975mmol)和碘乙烷(40μL,0.500mmol)。密封得到的反应混合物,在60℃在小瓶中搅拌过夜。使该混合物分配在乙酸乙酯与水之间。分离各相,再用乙酸乙酯萃取水相。将有机相干燥(Na2SO4),过滤并浓缩。将粗残余物通过硅胶色谱法纯化(4g硅胶柱;0-10%甲醇/二氯甲烷的线性梯度),得到1-乙基-8-[(4-甲氧基苯基)甲氧基]-6-吗啉代-喹喔啉-2-酮(55mg,32%收率)。1H NMR(400MHz,DMSO-d6)δ7.46(d,J=8.7Hz,2H),7.16(d,J=2.5Hz,1H),6.99-6.93(m,2H),6.86(d,J=2.5Hz,1H),5.26(s,2H),4.43(q,J=7.0Hz,2H),3.78(m,4H),3.76(s,3H),3.23(m,4H),1.40(t,J=7.1Hz,3H)。ESI-MS m/z计算值395.18,实测值396.23(M+1)。
步骤3:1-乙基-8-羟基-6-吗啉代-喹喔啉-2-酮
向1-乙基-8-[(4-甲氧基苯基)甲氧基]-6-吗啉代-喹喔啉-2-酮(50mg,0.1264mmol)在二氯甲烷(约1.0mL)中的溶液中添加三氟乙酸。浓缩得到的红色反应溶液,将其未经进一步操作使用。ESI-MS m/z计算值275.13,实测值276.14(M+1)。
6-溴-8-羟基-1-甲基喹喔啉-2(1H)-酮
将6-溴-8-[(4-甲氧基苯基)甲氧基]-1-甲基-喹喔啉-2-酮(4g,10.66mmol)在乙酸(56mL)中的溶液加热至100℃5小时。将该反应冷却至室温,保持静置过夜,导致黄色沉淀形成。通过真空过滤收集固体,用乙醚洗涤,真空干燥,得到6-溴-8-羟基-1-甲基-喹喔啉-2-酮(1.92g,69%收率)。1H NMR(400MHz,DMSO-d6)δ8.21(s,1H),7.44(d,J=2.3Hz,1H),7.19(d,J=2.3Hz,1H),3.86(s,3H)。ESI-MS m/z计算值253.97,实测值254.97(M+1)。
8-羟基-1-甲基-6-(6-氧杂-3-氮杂二环[3.1.1]庚-3-基)喹喔啉-2-酮
在密封小瓶中在氮气气氛中合并6-溴-8-羟基-1-甲基-喹喔啉-2-酮(312mg,1.223mmol),6-氧杂-3-氮杂二环[3.1.1]庚烷(盐酸盐;201mg,1.482mmol),RuPhos-G3-palladacycle(52mg,0.062mmol)和RuPhos(29mg,0.062mmol)。添加双(三甲基甲硅烷基)氨基锂(3mL的1.0M的四氢呋喃溶液,3.000mmol),将小瓶加热至65℃过夜。将该反应混合物冷却至室温,用乙酸乙酯稀释,过滤。浓缩滤液,通过氨基-官能化的硅胶色谱法纯化粗残余物(12g柱,0-10%甲醇/二氯甲烷的线性梯度),得到8-羟基-1-甲基-6-(6-氧杂-3-氮杂二环[3.1.1]庚-3-基)喹喔啉-2-酮(214mg,64%收率)。ESI-MS m/z计算值273.11,实测值274.24(M+1)。
6-(3,6-二氢-2H-吡喃-4-基)-8-羟基-1-甲基-喹喔啉-2-酮的合成:
步骤1:6-(3,6-二氢-2H-吡喃-4-基)-8-((4-甲氧基苄基)氧基)-1-甲基喹喔啉-2(1H)-酮
将6-溴-8-[(4-甲氧基苯基)甲氧基]-1-甲基-喹喔啉-2-酮(4.0g,10.66mmol),2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(2.72g,12.95mmol),碳酸钠(8mL的2.0M水溶液,16.00mmol)和二噁烷(40mL)的混合物通过使氮气经过该混合物起泡脱气10min。添加[1,1’-双(二苯基膦基)二茂铁]-二氯钯(II)(二氯甲烷复合物;881mg,1.079mmol)。将得到的反应混合物再脱气5分钟。然后加热至85℃4小时。将该混合物冷却至室温,使其分配在水与乙酸乙酯之间。分离各层,再用乙酸乙酯萃取水层。用盐水洗涤合并的有机层,干燥(MgSO4),过滤并浓缩。将粗残余物通过硅胶色谱法纯化(330g硅胶柱,0-50%乙酸乙酯/庚烷的线性梯度),得到6-(3,6-二氢-2H-吡喃-4-基)-8-[(4-甲氧基苯基)甲氧基]-1-甲基-喹喔啉-2-酮(2.81g,69%收率),为黄色固体。1H NMR(400MHz,DMSO-d6)δ8.21(s,1H),7.52-7.42(m,4H),7.02-6.94(m,2H),6.48-6.42(m,1H),5.22(s,2H),4.27(q,J=2.8Hz,2H),3.85(t,J=5.5Hz,2H),3.78(s,3H),3.77(s,3H)。ESI-MS m/z计算值378.16,实测值379.17(M+1)。
步骤2:6-(3,6-二氢-2H-吡喃-4-基)-8-羟基-1-甲基-喹喔啉-2-酮
向6-(3,6-二氢-2H-吡喃-4-基)-8-[(4-甲氧基苯基)甲氧基]-1-甲基-喹喔啉-2-酮(1.81g,4.783mmol)在二氯甲烷(20mL)中的溶液中添加三氟乙酸(5.0mL,64.90mmol)。将得到的反应溶液搅拌2小时,浓缩。使粗残余物分配在乙酸乙酯与饱和碳酸氢钠水溶液之间。分离各层,再用乙酸乙酯萃取水相。用盐水洗涤合并的有机萃取物,干燥(MgSO4),过滤并浓缩。添加二氯甲烷,导致棕色沉淀形成,得到6-(3,6-二氢-2H-吡喃-4-基)-8-羟基-1-甲基-喹喔啉-2-酮(1.10g,82%收率)。1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.18(s,1H),7.32(d,J=2.1Hz,1H),7.20(d,J=2.2Hz,1H),6.26(dp,J=3.1,1.5Hz,1H),5.76(s,1H),4.24(q,J=2.8Hz,2H),3.88(s,3H),3.83(t,J=5.5Hz,2H),2.48-2.40(m,2H)。ESI-MSm/z计算值258.10,实测值259.16(M+1)。
部分II:甲磺酸酯中间体的制备
部分II中描述了用于制备甲磺酸酯中间体的合成方法。使用这些中间体与适当选择的8-羟基-1-甲基喹喔啉-2(1H)-酮中间体(部分I中所述),以便使用部分III中所述的方法制备表A中的化合物。
甲磺酸(1,4-反式)-4-(嘧啶-2-基氧基)环己酯
步骤1:(1,4-反式)-4-((叔丁基二甲基甲硅烷基)氧基)环己-1-醇
