CN1921891B - 连接到杯芳烃上的生长因子结合化合物 - Google Patents
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Abstract
本发明公开了具有多个连接到非肽有机骨架上的无环间苯二酸基团的生长因子结合化合物及其药物组合物。还教导了该生长因子结合化合物或生长因子结合组合物的给药和使用方法。这些新型的生长因子结合化合物可用于治疗血管生成、过度细胞增殖、肿瘤生长及其组合,并且抑制生长因子与细胞的结合和磷酸化。
Description
相关申请的交叉参考
本申请要求2004年1月27日提交的美国临时申请第60/539,613号的优先权,其全文(包括任何图、表、核酸序列、氨基酸序列和附图)在此引入作为参考。
本发明是借助政府资助,在National Institute of Health/NationalCancer Institute Grant第CA78038号资助的研究项目下进行的。联邦政府对本发明享有一定的权利。
发明背景
肿瘤生长至体积超过几立方毫米的能力依赖于在这些肿瘤的微环境中新血管的形成(Ferrara,N.Nat Rev Cancer,2002,2:795-803;Kerbel,R.S.Carcinogenesis,2000,21:505-15;Carmeliet,P.和Jain,R.K.Nature,2000,407:249-57;Yancopoulos,G.D.等人Nature,2000,407:242-8)。这种血管生成过程是由肿瘤分泌的几种关键生长因子引发的。这些生长因子不仅在内皮细胞上结合它们的受体并刺激它们的增殖(这引发新血管的形成),还在保持血管完整性的佐细胞(例如周细胞)上结合受体(Ferrara,N.NatRev Cancer,2002,2:795-803;Kerbel,R.S.Carcinogenesis,2000,21:505-15;Carmeliet,P.和Jain,R.K.Nature,2000,407:249-57;Yancopoulos,G.D.等人Nature,2000,407:242-8;Helmlinger,G.,等人Nat Med,1997,3:177-82;Holash,J.等人Science,1999,284:1994-8)。最常被研究的生长因子包括血管内皮生长因子(VEGF)和血小板衍生生长因子(PDGF)。一些研究已经证实,这两种生长因子参与了血管生成过程,其中VEGF主要在引发新血管的形成中发挥关键作用,而PDGF参与了这些血管的维持(Bergers,G.等人J Clin Invest,2003,111:1287-95;Dvorak,H.F.J ClinOncol,2002,20:4368-80;Ferrara,N.Curr Top Microbiol Immunol,1999,237:1-30;Dvorak,H.F.等人Curr Top Microbiol Immunol,1999,237:97-132;Eriksson,U.和Alitalo,K.Curr Top Microbiol Immunol,1999,237:41-57)。
这种观察结果激起了人们对设计抑制VEGF及PDGF功能的方案(其最终目的是抑制血管生成和饿死肿瘤)的兴趣。已采用的方法是基于靶向这些生长因子作用机制中包含的生物化学步骤。这些方法包括使用这些生物因子的抗体来抑制VEGF和PDGF与其各自受体的结合。这些抗体之一,AVASTIN(其靶向VEGF)目前已被批准临床用于转移性结直肠癌患者(Zhang,W.等人Angiogenesis,2002,5:35-44;Ferrara,N.Semin Oncol,2002,29:10-4)。