CN101252931A - 用于治疗癌症的4-苯胺基-3-喹啉甲腈 - Google Patents
用于治疗癌症的4-苯胺基-3-喹啉甲腈 Download PDFInfo
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Abstract
本发明涉及一种使用式(I)化合物或其药学上可接受的盐来预防、治疗和/或抑制癌症的方法。本发明还涉及含有式(I)化合物的药物组合物。
Description
发明背景
技术领域
本发明涉及一种使用4-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈(SKI-606),式(I)化合物治疗癌症的方法和含有相同化合物的组合物。
背景技术
多种4-苯胺-3-喹啉甲腈衍生物显示出具有抗肿瘤活性,这使得它们作为化疗试剂用于治疗多种癌症,包括胰腺癌、淋巴癌和前列腺癌。美国专利6002008、6384051、6432979和6617333公开了一定的4-苯胺基-3-喹啉甲腈衍生物显示出具有抗肿瘤活性。
酪氨酸蛋白激酶由功能上相关的受体和非受体组成,可通过特定酪氨酸残基的磷酸化作用发信号给酶以调节细胞生长、活化、区分、发展和转化。受体酪氨酸激酶,如表皮生长因子受体(EGFR)由细胞外配合体结合域、一个单独的横跨膜的领域和一个细胞内酪氨酸激酶域组成。非受体酪氨酸激酶,如Src和Abl是可溶性细胞质酶具有多重调整和蛋白-结合域。
Src酪氨酸激酶家族是一组通过功能和序列相似度定义的非受体酪氨酸激酶。这个家族的三个成员被广泛表达:Src,Yes和FynB。其它6个成员,LcK,Lyn,FynT,Fgr,Hck和Blk,在造血细胞中显著表达。对于非受体酪氨酸蛋白激酶的结构和功能的深度评论和它们在人类癌症中的相关性已经被公开。
Src非受体酪氨酸蛋白激酶是Src家族的原型。Src是由生长因子受体和G-蛋白耦合受体调节的路径的下位组分,被认为可用于调整来自于这些不同路径的信号。已知被Src家族激酶磷酸化的细胞内靶向蛋白的名单是巨大的并持续增长,包括粘连激酶、焦点粘连蛋白(FAK)和其它许多。
Src在多数癌包括大多数的胰腺癌、黑素瘤、头颈癌和卵巢癌中被向上调节。Src在前列腺肿瘤系中也被激活。Src mRNA水平在人类腮腺肿瘤中高于正常组织样本。巴雷特食道和食道癌也过分表达Src。
既然c-Src酪氨酸激酶在大多数人类癌症中是恶性细胞行为的决定因素,我们就试着去确定抑制c-Src在胰腺癌化学敏感性表达的作用。
基于上述观察,抑制Src的化合物可能在治疗具有这些或其它癌症的病人有效。4-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈已经被证实在预防、治疗或抑制上述原则的癌症上有效。
发明概述
本发明涉及一种预防、治疗或抑制癌症的方法,所述方法包括给予治疗有效量的式
(I)化合物,
4-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈,或其药学上可接受的盐。
本发明也涉及一种治疗胰腺癌的方法,所述方法包括联合给予治疗有效量的式(I)化合物或其药学上可接受的盐与吉西他滨或其药学上可接受的盐。
本发明的另一方面是含有治疗有效量的式(I)化合物或其药学上可接受的盐和药学上可接受的载体的药物组合物。
附图简述
图1.显示头和颈系HN5对4-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈的反应。
发明详述
术语“癌症”指的是由异常和不可控制的细胞分裂所致的任何恶性增长或肿瘤。它可能通过淋巴系统或血流扩散到身体的其它部位。本申请描述的治疗癌症的方法的目的,癌症包括胰腺、淋巴和前列腺癌。
药学上可接受的盐,例如,衍生于有机和无机酸如:醋酸、乳酸、羧酸、柠檬酸、苯乙烯酸、酒石酸、琥珀酸、富马酸、马来酸、扁桃酸、苹果酸、酢浆草酸、丙酸、盐酸、氢溴酸、磷酸、硝石酸、硫酸、乙二醇酸、甲磺酸、乙磺酸、甲苯磺酸、水杨酸、安息香酸和相似的已知可接受的酸。