向(1,4-反式)-环己-1,4-二醇(70g,602.6mmol)和咪唑(130g,1.910mol)在二氯甲烷(1.5L)中的溶液中一次性添加叔丁基-氯-二甲基-硅烷(100g,663.5mmol)。将得到的反应混合物温热至室温,搅拌24h,此时TLC-分析揭示出原料,期望的产物和双-加成产物的混合物。将该反应混合物倾入到水(300mL)中。分离有机层,用二氯甲烷(100mL)萃取水层。用水(100mL)和盐水(100mL)洗涤合并的有机层,干燥(Na2SO4),过滤并减压浓缩。将粗残余物通过硅胶色谱法纯化(800g硅胶柱,0-50%乙酸乙酯的庚烷溶液的线性梯度),得到(1,4-反式)-4-[叔丁基(二甲基)甲硅烷基]氧基环己醇(58g,41%),为白色固体。1H NMR(400MHz,DMSO-d6)δ4.44(d,J=4.1Hz,1H),3.69-3.50(m,1H),3.48-3.35(m,1H),1.84-1.60(m,4H),1.37-1.09(m,4H),0.84(s,9H),0.02(s,6H)。
步骤2:2-(((1,4-反式)-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)嘧啶
向2℃的(1,4-反式)-4-[叔丁基(二甲基)甲硅烷基]氧基环己醇(13.7g,58.86mmol)和2-氯嘧啶(9g,74.65mmol)在N,N-二甲基甲酰胺(100mL)中的溶液中一次性添加氢化钠(5g的60%w/w的矿物油混悬液,125.0mmol)。将得到的反应混合物温热至室温,历时30分钟,再持续搅拌10小时。将该反应混合物倾入到冰冷水(400mL)中,导致黄褐色固体沉淀。通过真空过滤收集固体,用水冲洗(3×100mL),在50℃真空烘箱中干燥16h,得到(1,4-反式)-叔丁基-二甲基-(4-嘧啶-2-基氧基环-己氧基)硅烷(18.8g,95%纯度,98%收率),将其未经进一步纯化使用。1H NMR(300MHz,DMSO-d6)δ8.57(d,J=4.8Hz,2H),7.08(t,J=4.8Hz,1H),5.04-4.80(m,1H),3.90-3.68(m,1H),2.11-1.95(m,2H),1.93-1.76(m,2H),1.64-1.47(m,2H),1.46-1.30(m,2H),0.87(s,9H),0.05(s,6H)。
步骤3:(1,4-反式)-4-(嘧啶-2-基氧基)环己-1-醇
向(1,4-反式)-叔丁基-二甲基-(4-嘧啶-2-基氧基环己氧基)硅烷(26g,83.44mmol)在四氢呋喃(150mL)和甲醇(6mL)的混合物中添加三乙胺三氢氟化物(triethylamine trihydrofluoride)(40g,248.1mmol)。将得到的反应混合物在室温搅拌24小时。用冰浴将该反应混合物冷却至0℃,添加氢氧化铵水溶液(30g,30%w/w,256.8mmol),然后添加水(100mL)和乙酸乙酯(200mL)。分离有机层,再用乙酸乙酯(100mL)萃取水层。用水(100mL)和盐水洗涤合并的有机萃取物,干燥(Na2SO4),过滤并减压浓缩,得到(1,4-反式)-4-嘧啶-2-基氧基环己醇(16.2g,99%),为淡黄色粘性油状物。1H NMR(300MHz,CDCl3)δ8.48(d,J=4.8Hz,2H),6.89(t,J=4.8Hz,1H),5.09-4.87(m,1H),3.91-3.62(m,1H),2.29-2.10(m,2H),2.10-1.95(m,2H),1.68-1.36(m,4H)。
步骤4:甲磺酸(1,4-反式)-4-(嘧啶-2-基氧基)环己酯
向0℃的(1,4-反式)-4-嘧啶-2-基氧基环己醇(16.2g,82.6mmol)和二异丙基乙胺(40mL,229.6mmol)在二氯甲烷中的溶液中滴加甲磺酰氯(8mL,103.4mmol)在二氯甲烷(50mL)中的溶液,历时25分钟。将得到的反应混合物在0℃搅拌30分钟。
通过添加饱和碳酸氢钠水溶液(100mL)使反应混合物淬灭。分离有机层,再用二氯甲烷(100mL)萃取水层。用饱和碳酸氢钠水溶液洗涤合并的有机层,干燥(Na2SO4),过滤并减压浓缩。将粗残余物通过硅胶色谱法纯化(330g Isco金柱,0-50%乙酸乙酯/二氯甲烷的线性梯度),得到甲磺酸(1,4-反式)-(4-嘧啶-2-基氧基环己基)酯(19.4g,85%收率),为白色固体。1H NMR(400MHz,CDCl3)δ8.49(d,J=4.8Hz,2H),6.91(t,J=4.8Hz,1H),5.25-5.02(m,1H),4.98-4.77(m,1H),3.03(s,3H),2.33-2.04(m,4H),1.95-1.72(m,4H)。ESI-MS m/z计算值272.32,实测值273.07(M+1)。
甲磺酸(1,4-反式)-4-((5-甲氧基嘧啶-2-基)氧基)环己酯
通过用上述对甲磺酸(1,4-反式)-4-(嘧啶-2-基氧基)环己酯所述相同的4-步骤合成顺序制备。1H NMR(400MHz,CDCl3)δ8.17(s,2H),5.13-4.95(m,1H),4.94-4.73(m,1H),3.85(s,3H),3.02(s,3H),2.37-1.99(m,4H),1.94-1.68(m,4H)。
甲磺酸(1,4-反式)-4-((2-甲基嘧啶-4-基)氧基)环己酯
步骤1:4-(((1,4-反式)-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2-甲基嘧啶
向2℃的(1,4-反式)-环己-1,4-二醇(2g,17.05mmol)和4-氯-2-甲基-嘧啶(1.5g,11.67mmol)在N,N-二甲基甲酰胺(10mL)中的溶液中一次性添加氢化钠(950mg的60%w/w的矿物油混悬液,23.75mmol)。除去冷却浴,将该反应混合物温热至60℃2小时。将该反应混合物冷却至室温,倾入到冰冷水(60mL)中,导致黄褐色成形成。通过真空过滤收集固体,用水冲洗(2×10mL),在60℃真空烘箱中干燥14h,得到不期望的双-加合物2-甲基-4-[4-(2-甲基嘧啶-4-基)氧基环己氧基]嘧啶(1.1g,31%)。用2-甲基-四氢呋喃(4×60mL)萃取来自真空过滤的滤液,干燥合并的滤液(Na2SO4),过滤并减压浓缩,得到黄色油状物,通过硅胶色谱法纯化(线性梯度0-100%乙酸乙酯/庚烷),得到期望的产物(1,4-反式)-4-(2-甲基嘧啶-4-基)氧基环己醇(1.23g,95%纯度,48%收率),为白色固体。1H NMR(300MHz,CD3OD)δ8.39-8.18(m,1H),6.76-6.38(m,1H),5.24-5.02(m,1H),3.81-3.62(m,1H),3.54(s,1H),2.66-2.39(m,3H),2.26-1.80(m,4H),1.69-1.15(m,4H)。ESI-MS m/z计算值208.26,实测值209.13(M+1)。