另一方法涉及PDGF和VEGF受体的酪氨酸激酶活性抑制剂的开发,从而抑制这些生长因子引发的下游信号转导途径(Kerbel,R.S.Carcinogenesis,2000,21:505-15;Jain,R.K.Semin Oncol,2002,29:3-9;Morin,M.J.Oncogene,2000,19:6574-83;Miao,R.Q.等人Blood,2002,100:3245-52;Laird,A.D.等人Cancer Res,2000,60:4152-60;Wedge,S.R.等人Cancer Res,2000,60:970-5)。这些试剂多数模拟ATP的结构,并且一些是目前在临床试验中有效的抗癌剂。然而,它们都还没有被FDA批准。
AVASTIN(贝伐单抗(bevacizumab))(其将转移性结直肠癌患者的中位生存期提高5个月)的FDA批准,进一步证实了靶向血管生成过程的方案为一种癌症的治疗方法(Ferrara,N.Semin Oncol,2002,29:10-4)。然而,需要进行更多研究以充分开发该方法。例如,在其他临床试验中,AVASTIN不能延长转移性乳癌患者的寿命。对这种矛盾的活性的一种可能解释在于,晚期转移性乳癌可能通过其他生长因子避开了抗-VEGF血管生成疗法。实际上,对该意见的支持来自临床前研究,其表明早期乳癌主要分泌VEGF,而晚期乳癌还分泌其他生长因子(Relf,M.等人Cancer Res,1997,57:963-9)。此外,在动物胰腺癌模型中,SU5416,一种VEGF受体酪氨酸激酶抑制剂,抑制了胰腺癌的早期发展,但没有抑制晚期发展。更重要地是,在相同模型中用SU6668(其同时抑制VEGF和PDGF受体酪氨酸激酶)进行的治疗,引起晚期胰腺癌在发展晚期的消退(Bergers,G.等人J Clin Invest,2003,111:1287-95),这表明抗-VEGF治疗法的失败可能是由于其仅抑制血管的开始而不能抑制血管维持。对该意见的进一步支持来自最近的研究,其中在成神经细胞瘤细胞移植到小鼠肾脏上的动物模型中,AVASTIN抑制了新血管的生成,但是对于抑制已经形成的血管是无效的(Huang,J.等人Proc Natl Acad Sci美国,2003,100:7785-90)。综上所述,目前对血管生成过程的理解暗示,同时靶向引发血管开始的生长因子(即,VEGF)和维持血管的生长因子(即,PDGF)是比仅靶向一种生长因子更有效的癌症治疗方法。
发明概述
本发明的一个目的是设计一类化合物,其与VEGF和/或PDGF结合,并抑制这些生长因子与其各自的细胞表面受体结合。例如,发现化合物GFB204是VEGF-和PDGF-刺激的其受体酪氨酸激酶磷酸化和信号传导(Erk1/2,Akt和STAT3)的有效和选择性抑制剂。这种试剂还有效地抑制了体外内皮细胞移动和毛细血管网形成,以及在裸鼠异种移植物中体内的血管生成和人类肿瘤生长。
本发明的进一步目的是提供上述类型的化合物的药物组合物及其施用方法。
附图简述
图1显示了本发明的GFB204的结构,其含有连接到非肽有机骨架(scaffold)上的无环间苯二酸基团,以及GFB-111的结构。
图2A-2C表明,GFB204在小鼠成纤维细胞中抑制125I-VEGF和125I-PDGF但不抑制125I-EGF结合到它们的受体上。分别用125I-VEGF、125I-PDGF和125I-EGF(50000cpm/孔)与浓度递增的GFB204一起培养Flk-1/NIH 3T3、NIH 3T3和EGFR/NIH 3T3细胞。在如“材料和方法”中所述,在测定125I计数之前将细胞在4℃培养0.5小时,然后用PBS洗涤三次并用裂解缓冲剂洗涤三次。使用过量冷VEGF、PDGF和EGF获得非特异性结合水平。图2A-2C分别显示了PDGFR、Flk-1和EGFR的特异性结合(%对照)。
图2D和2E表明,当分别在PDGF和VEGF中加入增加量的GFB204时,如生长因子色氨酸所示,GFB-204与PDGF和VEGF结合。通过分别在295纳米和228纳米激发并在334纳米发射,监测荧光。