式(I)化合物可口服,通过腹膜内、肌内或静脉注射、输液、脂质体介导给予、局部、鼻、肛门、阴道、舌下、尿道、真皮、膜内、眼睛或耳给予。为了获得式(I)化合物的持续供应,优选化合物是单元剂量形式。合适的单元剂量形式包括片剂、胶囊剂和在小袋或安瓿中的粉末。这些单元剂量形式可含有0.1至300mg式(I)化合物,优选2至100mg。进一步优选单元剂量形式含有50至150mg式(I)化合物。式(I)化合物可口服给予。一天给予1至6次,通常一天1至4次。有效量为本领域技术人员已知;也将依赖于化合物的形式。本领域技术人员常规可通过经验活性测试来确定化合物在生物鉴定中的生物活性以此来确定给予的剂量。
本发明也涉及一种含有治疗有效量的44-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈,式(I)化合物,或其药学上可接受的盐,和药学上可接受的载体的药物组合物。载体可为,例如稀释剂、气雾剂、局部载体、水性溶液、非水性溶液或固体载体。载体可为聚合物或牙膏。本发明中的载体包含药学上可接受的任意标准载体,如磷酸盐缓冲溶液、醋酸盐缓冲溶液、水、乳剂如油/水乳剂或甘油三酸酯乳剂,多种润湿剂,片剂,包衣片剂和胶囊剂。含有式(I)化合物的组合物可与常规辅料制剂,如填充剂、崩解剂、粘合剂、润滑剂、矫味剂或颜色添加剂。
当经口或局部给予时,这些化合物可通过不同的载体给予个体。特别地,这些载体含有辅料如淀粉、奶、糖、特定种类的粘土、凝胶、硬脂酸、滑石、植物脂肪或油、树脂或乙二醇。特定的载体根据需要的给予方式来选择,如,磷酸盐缓冲溶液(PBS)可用于静脉或系统给予,植物脂肪、奶油、药膏、油膏或凝胶可用于局部给予。
式(I)化合物可与适当的稀释剂、防腐剂、增溶剂、乳化剂、用于治疗或预防肿瘤的辅料和/或载体一起给予。这些组合物是液体或冻干的或别的方式干燥的剂型并且包含含有多种缓冲成分的辅料(例如,Tris-HCl、醋酸盐、磷酸盐),PH和离子强度,添加剂如白蛋白或白凝胶以防止表面吸收,清洁剂(例如,吐温20,吐温80,普郎尼克F68,胆酸盐),增溶剂(例如,甘油,聚乙烯丙三醇),抗氧化剂(例如抗坏血酸、钠),防腐剂(例如,噻汞撒、苯甲醇、),膨胀剂或张力修饰剂(例如,乳糖,甘露醇),聚合物共价组合如聚乙二醇、配位金属离子、或化合物引入水凝胶或脂质体的微粒制剂,微乳,微囊、单层或多层囊,红细胞血影或球芽。这些组合物将会影响化合物或组合物的物理状态、溶解度、稳定性、体内释放率和体内清楚率。组合物的选择将决定与可治疗或预防肿瘤的化合物的物理和化学性质。
式(I)化合物可通过在一段时间可持续释放化合物的胶囊来局部给予。控释或缓释组合物包括在亲脂性不为的制剂(例如,脂肪酸、蜡、油)。
本发明进一步提供了一种使用式(I)化合物作为活性物质预防、治疗和/或抑制癌症的方法。基于在此呈现和得到的结果,SKI-606可用于预防、治疗或抑制癌症通过抑制恶性细胞的增殖。SKI-606抑制Src催化的细胞内蛋白质的磷酸化和细胞增殖。因此,给予人治疗有效量的SKI-606可预防或抑制癌症的形成通过抑制增殖,或可治疗已得癌症病人通过防止或抑制肿瘤的进一步增长和/或使肿瘤尺寸变小或根除。出于本发明的目的,术语“抑制”指的是延迟、阻止或停止恶性细胞增殖,推测通过阻止或抑制Src催化的磷酸化作用。出于本发明的目的属于“阻止”指的是通过预防性治疗转移或阻止恶性或肿瘤性增长的持续,或阻止、抑制或终止疾病的进一步进行。出于本发明的目的属于“治疗”指的是给予有需要的病人治疗有效量的SKI-606以预防性地防止癌症的发展,抑制或终止癌症的进展,或恶性或肿瘤性生长,逆转癌症的发展,或恶性或肿瘤性生长,或根除癌症,或恶性或肿瘤性生长。
本发明进一步提供一种治疗人类癌症的方法,包括给予感染个体治疗有效量的4-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈,其药学上可接受的盐,或含有相同化合物的药物组合物。提供给病人的剂量将会依据给予什么、给予的目的,给予的形式诸如此类而改变。“治疗有效量”是足够以治愈或改善癌症症状的量。
式(I)化合物可单独使用或与其它可用于治疗癌症的化合物合用。这些化合物包括但不限于甲磺酸伊马替尼(GLEEVEC)、羟基脲、IFN-á、细胞毒害剂、化疗试剂、NSAIDS,吉西他滨EGFR抑制剂、MEK抑制剂、法呢酰基转移酶、吉西他滨、或avastin或渥曼青霉素或其药学上可接受的盐。
本发明方法的一个优选的实施例包括给予治疗有效量的式(I)化合物与治疗有效量的吉西他滨或avastin。更优选地式(I)化合物与吉西他滨一起给药。