步骤2:
用浓盐酸(16mL的12M溶液,192.0mmol)处理叔丁基-二甲基-[4-(2-甲基嘧啶-4-基)氧基环己氧基]硅烷(17.82g,54.70mmol)在异丙醇(225mL)中的溶液。将得到的反应混合物在室温搅拌2小时。减压浓缩该反应混合物,将残余物与乙酸乙酯(2x 200mL)一起共沸,得到黄褐色固体。再通过与甲基叔丁基醚(100mL)一起研磨进一步纯化粗残余物,在50℃真空烘箱中干燥14h,得到(1,4-反式)-4-(2-甲基嘧啶-4-基)氧基环己醇(11.57g,98%),为黄褐色固体,将其未经进一步纯化使用。1H NMR(300MHz,DMSO-d6)δ8.62(d,J=6.6Hz,1H),7.07(d,J=6.6Hz,1H),5.30-4.95(m,1H),3.64-3.42(m,1H),2.66(s,3H),2.17-1.95(m,2H),1.95-1.75(m,2H),1.65-1.43(m,2H),1.43-1.22(m,2H)。
步骤3:甲磺酸(1,4-反式)-4-((2-甲基嘧啶-4-基)氧基)环己酯
根据上述对制备甲磺酸(1,4-反式)-4-(嘧啶-2-基氧基)环己酯所述的方法进行甲磺酸酯形成。(1,4-反式)-4-(2-甲基嘧啶-4-基)氧基环己醇用作原料,得到甲磺酸(1,4-反式)-4-((2-甲基嘧啶-4-基)氧基)环己酯(85%收率),为黄褐色固体。1H NMR(300MHz,CDCl3)δ8.31(d,J=5.8Hz,1H),6.47(d,J=5.8Hz,1H),5.35-5.13(m,1H),5.00-4.75(m,1H),3.04(s,3H),2.59(s,3H),2.28-2.03(m,4H),1.96-1.64(m,4H)。ESI-MS m/z计算值286.35,实测值287.07(M+1)。
甲磺酸(1,4-反式)-4-((5-甲基嘧啶-2-基)氧基)环己酯
通过如上所示的合成方案,使用该部分中的上述反应条件制备。1H NMR(300MHz,CDCl3)δ8.31(s,2H),5.17-4.99(m,1H),4.97-4.74(m,1H),3.02(s,3H),2.22(s,3H),2.20-2.01(m,4H),1.94-1.71(m,4H)。ESI-MS m/z计算值286.35,实测值287.16(M+1)。
甲磺酸(1,4-反式)-4-(嘧啶-2-基氨基)环己酯
步骤1:(1,4-反式)-4-(嘧啶-2-基氨基)环己-1-醇
将2-氯嘧啶(70.30g,613.8mmol)和反式-1,4-氨基环己醇(71.77g,604.5mmol)溶于异丙醇(400mL)。添加N,N-二异丙基乙胺(120mL,689mmol),将得到的溶液加热至回流过夜。减压蒸发溶剂,将保留的固体混悬于二氯甲烷,通过硅胶垫过滤。首先用二氯甲烷洗脱硅胶垫,以洗脱残留的原料,然后用乙酸乙酯洗脱期望的产物。减压蒸发来自乙酸乙酯洗脱液的滤液,得到(1,4-反式)-4-(嘧啶-2-基氨基)环己-1-醇,为白色固体。1H NMR(300MHz,CDCl3)δ8.25(d,J=4.8Hz,2H),6.50(t,J=4.8Hz,1H),5.16(d,J=7.4Hz,1H),3.95-3.54(m,2H),2.25-1.91(m,5H),1.60-1.13(m,4H)。
步骤2:甲磺酸(1,4-反式)-4-(嘧啶-2-基氨基)环己酯
向0℃的(1,4-反式)-4-(嘧啶-2-基氨基)环己-1-醇(52g,55.53mmol)在二氯甲烷(727mL)中的混悬液中添加二异丙基乙胺(90mL,516.7mmol)。通过注射器按照允许内部温度保持在或低于20℃的速率添加甲磺酰氯(35mL,452.2mmol)。将该反应再搅拌1小时,用二氯甲烷稀释,用饱和碳酸氢钠水溶液洗涤。干燥有机层(MgSO4),通过短硅胶垫过滤。用20%乙酸乙酯/二氯甲烷洗脱垫,减压浓缩滤液,得到黄褐色固体。将固体溶于少量二氯甲烷。添加戊烷,直至产物开始结晶。用干冰/丙酮浴冷却该混合物,通过真空过滤收集固体,用戊烷洗涤,真空干燥,得到甲磺酸(1,4-反式)-4-(嘧啶-2-基氨基)环己酯(59.72g,82%收率),为浅黄褐色固体。1H NMR(300MHz,CDCl3)δ8.27(d,J=2H),6.54(t,J=4.8Hz,1H),5.13(d,J=7.6Hz,1H),4.69(tt,J=10.5,4.0Hz,1H),3.98-3.73(m,1H),3.03(s,3H),2.21(dd,J=9.3,4.2Hz,4H),1.91-1.67(m,2H),1.51-1.25(m,2H)。
在先已经报道了获得如上所示类型的其它甲磺酸酯的合成路线,其中R等于取代或未取代的芳族环,取代或未取代的杂芳族环或氨基甲酸酯(US20140275059A1),因此在此不再描述。
部分III:使用甲磺酸酯置换作为最终步骤制备的化合物
使用如下方法,由适当选择的8-羟基-喹喔啉酮(部分I中所述)和甲磺酸酯中间体(部分II中所述)制备部分III中所述的化合物。通过部分III中的方法制备的化合物的分析数据如表A中所示。
方法A-A
1-甲基-6-吗啉代-8-(((1,4-顺式)-4-(嘧啶-2-基氨基)环己基)氧基)喹喔啉-2(1H)-酮
向8-羟基-1-甲基-6-吗啉代-喹喔啉-2-酮(7.65g,15.63mmol)在N,N-二甲基甲酰胺(100mL)中的溶液中添加反式甲磺酸-4-(嘧啶-2-基氨基)环己酯(30.34g,111.8mmol)和碳酸铯(35.64g,109.4mmol)。将该混合物加热至60℃过夜。将该反应混合物冷却至室温,用C盐过滤。用N,N-二甲基甲酰胺洗涤C盐垫,真空蒸发滤液,得到深色油状物,其在高真空下固化。将该固体溶于二氯甲烷,用硅胶垫过滤,用5%甲醇/乙酸乙酯洗脱。蒸发滤液,得到浅黄色固体。将该固体溶于二氯甲烷,通过硅胶色谱法纯化(330g硅胶柱;等度3%甲醇/乙酸乙酯),得到亮黄色固体。用少量已经用干冰/丙酮浴预冷却的乙酸乙酯洗涤该固体,随后用庚烷洗涤。最终,在60℃高真空干燥该物质,得到1-甲基-6-吗啉代-8-(((1,4-顺式)-4-(嘧啶-2-基氨基)环己基)氧基)喹喔啉-2(1H)-酮。
方法A-B
1-甲基-6-吗啉代-8-(((1,4-顺式)-4-(嘧啶-2-基氧基)环己基)氧基)喹喔啉-2(1H)-酮