图3A和3B表明GFB204对生长因子刺激的Erk1、Erk2、Akt和STAT3磷酸化的作用。GFB204抑制了VEGF和PDGF刺激的Flk-1酪氨酸磷酸化和Erk1/Erk2磷酸化(图3A)。用浓度递增的GFB204处理NIH3T3细胞或Flk-1/NIH 3T3细胞5分钟,然后分别用PDGFBB(10纳克/毫升)或VEGF(50纳克/毫升)刺激10分钟。然后将细胞裂解并用磷酸酪氨酸-Flk-1的特异抗体或用对于PDGFR酪氨酸磷酸化的抗-磷酸酪氨酸特异抗体或磷酸(phospho)-Erk1/2的特异抗体进行SDS-PAGE蛋白质印迹。GFB204作用于生长因子刺激的Erk1、Erk2、Akt和STAT3磷酸化(图3B)。在用PDGF(NIH 3T3)、VEGF(Flk-1/NIH 3T3)、EGF(EGFR/NIH 3T3)、bFGF(NIH 3T3)或IGF-1(IGF-1R/NIH 3T3)刺激之前,用GFB204(10μM)处理NIH 3T3、Flk-1/NIH 3T3、IGF-1R/NIH3T3或EGFR/NIH 3T3细胞。然后收获细胞并用磷酸-Erk 1/2、磷酸-Ark和磷酸-STAT3的特异抗体进行SDS-PAGE蛋白质印迹。
图4A-4C显示了GFB204体外对血管生成的作用。GFB204以剂量-反应(dose-response)方式抑制了毛细血管网的形成(图4C)。将人类大脑中动脉内皮细胞(5×104)接种到Matrigel上,并如“材料和方法”中所述在存在(图4B)或不存在(图4A)GFB204的情况下用VEGF培养细胞。
图5A-5C表明,GFB204有效地抑制了体外VEGF依赖型人类大脑内皮细胞移动。使用如“材料和方法”中所述的改良的Boyden chamber测定法评测成人大脑内皮细胞的移动。在外室(outer chamber)中在含2%FBS的介质中加入载体对照物(图5A)或GFB204(图5B),并在培养18小时后测定移动到含GEGF的下室(lower chamber)中的细胞数量(图5C)。
图6表明,GFB204抑制了裸鼠中的A-549异种移植物的生长(图6)。将A-549细胞植入裸鼠胁腹,并在肿瘤达到大约100立方毫米的平均尺寸时,将小鼠随机打乱并用载体(◆)或GFB204以1毫克/千克(■)和5毫克/千克(●)处理,并如“材料和方法”中所述测量肿瘤尺寸。如“材料和方法”中所述,在最后的腹腔注射后两小时,处理肿瘤以便进行CD31IHC染色。
图7A-7B显示了在对照物(图7A)和GFB204(图7B)的最后腹腔注射后两小时处理的肿瘤,如“材料和方法”中所述进行的CD31 IHC染色。如“材料和方法”中所述测定微血管密度的量(400X)。SE,标准误差。图7A和7B微血管计数;图7A=11.3±1.9;图7B=2.6±0.9。
材料和方法
GFB对生长因子依赖型受体酪氨酸磷酸化的抑制。用GFB预处理饥饿的Flk-1/KDR-超表达的NIH 3T3细胞(Flk-1/NIH 3T3)或NIH 3T3细胞5分钟,然后分别用VEGF(50纳克/毫升)或PDGF-BB(10纳克/毫升)刺激10分钟。然后收获细胞并裂解,并通过SDS-PAGE分离来自裂解物的蛋白质并转移到硝化纤维上。然后,对于活化的Flk-1用抗-磷酸-VEGFR抗体(Cell Signaling Technologies,Beverly,MA)或对于活化的PDGFR用抗-磷酸-酪氨酸抗体(4G10,Upstate Biotechnology,Lake Placid,NY)对膜进行免疫印迹。使用Bio-Rad Model GS-700图像光密度仪量化磷酸酪氨酸Flk-1和PDGFR。(Bio-Rad Laboratories,Inc,Hercules,CA)(Blaskovich,M.A.等人Nat Biotechnol,2000,18:1065-70)。