本发明方法的另一个优选的实施例包括给予治疗有效量的式(I)化合物与治疗有效量的吉西他滨和avastin的联合给药。
本发明方法的另一个优选的实施例包括联合给予式(I)化合物或其药学上可接受的盐与吉西他滨和avastin或其药学上可接受的盐以治疗胰腺癌。
一个实施本发明方法和/或用于本发明组合物的优选化合物是4-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈和其药学上可接受的盐。
式(I)化合物根据美国专利6002008的方法制备,这些方法在这里被引用作为参考。
反应在溶剂中进行,该溶剂适于使用的试剂和原料以及进行的转化作用。有机合成领域技术人员公知存在于分子中的多种功能必须与被提议的化学转化作用相一致。当非特定时,合成步骤的顺序、保护基团和去保护条件的选择对本领域技术人员是显而易见的。此外,在一些例子中,起始原料的取代基与一定反应条件不相容。与给定取代基相关的限定对本领域技术人员是显而易见的。适宜时反应在惰性气体条件下进行。
式I化合物由7-(3-氯丙氧基)-4-[(2,4-二氯-5-甲氧苯基)氨基]-6-甲氧基-3-喹啉甲腈与N-甲基哌嗪在纯的碘化钠或在溶剂如乙二醇二甲基醚的碘化钠存在下反应制得。这些化合物的制备已经在文献[Boschelli,D.H.,等人,J.Med.Chem.,44,3965(2001)]被报道,在这里引用作为参考。
附图详述
图1.头和颈肿瘤系HN5对4-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈的反应。缺乏血浆的HN5细胞用化合物处理4小时,之后加入EGF至50ng/ml,保持10分钟。分析溶解产物的Stat3Y705、c-Cbl Y731和Y774以及小窝蛋白Y14的磷酸化作用。结果证实小窝蛋白Y14、c-Cbl Y731和Stat3 Y705的磷酸化作用被4-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈减少。
酶分析
式(I)化合物抑制靶向肽的Src催化的磷酸化作用。4-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈抑制同类酶分析(FRET/Lance格式)中Src催化的磷酸化作用,具有IC50值为3.5nM。4-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈与多种酶的活性比较见表1。
Src和Abl激酶Lance分析:重组人类Src酶得于PanVera(P3044)。相应于Cdk1的6-20残基的肽被用作src酶分析的底物(生物素-KVEKIGEGTYGVVYK-COOH)。野生型c-Abl和v-Abl分别购买于Panvera(P3049)和Calbiochem(#102555)。用于Abl激酶分析的肽得于Synpep(生物素-NH-KEEEAIYAAPFAKKK-COOH)。对Src和Abl激酶分析而言,同类荧光共振能量转移激酶分析使用铕/APC检测格式(LANCE,Perkin Elmer)进行。Src酶(10ng)或Abl酶(2.5ng c-Abl,2.5ng v-Abl)与肽混合(对两个底物肽最后浓度均为2μM),50mM Hepes(pH 7.5),10mM MgCl2,20ug/ml BSA,和0.001%Brij-35(Sigma)。加入化合物至最后DMSO浓度为1%,对Src在37℃培育70分钟,对Abl在27℃培育30分钟。反应用EDTA终止,最后浓度为30mM EDTA/25mM Hepes(pH 7.5)/10μg/ml BSA。混合物与Eu-标记抗体PT66(Perkin Elmer,AD0068)和-APC(Perkin Elmer,CR130-100)在50mM Hepes(pH7.5)/20μg/ml BSA中结合,根据生产商的说明培育30分钟。反应用Wallac Victor监测,激发在340nm,释放在665nm。数据用LSW数据分析插件程序为Excel(Microsoft)分析。
PKA,PKC,S6激酶,CAMKII and p38激酶分析