向8-羟基-1-甲基-6-吗啉代-喹喔啉-2-酮(34.5mg,0.132mmol)在N,N-二甲基甲酰胺(690μL)中的溶液中添加反式-甲磺酸(4-嘧啶-2-基氧基环己基)酯(68.0mg,0.247mmol)和碳酸铯(215mg,0.660mmol)。将该混合物加热至90℃5小时。将该反应混合物冷却至室温,使其分配在二氯甲烷与水之间。收集各相,蒸发。将粗残余物溶于少量DMSO,通过C18制备型HPLC纯化(乙腈/含有三氟乙酸添加剂的水),合并相关级分,浓缩至干。将由此得到的物质溶于二氯甲烷,用饱和碳酸氢钠水溶液洗涤。收集有机相,干燥(Na2SO4),过滤并浓缩,得到1-甲基-6-吗啉代-8-(((1,4-顺式)-4-(嘧啶-2-基氧基)环己基)氧基)喹喔啉-2(1H)-酮(16.1mg,25%收率)。
注意:还通过硅胶色谱法纯化了通过该方法制备的分子(甲醇/二氯甲烷)。
方法A-C
1,3-二甲基-6-吗啉代-8-(((1,4-顺式)-4-(嘧啶-2-基氨基)环己基)氧基)喹喔啉-2(1H)-酮
向8-羟基-1,3-二甲基-6-吗啉代-喹喔啉-2-酮(48.7mg,0.177mmol)和碳酸铯(572mg,1.756mmol)在N,N-二甲基甲酰胺(1.1mL)中的混合物中添加甲磺酸(反式)-[4-(嘧啶-2-基氨基)环己基]酯(147mg,0.542mmol)。将得到的混合物在100℃搅拌过夜。将该反应冷却至室温,使其分配在甲基叔丁基醚与水之间。分离各相,再用甲基叔丁基醚萃取水相。用盐水洗涤有机相,干燥(Na2SO4),过滤并浓缩。将粗残余物通过硅胶色谱法纯化(4g硅胶柱,采用0-10%甲醇/二氯甲烷的线性梯度;然后是第二次硅胶纯化,采用0-100%乙酸乙酯/庚烷的线性梯度),得到1,3-二甲基-6-吗啉代-8-(((1,4-顺式)-4-(嘧啶-2-基氨基)环己基)氧基)-喹喔啉-2(1H)-酮(17.3mg,21%收率)。
注意:还通过反相C18制备型HPLC(乙腈/含有三氟乙酸或氢氧化铵调节剂的水)或反相C18-衍生的硅胶色谱法(乙腈/含有三氟乙酸添加剂的水)纯化了通过该方法制备的分子。
方法A-D
6-溴-1-甲基-8-[(1,4-顺式)-4-(嘧啶-2-基氨基)环己氧基]喹喔啉-2-酮
向6-溴-8-羟基-1-甲基-喹喔啉-2-酮(954mg,3.740mmol)和甲磺酸[4-(嘧啶-2-基氨基)环己基]酯(3.1g,11.42mmol)在二甲亚砜(7.0mL)中的溶液中添加碳酸铷(2.49g,10.78mmol)。将得到的混合物在80℃搅拌过夜。将该反应混合物冷却至室温,使其分配在二氯甲烷与水之间。分离各相,再用二氯甲烷萃取水相。浓缩有机相,真空干燥过夜。将粗残余物通过硅胶色谱法纯化(80g硅胶柱,0-5%甲醇/二氯甲烷的线性梯度),得到6-溴-1-甲基-8-[4-(嘧啶-2-基氨基)环己氧基]喹喔啉-2-酮(700mg,42%收率)。
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部分IV:溴-喹喔啉酮中间体的制备
部分IV包含用于制备本专利另外部分中未描述的官能化6-溴-1-甲基喹喔啉-2(1H)-酮中间体的合成方法。使用这些中间体与适当选择的胺或硼酸酯偶联伙伴(couplingpartner),以便制备表B中的化合物。
6-溴-1-甲基-8-(4-嘧啶-2-基氧基环己氧基)喹喔啉-2-酮
将6-溴-8-羟基-1-甲基-喹喔啉-2-酮(299mg,1.172mmol),甲磺酸(4-嘧啶-2-基氧基环己基)酯(517mg,1.899mmol),碳酸铯(501mg,1.538mmol)和N,N-二甲基甲酰胺(6.0mL)的混合物加热至100℃4小时。将该反应混合物冷却至室温,过滤。通过反相色谱法纯化滤液(100g Isco RediSep Rf C18-衍生的硅胶柱;25-60%乙腈/含有三氟乙酸调节剂的水的线性梯度)。使包含产物的级分分配在乙酸乙酯与饱和碳酸氢钠水溶液之间。分离各相,再用乙酸乙酯萃取水相。用盐水洗涤合并的有机层,干燥(MgSO4),过滤并浓缩,得到6-溴-1-甲基-8-(4-嘧啶-2-基氧基环己氧基)喹喔啉-2-酮(320.6mg,63%收率)。1H NMR(300MHz,DMSO-d6)δ8.60(d,J=4.8Hz,2H),8.25(s,1H),7.58(d,J=2.1Hz,1H),7.51(d,J=2.2Hz,1H),7.12(t,J=4.8Hz,1H),5.22-5.09(m,2H),4.85-4.72(m,2H),3.88(s,3H),2.03-1.85(m,8H)。ESI-MS m/z计算值430.06,实测值431.16(M+1)。
6-溴-8-(((1,4-顺式)-4-((5-甲氧基嘧啶-2-基)氧基)环己基)氧基)-1-甲基喹喔啉-2(1H)-酮
通过与上述对6-溴-1-甲基-8-((1,4-顺式)-4-嘧啶-2-基氧基环己氧基)喹喔啉-2-酮所述类似的方法制备。1H NMR(400MHz,CDCl3)δ8.30(s,1H),8.22(s,2H),7.63(d,J=2.2Hz,1H),7.19(d,J=2.2Hz,1H),5.20-5.10(m,1H),4.58-4.47(m,1H),4.01(s,3H),3.89(s,3H),2.26-1.85(m,8H)。ESI-MS m/z计算值460.07,实测值461.13(M+1)。
6-溴-1-甲基-8-(((1,4-顺式)-4-((5-甲基嘧啶-2-基)氧基)环己基)氧基)喹喔啉-2(1H)-酮
通过与上述对上述6-溴-1-甲基-8-((1,4-顺式)-4-嘧啶-2-基氧基环己氧基)喹喔啉-2-酮类似的方法制备。1H NMR(400MHz,CDCl3)δ8.21(d,J=0.9Hz,2H),8.14(s,1H),7.48(d,J=2.2Hz,1H),7.04(d,J=2.2Hz,1H),5.13-4.99(m,1H),4.43-4.30(m,1H),3.86(s,3H),2.11(s,3H),2.09-1.93(m,4H),1.93-1.71(m,4H)。ESI-MS m/z计算值444.08,实测值445.11(M+1)。
6-溴-1-甲基-8-(((1,4-顺式)-4-((2-甲基嘧啶-4-基)氧基)环己基)氧基)喹喔啉-2(1H)-酮
通过与上述对6-溴-1-甲基-8-((1,4-顺式)-4-嘧啶-2-基氧基环己氧基)喹喔啉-2-酮所述类似的方法制备。1H NMR(400MHz,CDCl3)δ8.36(d,J=5.8Hz,1H),8.31(s,1H),7.65(d,J=2.1Hz,1H),7.29(s,8H),6.57(d,J=5.8Hz,1H),5.43-5.35(m,1H),4.61-4.51(m,1H),4.03(s,3H),2.62(s,3H),2.18-1.86(m,8H)。ESI-MS m/z计算值444.08,实测值445.11(M+1)。