生长因子介导的Erk1/2、Akt和STAT3磷酸化的刺激。用指定浓度的GFB204预处理饥饿的NIH 3T3细胞(PDGF-BB,bFGF)、超表达EGFR(EGFR/NIH 3T3,EGF)、Flk-1(Flk-1/NIH 3T3,VEGF)和IGF-1R NIH3T3(IGF-1R/NIH 3T3,IGF-1)的NIH 3T3细胞5分钟,然后用PDGF-BB(10纳克/毫升)、EGF(100纳克/毫升)、bFGF(50纳克/毫升)、VEGF(50纳克/毫升)和IGF-1(50纳克/毫升)刺激10分钟。在SDS-PAGE凝胶上电泳裂解物,然后移动到硝化纤维上,并如我们之前所述用抗-磷酸化Erk1/Erk2(Cell Signaling Technologies)抗-磷酸化Akt或抗-磷酸化STAT3进行蛋白质印迹(Blaskovich,M.A.等人Cancer Res,2003,63:1270-9)。
125I-生长因子与其受体的结合。如前所述,进行125I-VEGF、125I-PDGF和125I-EGF与它们各自受体的结合测定(Blaskovich,M.A.等人NatBiotechnol,2000,18:1065-70.)。简要地,分别用125I-VEGF、125I-PDGF和125I-EGF(50,000cpm/孔)与浓度递增的GFB204-起培养Flk-1/NIH 3T3细胞、NIH 3T3细胞和EGFR/NIH 3T3细胞。将细胞在4℃培养0.5小时,然后用PBS洗涤三次,并用25mM Tris,pH 8.0,1%Triton-X-100、10%甘油和1%SDS洗涤三次,然后在γ射线计数器(Beckmann Inc.)上测定125I计数。使用过量冷的生长因子获得非特异性结合水平。
毛细血管网形成。在4℃将200微升Matrigel置于24孔培养板的每个孔中,并通过如前所述在37℃孵育来进行聚合(Papadimitriou,E.等人Biochem Biophys Res Commun,2001,282:306-13)。将人类大脑中动脉内皮细胞(5×104)接种到在含有VEGF(20纳克/毫升)的1毫升EBM中的Matrigel上。在存在或不存在图例所示浓度的GFB204的情况下培养细胞。使用10X物镜拍摄每一样品,并使用Image Pro Plus软件(MediaCybernetic,Inc.,MD)量化每张照片中的管状结构的总长度。
人类大脑内皮细胞移动测定法。使用改良的Boyden chamber测定法评测成人大脑内皮细胞的移动(BD BioCoat Matrigel Invasion Chamber)(Papadimitriou,E.等人Biochem Biophys Res Commun,2001,282:306-13)。将细胞以4×104/毫升覆盖在涂有Matrigel基膜基质(basement membrane matrix)薄层的8微米孔径膜上。在外室中,在介质中加入GFB204,并将细胞在下室中在VEGF依赖型条件下培养18小时(VEGF 20纳克/毫升)。用棉签从上表面去除未侵入(non-invading)细胞。然后用4%低聚甲醛固定膜的插入(insert)并用结晶紫染料染色。在随机选定的显微镜视野(10X)中计算移动的细胞数,由此量化移动到过滤器下表面中的细胞数。使用独立样本的学生t-检验分析样本的显著差异。
裸鼠肿瘤异种移植模型中的抗肿瘤活性。按照Institutional AnimalCare and Use Committee(IACUC)程序和准则喂养裸鼠(Charles River,Wilmington,MA)。收获A-549细胞并重悬浮在PBS中,然后如前所述皮下注入8周龄的雌裸鼠的右和左胁腹(10×106细胞/胁腹)(Sun,J.等人Cancer Res,1999,59:4919-26)。当肿瘤达到大约100立方毫米时,动物每天用0.2毫升溶液腹腔给药一次。对照动物接收载体,而处理的动物注射GFB204(1或5毫克/千克/天)。通过如前所述测量长度(l)和宽度(w)并计算体积(V=lw2/2),确定肿瘤体积(Sun,J.等人Cancer Res,1999,59:4919-26)。使用学生t-检验评测对照与处理动物之间的统计显著性。