分析用于PKA(Upstate #14- 114),PKC(Upstate #14-232)和S6K(Upstate#14-333)的激酶分析。ELISA格式用于CAMK-II(Upstate #14-217和p38(重组蛋白在室内生产和纯化)
SCINTIPLATE分析
96孔SA Cov Scintiplate(#1450-551)板在酶分析实验之前用PBS(0.1%Triton X100)冲洗4次。
·60μl混合物*(见下表)
·20μl化合物(在10%DMSO里)20分钟预培养
·20μl底物1uM(见下表)
下表所示体积用于96孔板
激酶 | PKA | PKC | S6K |
#孔数 | 96.0 | 96.0 | 96.0 |
#反应 | 110.0 | 110.0 | 110.0 |
总体积 | 6600.0 | 6600.0 | 6600.0 |
水 | 5452.5 | 5321.0 | 5343 |
10×缓冲液 | 1100.0 | 1100.0 | 1100.0 |
DTT 1M | 30.0 | 30.0 | 30.8 |
ATP 1mM | 11.0 | 11.0 | 11.0 |
ATP33P | 6.0 | 6.0 | 6.0 |
激酶 | 0.55 | 22 | 110 |
μl/反应 | 0.005 | 0.2 | 1 |
脂质活化剂 | 110 | ||
酶底物(1μM) | 1463 | 1463 | 1464 |
反应时间 | 20’ | 30’ | 80’ |
肽1323(LSP16Bio:Bio-RTPKLARQASIELPSM:LSP-1 aa 243-258.Ser252是磷酸化作用位点)
肽1463(PKA底物:Bio-GRTGRRNSI)
肽1464(S6K底物:Bio-RRRLSSLRA)
底物加入时反应开始。
1-停止反应根据表中所示的时间使用20μl的0.5M EDTA。在反应开始以后持续培育板不超过一小时,如果是S6K则为80分钟。
2-洗涤(PBS+0.1%TritonX100)洗6次(250λ/孔)
3-计数(Wallac Trilux计数器)
IIELISA
接下来是ELISAs中使用的激酶的分析条件。p38用显性的活性变种MKK6激活。
体积(毫升) | p38 | CAMKII |
#孔数 | 96.0 | 96 |
#反应 | 110.0 | 110.0 |
总体积 | 6600.0 | 6600.0 |
水 | 5357.3 | 5464.5 |
10*缓冲液 | 1100.0 | 1100.0 |
DTT 1M | 30.0 | 30.0 |
100mMATP | 2.8 | 3.3 |
激酶(体积或最终浓缩物) | 60nM | 2 |
μl/反应 | 0.02 | |
钙调节蛋白(1mg/ml) | 44 | |
CaCl2(1M) | 11 | |
1738 | 1323 | |
反应时间 | 30’ | 30’ |
1738肽(MK2T334:Bio-QSTKVPQTPLHTSRVL)
1895肽(胃泌素1-17:Bio-KKEGPWLEEEEEAYGWMD)
激酶分析预分析以相同的形式进行:见上述步骤1至3。检测板是TMuncMaxiSorb,用以1∶400比例在PBS中的Amersham山羊抗-GST抗体以100μl/孔涂层2小时。反应板是Costar板,在0.1%凝胶时用阻止缓冲液阻止2小时,每孔200μl。
如下准备ERK/ADB混合物:
每毫升ADB10μl GST-ERK2
将60μl ERK/ADB混合物加入阴性对照孔(12行)
准备MEK/ERK/ADB混合物(MEA)通过添加活性MEK1
在分析板中加入60μl//孔MEA
加入20μl cmpd 10%DMSO
准备5xATP/ADB通过加入500uMATPtoADB
每孔20μl ATP/ADB以开始反应。30C培育1小时。
每孔中加入20μl 0.5M EDTA停止反应。
4-含磷肽检测:
抗体:为了检测磷酸化肽,亲和力纯化多克隆磷-特异抗体60521和64273分别代替1323和1738使用。
为了分别检测磷酸化1323和1738,加入100μl终止性缓冲液,补充纯化的60521(0.46mg/ml)1%BSA1∶20000和抗兔子-Eu(PE#AD0105)1∶4000或纯化的642731∶4000和抗-兔子-Eu at 1∶2000。