部分V:使用BUCHWALD偶联或SUZUKI偶联作为最终步骤制备的化合物
使用下述方法,由适当选择的官能化的6-溴-1-甲基喹喔啉-2(1H)-酮(部分IV中所述)和胺(在Buchwald偶联的情况下)或硼酸酯(在Suzuki偶联的情况下)制备该部分中所述的化合物。该部分中化合物的分析数据如表B中所示。
方法B-A
6-(6-氧杂-3-氮杂二环[3.1.1]庚-3-基)-1-甲基-8-(((1,4-顺式)-4-(嘧啶-2-基氨基)-环己基)氧基)喹喔啉-2(1H)-酮
将6-溴-1-甲基-8-[4-(嘧啶-2-基氨基)环己基氧基]喹喔啉-2-酮(74mg,0.167mmol),6-氧杂-3-氮杂二环[3.1.1]庚烷(盐酸盐;61mg,0.450mmol),碳酸铯(263mg,0.807mmol),RuPhos-G3-Palladacycle(30mg,0.036mmol),RuPhos(17mg,0.036mmol)和二噁烷(700μL)的混合物在100℃搅拌过夜。将该反应混合物冷却至室温,使其分配在乙酸乙酯与水之间。分离各相,再用乙酸乙酯萃取水层。将有机相干燥(Na2SO4),过滤并浓缩。将粗残余物通过硅胶色谱法纯化(12g硅胶柱,0-5%甲醇/二氯甲烷的线性梯度),得到6-(6-氧杂-3-氮杂二环[3.1.1]庚-3-基)-1-甲基-8-(((1,4-顺式)-4-(嘧啶-2-基氨基)环己基)氧基)喹喔啉-2(1H)-酮(17.0mg,22%收率)。
注意:还通过C18制备型HPLC(乙腈/含有三氟乙酸或氢氧化铵调节剂的水)纯化了通过该方法制备的分子。
方法B-B
6-(3,6-二氢-2H-吡喃-4-基)-1-甲基-8-(((1,4-顺式)-4-(嘧啶-2-基氨基)环己基)-氧基)喹喔啉-2(1H)-酮
向6-溴-1-甲基-8-[4-(嘧啶-2-基氨基)环己氧基]喹喔啉-2-酮(62mg,0.140mmol),2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(44mg,0.209mmol),碳酸钠(207μL的2M水溶液,0.414mmol)和二噁烷(1.1mL)的混合物中添加[1,1’-双(二苯基膦基)二茂铁]-二氯钯(II)(二氯甲烷复合物;10mg,0.014mmol)。将得到的反应混合物在100℃搅拌2小时。过滤该反应混合物,直接通过C18制备型HPLC(乙腈/含有三氟乙酸调节剂的水)纯化滤液,合并相关级分,浓缩至干。由此将该物质溶于二氯甲烷,用饱和碳酸氢钠水溶液洗涤。收集有机相,干燥(Na2SO4),过滤,浓缩并蒸发,得到6-(3,6-二氢-2H-吡喃-4-基)-1-甲基-8-(((1,4-顺式)-4-(嘧啶-2-基氨基)环己基)氧基)喹喔啉-2(1H)-酮(30mg,47%收率)。
注意:还通过硅胶色谱法(乙酸乙酯/二氯甲烷)纯化了通过该方法制备的分子。
方法B-C
1-甲基-6-(6-氧杂-3-氮杂二环[3.1.1]庚-3-基)-8-((1,4-顺式)-4-嘧啶-2-基氧基-环己氧基)-喹喔啉-2-酮
将6-溴-1-甲基-8-(4-嘧啶-2-基氧基环己氧基)喹喔啉-2-酮(80mg,0.186mmol)和碳酸铯(195mg,0.599mmol)在二噁烷(1.0mL)中的混悬液通过使氮气通过该混合物起泡脱气5分钟。添加RuPhos(9mg,0.019mmol)和乙酸钯(II)(2mg,0.009mmol),将该反应再脱气5分钟。最终,添加6-氧杂-3-氮杂二环[3.1.1]庚烷(31mg,0.313mmol),密封小瓶,加热至100℃3小时。将该反应混合物冷却至室温,过滤并浓缩。将粗残余物通过硅胶色谱法纯化(12g硅胶柱,使用等度乙酸乙酯),得到1-甲基-6-(6-氧杂-3-氮杂二环[3.1.1]庚-3-基)-8-((1,4-顺式)-4-嘧啶-2-基氧基环己氧基)喹喔啉-2-酮(36.5mg,43%收率)。
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基因编辑实施例
下列实施例,包括进行的实验和获得的结果仅出于示例性目的而提供,不应解释为对本公开的限制。
实施例1:材料和方法
方法:
细胞和培养
支气管上皮细胞(BEC)来源于被诊断为患有CFTRdF508/dF508基因型的囊性纤维化的人类供体。
诱导的多能干细胞(iPSC)来源于使用Yamanaka的重编程因子Oct4,Sox2,KLF4和c-Myc进行病毒转导后的人真皮成纤维细胞。衍生的iPSC能够分化为3个胚层,并包含具有23对染色体的正常核型。
原代人动员外周血(mPB)CD34+造血干细胞和先祖细胞(HSPC)购自Hemacare或AllCells。将细胞融化,洗涤并重悬于完全培养基中,该完全培养基由无血清培养基CellGro SCGM(CellGenix)组成并且补充细胞因子混合物(300ng/mL SCF,300ng/mLFlt3L,100ng/mL TPO,60ng/ml IL-3),密度为1-3x 105细胞/mL,并在电穿孔前在37℃/5%CO2温育箱中温育48小时。
DNA-PK抑制剂:
DNA-PK抑制剂化合物1用于基因编辑实施例。10mM储备溶液通过使用无水DMSO制备并且储存在-80℃下。
电穿孔:
使用的合成sgRNA为商购的Synthego的HPLC(高效液相色谱法),其纯化自Synthego,并且在5’和3的三个末端位置上包含化学修饰的核苷酸(2’-O-甲基3’-硫代磷酸)。带有修饰核苷酸的sgRNA的序列如下加下划线:
AAVS1 sgRNA:5’ACCCCACAGUGGGGCCACUAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUUUU 3’(SEQ ID NO:3)。
NAV1.7 sgRNA:
5’GGCUGAGCGUCCAUCAACCAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUUUU 3’(SEQ ID NO:4)
Cas9 mRNA购自TriLink Biotechnologies(L-7206)。Cas9 mRNA表达带有核定位信号的酿脓链球菌(Streptococcus pyogenes)SF370 Cas9蛋白质(CRISPR相关蛋白9)。spCas9 mRNA还包含CAP1结构,聚腺苷酸信号和修饰的尿苷,以便在哺乳动物细胞中得到最佳表达水平。