IHC研究。在抗肿瘤实验的最后一天,在10%中性缓冲福尔马林中提取和固定肿瘤6小时。固定之后,将组织样品加工成石蜡块。由parablocks获得组织切片(4微米厚)并使用标准组织学技术用苏木精和曙红(H&E)染色。还使用亲和素-生物素-过氧化物酶复合物技术(Blaskovich,M.A.等人Nat Biotechnol,2000,18:1065-70)对组织切片进行CD31免疫染色(BDBiosciences,San Diego,CA)。以1∶50稀释率使用小鼠单克隆抗体,然后进行微波抗原修复(循环4次,每次高功率(on high)在0.1M柠檬酸盐缓冲剂中进行5分钟)。
发明详述
本发明涉及生长因子结合化合物。更特别地,本发明涉及与生长因子(例如VEGF和/或PDGF)结合并能够抑制这些生长因子中的一种或多种与它们各自的细胞表面受体结合的化合物(例如表1所示的那些)。本发明还涉及包含一种或多种这些化合物和可药用载体的药物组合物。
此外,本发明涉及通过使一种或多种本发明的化合物(或包含一种或多种该化合物的组合物)与细胞体外或体内接触来抑制这些生长因子与细胞结合的方法。在其他方面,本发明包括通过使本发明的一种或多种化合物或组合物体外或体内与靶细胞接触来抑制生长因子刺激的磷酸化(例如Erk1、Erk2、Akt和/或STAT3的磷酸化),从而抑制血管生成的方法;和抑制癌症和/或肿瘤生长的方法。
在一个实施方案中,本发明涉及一种可用于抑制生长因子与细胞结合、用于抑制生长因子刺激的磷酸化、用于抑制血管生成、用于抑制癌症和肿瘤生长或用于上述用途的组合的方法,其中该方法包括使至少一种生长因子结合化合物或任何生长因子结合化合物的可药用盐与细胞体外或体内接触;其中该生长因子结合化合物包含多个连接到非肽有机骨架上的无环间苯二酸基团;其中每种该生长因子结合化合物,或任何生长因子结合化合物的可药用盐可以负载或不负载在可药用载体上,但具有下列通式的化合物除外:
其中每个R1是
且每个R2是
在另一个实施方案中,对患者局部或全身施用本发明的药物组合物以实现血管生成抑制、肿瘤生长抑制和/或癌症抑制。
在一个实施方案中,本发明包括包含多个连接到非肽有机骨架上的无环间苯二酸基团的生长因子结合化合物。在另一个实施方案中,有机骨架是杯[4]芳烃骨架。本发明的化合物的无环间苯二酸基团可以用酸性团和/或疏水基官能化。
在另一实施方案中,本发明的生长因子结合化合物具有通式结构:
其中每个R1独立地选自下列化学基团:
并且每个R2独立地选自下列化学基团:
在实施方案中,本发明的化合物选自GFB201、GFB202、GFB203、GFB204、GFB205、GFB206、GFB207、GFB208、GFB209、GFB210、GFB211、GFB212、GFB213、GFB214、GFB215、GFB216、GFB217、GFB218和GFB219(如表1所列)。
作为本发明化合物的靶标或作用对象的生长因子,可以包括但不限于,血小板衍生生长因子和/或血管内皮生长因子。
在另一方面,本发明提供了包含至少一种如本文所公开的本发明化合物或其可药用盐;和可药用载体的组合物。
在另一方面,本发明提供了一种治疗患有下述疾病的患者的方法,该疾病包括过度细胞增殖、过度血管生成、肿瘤或上述任何疾病的组合,其中该方法包括给予患者有效量的本发明化合物或组合物。在实施方案中,肿瘤可以表达提高量的生长因子,例如血小板衍生生长因子和/或血管内皮生长因子。此外,提高的PDGF和VEGF量可能来自生血管内皮细胞和脉管引起的肿瘤微环境。