为了检测磷酸化的1895,加入100μl终止性缓冲液,补充1%BSA具有抗-含磷酪氨酸PT100(细胞信号#9411)1∶1000和抗-小鼠-Eu(PE#AD0124)。
培育1小时RT(混合器)
洗6×250μl PBS 0.1%Tween 20
加入100μl提高溶液(Wallac Cat# 1244-105)
培育10分钟RT(混合器)
用VictorII读(HTS铕草案在我们的阅读机)
缓冲液
激酶缓冲液10X
200mM Hepes pH 7.5,100mM MgCl2
ADB IX:
20mM MOPS 7.2,25mM β-甘油磷酸,5mM EGTA,1mM原矾酸钠,20mM MgCl2,1mMDTT
终止性缓冲液:
10mM MOPS 7.5,150mM NaCl,0.05%Tween 20,
0.1% Gelatin,0.02%NaN3
Raf/MEK激酶ELISA
试剂:sf9昆虫细胞溶解产物含有全长6his-标签的重组人类c-Raf。(特异活性:~200U/ml)。人类非活性Mek-1-GST和人类GST-MAP激酶(重组蛋白产于E.coli)。
Rafl激酶阶式分析步骤:
Raf-1(c-Raf)用于磷酸化和激活非活性GST-MEK1,然后可磷酸化和激活非活性p42GST-MAPK,接下来通过购于Sigma(cat.# 77439219041)的特异磷抗体来测量TEY序列(aa′s 202-204)的磷酸化作用。
激酶:分析草案
原料溶液:
Raf分析
1.分析稀释缓冲液(ADB):20mM MOPS,PH 7.2,25mM β-磷酸甘油,5mMEGTA,1mM原矾酸钠,1mM二硫苏糖醇
2.镁/ATP混合物:500μM冷ATP和75mM氯化镁在ADB中
3.活性激酶:人类活性c-Raf:在每个分析0.4U点使用
4.非活性GST-MEK1:在每个分析0.1μg点使用
5.非活性GST-p42MAP激酶:在每个分析1.0μg点使用
ELISA
1.TBST-Tris(50mM,pH 7.5),NaCl(150mM),Tween-20(0.05%)
2.Superblock(Perce)
3.抗-GST Ab(Pharmacia)
4.抗-Phospho MAPK(Sigma)
5.抗-小鼠Ab/铕缀合物(Wallac)
分析步骤:
第一步:GST-MEK和GST-MAPK的c-Raf依赖性活化
1.每个分析物中加入20ml ADB(例如.96孔板的每孔)
2.在ADB中加入10ml 0.5mM冷ATP和75mM氯化镁
3.加入2ml c-Raf(0.4U/分析物),与1.6ml非活性MEKl(0.4mg/分析物)共轭
4.加入4ml非活性GST-p42MAP激酶(1.0mg/分析物)
5.在震动培育器中30℃培育60分钟。
6.转移混合物至抗-GST Ab涂层的96孔板(GST涂层板,用PierceSuperblock终止)
7.在振动的培育器中在30℃培育60分钟
8.用TBST洗涤3次,加入抗-磷MAPK(Sigma)(1∶3000)
9.在振动的培育器中在30℃培育60分钟
10.用TBST洗涤3次,加入抗-小鼠Ab/铕缀合物(Wallac)(1∶500)
11.在振动的培育器中在30℃培育60分钟
12.用TBST洗涤3次,在Wallac Victor模式板阅读器下读板。
KDR激酶分析
原料
1)Nunc MaxiSorb 96F ELISA VWR 62409-024
2)肽底物:聚(Glu4-Tyr),Sigma(P-0275):在水中准备5mg/ml原料
3)TBS:BupH TBS Pierce(#28376);25mM Tris pH 7.2,150mM NaCl最后
4)TBST:冲洗缓冲液=TBS+0.05%Tween-20:对于500ml:TBS(上述)+2.5ml 10%Tween(制于TBS)
5)化合物:制备于DMSO,存储化合物在-80C
6)5XKDR激酶缓冲液
5X 1X 50ml的5X
20mM HEPES pH 7.4 4mM HEPES 1ml 1M HEPES
5mMMnCl2 1mMMnCl2 1.25ml 200mMMnCl2
100uMNa3VO4 20uMNa3VO4 0.1ml 50mMNa3VO4