供体ssODN购自IDT。ssODN包含10个核苷酸的插入序列,以通过TIDE测定法测定HDR事件,其侧翼是40个核苷酸的同源臂。ssODN总计包含90个核苷酸,并且在5’和3’末端的三个末端位置均具有硫代磷酸修饰的核苷酸。具有带下划线的硫代磷酸修饰的核苷酸的供体ssODN的序列如下:
AAVS1 PAM:
5’GGGTACTTTTATCTGTCCCCTCCACCCCACAGTGGGGCCAGAATTCTCAGCTAGGGACAGGATTGGTGACAGAAAAGCCCCATCCTTAGG3’(SEQ ID NO:5)
AAVS1 Non-PAM:
5’CCTAAGGATGGGGCTTTTCTGTCACCAATCCTGTCCCTAGCTGAGAATTCTGGCCCCACTGTGGGGTGGAGGGGACAGATAAAAGTACCC3’(SEQ ID NO:6)
NAV1.7 PAM:
5’AGCTGTCCATTGGGGAGCATGAGGGCTGAGCGTCCATCAACTGAGAATTCCCAGGGAGACCACACCGTTGCAGTCCACAGCACTGTGCAT3’(SEQ ID NO:7)
NAV1.7 Non-PAM:
5’ATGCACAGTGCTGTGGACTGCAACGGTGTGGTCTCCCTGGGAATTCTCAGTTGATGGACGCTCAGCCCTCATGCTCCCCAATGGACAGCT3’(SEQ ID NO:8)
所有电穿孔均使用Lonza 4D-NucleofectorTM系统进行。
对于BEC,使用以下条件进行电穿孔:通过使用程序CM-138,在20μl P4电穿孔缓冲液中使用1.8xE5细胞,250ng CAS9mRNA,500ng sgRNA和0.66μM ssODN。将电穿孔的细胞转移至含有100μl补充有DNA-PK抑制剂或未经处理的BEC培养基的96孔板中。将细胞在5%CO2温育箱中于37℃温育。
对于iPSC,使用以下条件:通过使用程序CA-137,在20μl P3电穿孔缓冲液中使用2.0xE5细胞,250ng的CAS9 mRNA,500ng的sgRNA和0.66μM的ssODN。将电穿孔的细胞转移至装有100μl的补充有10μM ROCK抑制剂Y-27632(Stem Cell Technologies)的含有或不含DNA-PK抑制剂的mTEsR1培养基(Stem Cell Technologies)的96孔板中,然后在37℃下在5%CO2温育箱中温育。
将CD34+细胞在融化后两天被电穿孔。使用以下条件进行电穿孔:使用程序CA-137,在100μl P3电穿孔缓冲液中使用2.0xE6细胞,15μg Cas9蛋白质(Feldan),15μgsgRNA,1μM ssODN。通过将电穿孔的细胞平均分为24孔板的8个孔中来转移,每个孔中包含不同浓度的DNA-PK抑制剂。将细胞在5%CO2温育箱中于37℃温育2天,并评估细胞存活率和基因编辑。
脂质介导的细胞转染:
在转染前一天,将BECs以1×E4细胞/孔的细胞密度接种在96-孔板中的BEC培养基中。首先,将0.15μl MessengerMax(ThermoFisher,LMRNA 003)稀释到5μl Opti-MEM中,并在室温下温育10min。同时,将80ng的Cas9 mRNA(Trilink,L-7206),20ng的sgRNA(Synthego)和1皮摩尔的ssODN添加到5μl Opti-MEM中,且然后与MessengerMAx溶液混合。将该混合物温育5min,然后添加到细胞中。将整个溶液添加到具有含有或不含DNA-PK抑制剂的100μl培养基96-孔板孔中的细胞中。将细胞在37℃下于5%CO2温育箱中温育。
细胞存活率的测定:
将细胞与5μg/ml Hoechst 33342(Life technologies:H3570)和0.5μg/ml的碘化丙啶(PI;Life technologies:P3566)一起在培养基中于37度温育1h。对细胞进行成像以便通过使用高含量成像系统(分子装置)测定阳性事件(活和死细胞)和PI阳性事件(死细胞)。相对细胞存活率计算如下:[(样品的Hoescht+事件-PI+事件)/对照的(Hoescht+事件-PI+事件)]*100。对照为模拟转染的细胞,且将其细胞存活率任意设定为100%。
使用Cell Titer Glo(CTG)试剂(Promega)测定CD34+HSPC细胞存活率。将100μl细胞混悬液与100μl完全CTG试剂混合。使用照度计测定化学发光信号,并且与对照细胞(未用DNA-PK抑制剂处理)相比计算活细胞%。
基因编辑比例的测定:
通过在37℃将细胞与50μl DNA Quickextract溶液(Epicentre)/孔的96孔板一起温育30min分离基因组DNA。将细胞提取物混合并转移到PCR板中,然后在65℃温育6min,并且在98℃温育2min。通过使用AccuPrimeTMPfx DNA聚合酶(Thermofisher,12344024),用1μl含基因组DNA的溶液进行PCR反应。PCR条件是在94℃下4分钟(1×),然后在94℃下15s,在60℃下15s和在60℃1min(40×)。纯化PCR产物,然后通过GENEWIZ对Sanger进行测序。以下跨越靶位点的引物对用于PCR(FW,正向;RV,反向)。通过Sanger测序使用的引物用星号(*)表示:
AAVS1_FW:5’GGACAACCCCAAAGTACCCC 3’(SEQ ID NO:9)
AAVS1_RV*:5’AGGATCAGTGAAACGCACCA 3’(SEQ ID NO:10)。
NAV1.7_FW*:5’GCCAGTGGGTTCAGTGGTAT 3’(SEQ ID NO:11)。
NAV1.7_RV:5’TCAGCATTATCCTTGCATTTTCTGT 3’(SEQ ID NO:12)。
使用TIDE(通过分解来追踪Indel)软件(http://tide.nki.nl)分析每个序列色谱图(另外参见Brinkman et al.,Nucleic Acids Research,第42卷,第22期,2014年12月16日,e168页)。模拟电穿孔的样品用作参比序列,且将参数设置为indel大小为30nt,且将分解窗口设置为覆盖具有高质量痕迹的最大可能窗口。总indel(插入和缺失)率直接从TIDE图获得。HDR率是插入10个核苷酸后事件的百分比。将NHEJ率计算为总Indel率-HDR率。使用GraphPad Prism 7软件制作图形并计算所有统计学信息。