在另一个实施方案中,本发明提供了一种治疗患有下述疾病的患者的方法,该疾病包括过度细胞增殖、过度血管生成、肿瘤或上述任何疾病的组合,其中该方法包括施用有效量的药物组合物,其中该药物组合物包含至少一种生长因子结合化合物或任何生长因子结合化合物的可药用盐及可药用载体;或一种或多种生长因子化合物,其中该生长因子结合化合物包含多个连接到非肽有机骨架上的无环间苯二酸基团,但具有下列通式结构的化合物除外:
其中每个R1是:
且每个R2是:
该制剂(在此也称作组合物)包括适合局部或全身给药的制剂,例如口服、直肠、鼻、局部(包括经皮、口腔和舌下)、阴道、胃肠道外(包括皮下、肌内、静脉和皮内)和肺部给药。该制剂可以方便地以单位剂型存在,并可以通过制药领域公知的任何方法制备。这些方法包括使活性成分与构成一种或多种助剂的载体结合。一般而言,如下制备该制剂:使活性成分与液体载体和/或细碎固体载体均匀并密切结合,然后如果需要,成型成产品。本发明适合口服的制剂可以各自含有预定量活性成分的离散单位形式存在,例如胶囊剂、扁囊剂或片剂;或作为水包油液体乳剂、油包水液体乳剂或作为水溶液(例如茶)中的补充剂。活性成分也可以大丸剂、干药糖剂或糊剂形式存在。
适合在口中局部给药的制剂包括:在增味基质(basis)(通常是蔗糖和阿拉伯胶或黄蓍胶)中包含活性成分的锭剂;在惰性基料(例如明胶和甘油,或蔗糖和阿拉伯胶)中包含活性成分的软锭剂;和在合适的液体载体中包含活性成分的漱口剂。
根据本发明用于局部给药的药物组合物可以配制成软膏剂、乳膏剂、混悬剂、洗剂、散剂、溶液剂、糊剂、凝胶剂、喷雾剂、气溶胶或油。备选地,制剂可以包括浸渍有活性成分和任选一种或多种赋形剂或稀释剂的贴剂或敷料,例如绷带或橡皮膏。
适合局部施用到眼的制剂还包括滴眼剂,其中将活性成分溶解或悬浮在合适的载体,尤其是适合该试剂的水溶剂中。
用于直肠给药的制剂可以含有合适基质(base)(包括例如可可脂或水杨酸酯)的栓剂存在。
适合阴道给药的制剂可以包含药剂以及本领域公知的合适载体的阴道栓剂、卫生栓、乳膏剂、凝胶剂、糊剂、泡沫或喷雾剂制剂存在。
载体是固体的适合鼻部给药的制剂包括具有例如大约20至大约500微米粒度的粗粉,其以下述方式给药,即使用鼻吸,经鼻孔从紧靠鼻子的容纳散剂的容器中迅速吸入。载体是通过雾化吸入器给药的液体时的合适制剂包括药剂的水或油溶液。
适合胃肠道外给药的制剂包括:可以含有抗氧化剂、缓冲剂、抑菌剂和使制剂与预期受者的血液等渗的溶质的水和非水的等渗无菌注射;和可以包含悬浮剂和增稠剂及设计为将化合物导向血液成分或一个或多个器官的脂质体或其他微粒系统的水和非水的无菌混悬剂。这些制剂可以存在于单位剂量或多次剂量或多次剂量密封容器,例如安瓿和小瓶中,并可以储存在冻干条件(lyophilized)下,这样仅需要在使用之前即时加入无菌液体载体(例如注射用水)。即时注射溶液和混悬剂可以由上述类型的无菌散剂、颗粒和药片制成。
优选的单位剂型制剂是含有药剂的如上所述的日剂量或单位、每日分剂量(subdose)或其适当部分的那些。应当理解的是,除了上文特别提到的成分外,本发明的制剂可以根据有关制剂的类型包括该领域中的其他常规药剂。例如,适合口服给药的制剂可以包含甜味剂、增稠剂和增香剂之类的其他试剂。本发明的药剂、组合物和方法还可以与其他合适的组合物和治疗方法组合使用。
各种递送系统是已知的并可用于施用本发明的化合物,例如封装在脂质体、微粒、微囊中;受体介导的胞吞作用等。递送方法包括但不限于,动脉内、肌内、静脉内、鼻内和口腔途径。在实施方案中,本发明的药物组合物可以局部施用到需要治疗的区域;这种局部给药可以例如通过外科手术中的局部输注、通过注射或通过插管方法实现。
治疗量可以凭经验确定并且取决于所治疗的病理、治疗对象和药剂的效力和毒性。类似地,本领域技术人员很容易确定合适的剂型配方和施用药剂的方法。