7)酶稀释液:0.1%BSA在4mMHEPES中,pH 7.4
8)2.5XATP[10uM最后]/MgCl2HEPES溶液:
2.5Xcone. rxn中的IX 10ml的2.5X
25uMATP 10uMATP 0.25ml1mMATP
25mMMgCl2 10mMMgCl2 1ml250mMMgCl2
10mM HEPES 4mM HEPES 0.1ml1M HEPES
8.65ml水
9)HEPES2.5X/MgCl2溶液(没有ATP):
2.5Xconc. rxn中的IX 5ml 2.5X
25mMMgCl2 10mMMgCl2 0.5ml 250mMMgCl2
10mMHEPES 4mMHEPES 0.05ml 1MHEPES
4.45ml水
10)ATP(FW 551):AmershamPharmacia#27-2056-01(25umol):100mM溶液
11)250mMMgCl2:SigmaM-8266,无水,FW95.21;1.19g/50ml水
12)分析缓冲液:PerkinElmer 1244-106
13)Eu-抗-PY(PT66):PerkinElmer AD0040(50ug,Sigma克隆PT66,抗-磷酪氨酸抗体)
14)增加溶液:PerkinElmer 1244-105
方法:
1.往Nunc MaxiSorb板加入TBS的25ug/ml的100μl聚(Glu4-Tyr)肽.培育1-4小时在RT.[或者:改变最后聚(Glu4-Tyr)肽浓度从~1-50ug/ml;或使用聚(Glu6-Ala3-Tyr)肽]
2.冲洗含肽的孔3次,使用200μl TBS
3.往每个孔中加入:29μl KDR激酶混合物[=KDR-IC+5X KDR激酶缓冲液+水(混合1∶1∶0.9)]结合10μl纯化的KDR-IC制剂,稀释的(ie,1∶5 to1∶20根据制剂而定)在0.1%BSA/4mM HEPES+10μl 5X KDR激酶缓冲液+9μl水PER反应孔。如果使用较多或较少的化合物容积则相应地调整水的容积。这些添加物可用Matrix多量吸管操作。
4.往每个孔中加入1μl化合物(50X DMSO溶液鉴于想要的最后的化合物浓度)(TV=30μl在这个点)
5.在RT培育约15分钟以使化合物与酶结合
6.往样品孔中加入20μl 2.5XATP/MgCl2/HEPES溶液,对KDR而言,反应的线性范围是~1-100nM,所以使用10uM.[或者:ATP最后的浓度可改变;在一些反应中使用没有ATP的2.5X MgCl2/HEPES,以确定每个酶制剂可行的低端范围]。
7.室温培育40分钟。[或者:分析反应30至60分钟;或37C反应温度,虽然这些与现在的KDR批次差异最小]
8.用200μl TBST冲洗板3次
9.加入在分析缓冲液中的1∶2000的75μl Eu-PY
10.培育45-60min@RT
11.用200μl TBST冲洗板3次
12.加入100μl的增加溶液(与RT平衡)
13.在VICTOR-TR-荧光板阅读器下读板
天然铕(荧光)读数转换为百分比抑制和/或基于未处理(不含化合物)对照孔的使用Excel模板的IC50值
表14-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈抗各种酶的活性
IC50(μM)
p38 0.95
CAMKII 6.25
PKA 5.03
PKC-a 1.47
P70S6K 6.09
KDR 7.00
Raf/mek 0.50
Src 0.0035
c-Abl 0.001
IC50=达到50%抑制的浓度
细胞增殖数据
式(I)化合物式一种Src激酶家族激酶和Abl激酶的选择性抑制剂。基于细胞的分析实验液用于检测4-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈的选择性。大鼠纤维原细胞过分表达一种致瘤形式的Src,其中人类c-Src的催化域被插入v-Src催化域以产生v-Src/人类c-Src融合蛋白。也可使用FynB,Lck,Lyn,和Hck,其它Src家族成员进行相似的取代。此外,表达致瘤形式的v-Abl,类胰岛素生长因子-I受体,纤维原细胞生长因子受体,血小板生长因子受体和Her2的相同细胞类型也被构建。这些细胞中的化合物活性用固定-独立生长分析来确定,基于通过表达纤维原细胞的致瘤蛋白得到固定-独立。在这些条件下的生长依赖于激酶的活性,激酶活性的抑制会阻止细胞的生长,以此反应出细胞靶向蛋白磷酸化作用的抑制。表2显示4-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈在这些条件下得到的增殖数据。