实施例2:DNA-PK抑制剂改善BEC中HDR基因编辑比例
图1示例了以下实施例中使用的基因编辑测定法的设计。为了研究DNA-PK抑制剂对HDR基因编辑率的影响,用spCAS9 mRNA,NAV1.7 sgRNA和NAV1.7非-PAM ssODN电穿孔BEC,然后与不同浓度的化合物1一起温育或未经处理(对照)。在电穿孔后72小时通过使用TIDE测定法确定基因编辑率。基因编辑率以百分比表示,并分类为HDR和NHEJ。细胞存活率以其中将对照细胞设定为100%的百分比表示。
如图2中所示,化合物1的DNA-PK抑制剂改善BEC中的基因编辑率。对于化合物1,NHEJ IC50为0.4450μM,HDR EC50为0.4448μM,且HDR TOP%为69.37。
实施例3:DNA-PK抑制剂改善CD34+细胞中HDR基因编辑比例
为了研究DNA-PK抑制剂对HDR基因编辑率的影响,用RNP(spCAS9蛋白质+NAV1.7sgRNA)和NAV1.7非-PAM ssODN电穿孔mPB CD34+细胞。然后将细胞与不同浓度的化合物1一起温育。电穿孔后48h,通过使用TIDE测定法确定基因编辑率。基因编辑率以百分比表示,并如图3A(供体B)和图3B(供体C)所示分类为HDR和NHEJ。细胞存活率以其中将对照细胞设定为100%的百分比表示。
如图3A和3B所示,化合物1的DNA-PK抑制剂改善CD34+细胞中的基因编辑率。供体B的HDR和Indel形成的EC50值分别为0.29μM和0.35μM。
实施例4:DNA-PK抑制剂改善iPSC中HDR基因编辑比例
为了研究DNA-PK抑制剂对HDR基因编辑率的影响,用spCAS9 mRNA,AAVS1 sgRNA和AAVS1 PAM ssODN电穿孔iPSC,然后与不同浓度的化合物1一起温育或未经处理(对照)。在电穿孔后72小时通过使用TIDE测定法确定基因编辑率。基因编辑率以百分比表示,并分类为HDR和NHEJ。细胞存活率以其中将对照细胞设定为100%的百分比表示。
如图4中所示,化合物1的DNA-PK抑制剂改善iPSC中的基因编辑率。对于化合物1,NHEJ IC50为0.474μM,HDR EC50为0.3253μM,且HDR TOP%为24.41。
实施例5:在ECmax下基因编辑动力学的测定
为了研究在EC max处的基因编辑动力学,用spCAS9 mRNA,AAVS1 sgRNA和AAVS1PAM ssODN电穿孔BEC,然后在不同时间与10μM化合物1一起温育或不处理(对照)。通过使用TIDE测定法确定基因编辑率,并以HDR和NHEJ的百分比表示。10μM为化合物1的最大增强浓度(ECmax)。
图5显示在HDR与NHEJ事件之间存在紧密反相关性。
实施例6:在EC50下基因编辑动力学的测定
用pCAS9 mRNA,AAVS1 sgRNA和AAVS1 PAM ssODN电穿孔BEC,然后在不同时间与0.7μM化合物1一起温育或未经处理(对照)。通过使用TIDE测定法确定基因编辑率,并以HDR和NHEJ的百分比表示。0.7μM为化合物1的增强浓度50(EC50)。图6示例DNA-PK抑制对BEC中HDR和NHEJ的时程。
实施例7:当基因编辑组分通过BEC中脂质介导的转染递送时DNA-PK抑制剂改善HDR比例
为了研究脂质介导的转染的效果,用spCAS9 mRNA,AAVS1 sgRNA和AAVS1 PAMssODN转染BEC,然后与不同浓度的化合物1一起温育或不进行处理(对照)。转染后72小时,通过使用TIDE测定法确定基因编辑率。图7显示随通过基于脂质的转染递送的化合物1的浓度增加,HDR效率提高。
总结:
将DNA-PK抑制剂添加至不同细胞类型和基因座的结果表明,跨细胞类型和基因座的HDR显著增强。在多种细胞类型中已显示出HDR基因编辑的增强,包括BEC,iPSC,CD34+HPSC(3种独立的供体)。已经在包括AAVS1.1,NaV1.7的多个基因座中显示了HDR基因编辑的增强。实验结果还证实,基于脂质的和电穿孔的递送是有效的。电穿孔的例子包括BEC,iPSC,CD34+HPSC和在BEC中使用基于脂质的递送系统进行递送。通过基因座,实验条件和细胞类型观察到HDR和NHEJ事件之间的紧密反相关性。
总结表:DNA-PK抑制剂改善HDR驱动的基因编辑
等效方案
尽管已经参照本公开的优选实施方案具体示出和描述了本公开,但是本领域技术人员将理解,在不脱离如所附权利要求所定义的本公开的精神和范围的情况下,可以在形式和细节上进行各种改变。采用不超过常规的实验,本领域技术人员将认识到或能够确定本文具体描述的本公开的具体实施方案的许多等效方案。这样的等同方案旨在被包括在权利要求的范围内。
Claims (41)
1.式(I)的化合物
其中m和n独立地为1或2;
X为O;
Y为价键,O或NR;其中R为H或C1-C4烷基;
R1为C1-C4烷基;
R2为
a)5-或6-元的包含一个或两个选自N,O和S的杂原子的杂芳基环,其中所述杂芳基环可以被0,1,2或3个取代基R3取代,取代基R3独立地选自CN,卤素,C1-C4-烷基,C3-C6环烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基,C(=O)NHR1’,和5-或6-元杂环烷基或杂芳基环,其中每个环包含1,2或3个选自N,O和S的杂原子;其中R1’为C1-C4烷基;或
b)COOR4,其中R4为C1-C4-烷基或苄基;
其中C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基和C1-C4-卤代烷氧基各自可以进一步被OR5或NR6R7取代,其中R5,R6和R7的每一个独立地为H,C1-C4烷基或C3-C6环烷基;或其中R6和R7与它们所连接的氮原子一起形成饱和5-或6-元环,其可以包含0或1个另外的选自N,O和S的杂原子,且其中所述环可以进一步被C1-C4-烷基取代;
环A选自:
其中W为N或CR3’;且Z为O或S;其中R3’为H或C1-C4烷基。
2.权利要求1的化合物,其中
R2为5-或6-元的包含一个或两个选自N,O和S的杂原子的杂芳基环,其中所述杂芳基环可以被0,1或2个取代基R3取代,取代基R3独立地选自CN,卤素,C1-C4-烷基或C3-C6-环烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基和C(=O)NHR1’,其中R1’为C1-C4-烷基。
3.权利要求1的化合物,其中R2为:
其中#表示R2连接至式(I)的化合物的其余部分的位置;且
o为0,1或2。