表2基于激酶依赖性细胞的实验
IC50(μM)
Src 0.1
Lck 0.02
Fyn 0.4
Lyn 0.15
Hck 0.8
v-Abl 0.1
Her2 2
IC50=50%抑制时的浓度
头和颈肿瘤系
式(I)化合物是过分表达Src的头和颈细胞线中肿瘤细胞增殖的潜在的抑制剂。一个具有代表性的增殖概图是4-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈与HN5系,示于图1,与下游靶蛋白磷酸化作用的抑制证据一起。
生物测试程序的说明
标准生长条件:
对于描述于表3中的实验,在用于特定细胞线的标准生长培养基中,在第0天在96孔细胞培养盘的每一孔中放入1000个细胞。第1天加入化合物。相关的细胞数在第4天测定。
细胞滴度测定-Glo方法
细胞滴度测定-Glo发光细胞生存能力测试(Promega#G7573),其中细胞用细胞浓度测定-Glo试剂溶解,短暂激动,在使用用于发光读数的Wallac盘读数器分析之前允许在室温放置30分钟。
MTS分析
一些分析借助于细胞浓度测定96分析来监测(Promega#G3580)。这项分析,在第4天,检测试剂被加入到96孔板,490nN的吸光率被测量到。
SRB分析
SulforhodamineB(SRB)分析用于一定黑素瘤系。在这项分析中,生长基中的血清浓度是5%和培养基体积是0.2ml。在第4天,0.05ml 50%的三氯乙酸加入到培养基中,板允许置于室温1小时。培养基被轻轻倒出,板用水冲洗3次。洗后的板干燥,然后加入0.08ml的SRB试剂(购于Sigma;0.4%SRB在1%醋酸中)。室温中10分钟后,板用1%的醋酸冲洗直到溶液中没有自由的红色残留。结合的SRB试剂用0.15ml 10mM Tris(不加酸)溶解。在混合器中激活5分钟后,吸收率为540nM。
体内研究
所有的动物研究都根据被认可的社会公共机构动物照顾和使用委员会草案进行。肿瘤细胞被悬浮至50百万细胞/ml,0.2ml细胞悬浮液被皮下注射到一只6-7周大的雌裸鼠的腰窝内(Charles River,Wilmington,MA)。一周后肿瘤大于200mm3的小鼠通过腹膜内注射被给予制剂或化合物,剂量为在0.2ml制剂中含有0.5%的甲基纤维素和0.4%的聚山梨酸酯80(Tween80)。
表3总结了对T-细胞白血病、前列腺癌、胰腺癌、黑素瘤和头颈肿瘤系用4-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈处理得到的增殖实验结果。也显示了给予的4-(2,4-二氯-5-甲氧基-苯氨基)-6-甲氧基-7-[3-(4-甲基-哌嗪-1-基)-丙氧基]-喹啉-3-甲腈在裸小鼠中延迟A375黑素瘤皮下肿瘤异种抑制物的生长。
表3
Claims (13)
2. 如权利要求1所述的方法,其中预防、治疗或抑制的癌症是胰腺癌。
3. 如权利要求1所述的方法,其中预防、治疗或抑制的癌症是淋巴癌。
4. 如权利要求1所述的方法,其中预防、治疗或抑制的癌症是前列腺癌。
5. 如权利要求1所述的方法,其中预防、治疗或抑制的癌症是头颈癌。
6. 如权利要求1所述的方法,其中预防、治疗或抑制的癌症是黑素瘤。
8. 如权利要求1所述的方法,其中化合物单独使用或与其它一种或多种用于治疗癌症的化合物联合施用。
9. 如权利要求8所述的方法,其中其它化合物选自甲磺酸伊马替尼、羟基脲、IFN-á、细胞毒害剂、genfitanib、吉西他滨、avastin和渥曼青霉素,或其药学上可接受的盐。
10. 如权利要求9所述的方法,其中其它化合物是吉西他滨。
11. 如权利要求9所述的方法,其中其它化合物是吉西他滨和avastin。
13. 如权利要求12所述的方法,所述方法进一步包括给予avastin或其药学上可接受的盐。
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