4.权利要求1的化合物,其中式(I)的化合物由结构式(II),结构式(II’),结构式(II”)或结构式(II”’)表示:
5.权利要求1的化合物,其中m和n的每一个为2。
6.权利要求1的化合物,其中R1为甲基。
7.权利要求1的化合物,其中R2为:
8.权利要求1的化合物,其中m和n的每一个为2,Y为价键,R1为甲基,R2为COOR4,且R4为C1-C4-烷基或苄基。
9.权利要求1的化合物,其中A为
10.权利要求1的化合物,其中A为
11.权利要求1的化合物,其中A为
12.权利要求1的化合物,其中A为
13.权利要求1的化合物,其中式(I)的化合物由结构式(III),结构式(III’),结构式(III”)或结构式(III”’)表示:
14.权利要求1的化合物,其中o为0,1或2,且R3各自独立地选自CN,卤素,NO2,C1-C2-烷基,C1-C4-卤代烷基,C1-C2-烷氧基,C1-C2-卤代烷氧基和C(=O)NHR1’,其中R1’为C1-C2烷基。
15.权利要求1的化合物,其选自如下化合物:
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16.基因组编辑系统和权利要求1的化合物或其药学上可接受的盐在制备用于编辑一种或多种细胞的一种或多种靶基因组区域的试剂盒中的用途,其中所述基因组编辑系统包含至少一种核酸内切酶组分和至少一种基因组靶向元件。
17.基因组编辑系统和权利要求1的化合物或其药学上可接受的盐在制备试剂盒中的用途,所述试剂盒用于至少部分通过同源介导修复(HDR)途径修复一种或多种细胞的一种或多种靶基因组区域中的DNA断裂,其中所述基因组编辑系统包含至少一种核酸内切酶组分和至少一种基因组靶向元件。
18.基因组编辑系统和权利要求1的化合物或其药学上可接受的盐在制备试剂盒中的用途,所述试剂盒用于抑制或阻抑通过非同源末端连接(NHEJ)途径修复一种或多种细胞的一种或多种靶基因组区域中的DNA断裂,其中所述基因组编辑系统包含至少一种核酸内切酶组分和至少一种基因组靶向元件。
19.基因组编辑系统和权利要求1的化合物或其药学上可接受的盐在制备试剂盒中的用途,所述试剂盒用于调节与靶基因相关的下游基因和/或蛋白质的表达,其中所述基因组编辑系统包含至少一种核酸内切酶组分和至少一种基因组靶向元件。
20.权利要求16的用途,其中所述试剂盒被配制成使得与在除了不使用所述化合物之外其他方面都相同的一种或多种细胞中的情况相比,编辑所述一种或多种细胞中所述靶基因组区域的效率提高。
21.权利要求17的用途,其中所述试剂盒被配制成使得与在除了不使用所述化合物之外其他方面都相同的一种或多种细胞中的情况相比,通过HDR途径修复所述一种或多种细胞中所述靶基因组区域处的DNA断裂的效率提高。
22.权利要求18的用途,其中所述试剂盒被配制成使得与在除了不使用所述化合物之外其他方面都相同的一种或多种细胞中的情况相比,抑制或阻抑通过NHEJ途径修复所述一种或多种细胞中所述靶基因组区域处的DNA断裂的效率提高。
23.权利要求19的用途,其中所述试剂盒被配制成使得与施用前所述一种或多种细胞中的基线表达水平相比,与所述靶基因相关的下游基因和/或蛋白质的表达提高、降低或者消除。
24.权利要求16的用途,其中使所述细胞在S或G2细胞周期阶段同步化。
25.权利要求16的用途,其中所述试剂盒被配制成使得施用或接触所述化合物的一种或多种细胞与尚未施用或接触所述化合物的一种或多种细胞相比具有提高的存活率。
26.权利要求16的用途,其中所述试剂盒被配置成将所述基因组编辑系统和所述化合物同时或依次施用到所述一种或多种细胞中。
27.权利要求16的用途,其中所述一种或多种细胞为培养细胞,生物体内的体内细胞,或来自生物体的离体细胞。
28.权利要求16的用途,其中所述基因组编辑系统选自基于兆核酸酶的系统,基于锌指核酸酶(ZFN)的系统,基于转录激活因子样效应物的核酸酶(TALEN)系统,基于CRISPR的系统或基于NgAgo的系统。
29.权利要求28的用途,其中所述基因组编辑系统为基于CRISPR的系统。
30.权利要求29的用途,其中所述基于CRISPR的系统为CRISPR-Cas系统或CRISPR-Cpf系统。
31.权利要求30的用途,其中所述基于CRISPR的系统为CRISPR-Cas系统,且其中所述CRISPR-Cas系统包括:(a)至少一种向导RNA元件,其包括:(i)包含与在一种或多种靶基因组区域处的核苷酸序列互补的核苷酸序列的靶向物RNA或包含编码所述靶向物RNA的核苷酸序列的核酸;和(ii)包含能够与所述靶向物RNA杂交的核苷酸序列的激活物RNA或包含编码所述激活物RNA的核苷酸序列的核酸;和(b)包含Cas蛋白质的Cas蛋白质元件或包含编码所述Cas蛋白质的核苷酸序列的核酸。
32.权利要求31的用途,其中所述靶向物RNA和激活物RNA融合为单一分子。
33.权利要求31的用途,其中所述Cas蛋白质为II型Cas9蛋白质。
34.权利要求33的用途,其中所述Cas9蛋白质为SaCas9,SpCas9,SpCas9n,Cas9-HF,Cas9-H840A,FokI-dCas9或D10A切口酶或其任意组合。
35.权利要求30的用途,其中所述基于CRISPR的系统为CRISPR-Cpf系统,且其中所述CRISPR-Cpf系统包括:(a)至少一种向导RNA元件,或包含编码所述向导RNA元件的核苷酸序列的核酸,所述向导RNA包含靶向物RNA,所述靶向物RNA包含与在一种或多种靶基因组区域处的核苷酸序列互补的核苷酸序列;和(b)包含Cpf蛋白质的Cpf蛋白质元件,或包含编码所述Cpf蛋白质的核苷酸序列的核酸。
36.权利要求16的用途,其中所述试剂盒配置成通过一种或多种载体,合成RNA或纳米制剂递送所述基因组编辑系统。
37.用于编辑一种或多种靶基因组区域的试剂盒或组合物,包含:
基因组编辑系统;和权利要求1的化合物或其药学上可接受的盐,其中所述基因组编辑系统包含至少一种核酸内切酶组分和至少一种基因组靶向元件。
38.药物组合物,包含权利要求1的化合物和药学上可接受的赋形剂。
39.权利要求1的化合物或包含所述化合物的药物组合物在制备用于使细胞对诱导DNA损伤的治疗剂或疾病状态敏感的药物中的用途。
40.权利要求1的化合物或包含所述化合物的药物组合物在制备用于增强用于治疗患者癌症的治疗方案的药物中的用途。
41.权利要求1的化合物或包含所述化合物的药物组合物在制备用于治疗患者癌症或抑制患者癌细胞生长的药物中的用途,所述药物是单独施用或者是与一种或多种另外的治疗剂组合施用。
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