该药物组合物可以通过多种途径中的任一种施用,例如通过口服、鼻内、胃肠道外施用或通过吸入疗法施用,并且可以以片剂、锭剂、颗粒剂、胶囊剂、丸剂、安瓿剂、栓剂或气溶胶形式成形。它们也可以以活性成分在水或非水稀释剂、糖浆剂、颗粒剂或散剂中的混悬剂、溶液剂和乳剂成形。除本发明的化合物外,该药物组合物还可以含有其他制药活性化合物或多种本发明的化合物。
理想地,该药剂的施用应该在疾病位置达到活性化合物的最大浓度。可以通过例如药剂的注射(任选在盐水中)或口服例如包含活性成分的片剂、胶囊剂或糖浆剂来达到疾病位置的最大浓度。
有利地,该组合物可以与其他药物或生物活性剂(例如抗癌剂)同时或依次施用。例子包括但不限于,抗氧化剂、自由基清除剂、肽、生长因子、抗生素、制菌剂、免疫抑制剂、抗凝药、缓冲剂、消炎剂、退热药、缓释粘合剂、麻醉剂、类固醇和皮质类固醇。
优选地,给药是经口、胃肠道外、皮下、静脉内、肌内、腹腔内、动脉内、经皮或经过粘膜进行的。
术语“癌症”是指任何细胞恶性肿瘤,其独特特性是缺乏正常控制,这导致不受控制的生长、缺乏分化并能够侵染局部组织,及移动的能力。癌症可以在任何器官的任何组织中产生。更具体地,癌症包括但不限于,前列腺癌、白血病、激素依赖型癌症、乳癌、结肠癌、肺癌、上皮癌、肝癌、食管癌、胃癌、脑癌和肾癌。
术语“治疗(treatment,treating)”和类似术语是指获得所需药理和/或生理作用,例如抑制癌细胞生长或诱发癌细胞凋亡。这种作用在完全或部分预防疾病或其症状方面可以是预防性的,和/或在部分或完全治愈疾病和/或由该疾病引起的不良作用方面可以是治疗性的。本文使用的“治疗”涵盖了对哺乳动物(特别是人类)的任何治疗,并包括:(a)在易感疾病但还没有诊断出患有该疾病的个体中,预防该疾病或症状(例如预防癌症)出现;(b)抑制该疾病(例如阻止其发展);或(c)减轻该疾病(例如减轻与该疾病有关的症状)。
术语“抗癌活性”是指能够充分抑制、减缓、干扰、降低、防止、延迟和/或阻止癌症和/或其转移(例如这种癌症的开始、生长、扩散和/或发展和/或转移)。
术语“施用”、“给药”和“接触”是指递送模式,包括但不限于,口服、直肠、胃肠道外、皮下、静脉内、肌内、腹腔内、动脉内、经皮或经过粘膜。优选口服。给药可以在目标位置局部进行或全身给药。本领域技术人员可以认识到,口服制剂的合适形式包括但不限于,片剂、丸剂、胶囊剂、锭剂、散剂、缓释片剂、液体制剂、液体混悬剂、凝胶剂、糖浆剂、结晶浆液、混悬剂等。例如,每日剂量可以以合适形式分成一次、二次或多次剂量,从而在一定时间段一次、两次或多次施用。
术语“治疗有效”是指足以充分改善与疾病或医药病症有关的某些症状的本发明化合物的量。例如,在癌症治疗中,减轻、防止、延迟、抑制或阻止该疾病任何症状的化合物是治疗有效的。化合物的治疗有效量不需要治愈该疾病,但是可以对疾病提供治疗,例如延缓、阻止或预防疾病发作,或改善疾病症状,或改变疾病期限,或例如使疾病较不严重或,加速患者恢复。
术语“独立地”是指本发明的生长因子结合化合物的四个R1取代基中的每个和四个R2取代基中的每个可以是相同的取代基或不同的取代基。
当本发明的化合物用于与其他药剂的结合疗法时,它们可以依次或同时用于个体。或者,本发明的药物组合物可以包含本文所述的本发明的化合物与本领域已知的另一治疗或预防剂的组合。
药用酸加成盐可以由无机和有机酸制成。盐可来自无机酸,所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、磷酸等。盐可来自有机酸,所述有机酸包括柠檬酸、乳酸、酒石酸、脂肪酸等。
盐也可以用碱形成。这些盐包括由无机或有机碱生成的盐,例如碱金属盐(例如镁或钙盐),和有机胺盐(例如吗啉、哌啶、二甲胺或二乙胺盐)。
本文所用的术语“可药用载体”包括任何和所有溶剂(例如磷酸盐缓冲的盐水缓冲剂、水、盐水)、分散介质、涂料、抗菌剂和抗真菌剂、等渗和吸收延缓剂等。这些介质和试剂在药用活性物质中的应用是本领域公知的。除非任何传统介质或试剂与活性成分不相容,其被认为可以用于治疗组合物。也可以在组合物中加入补充的活性成分。按照用于制备药物组合物的已知方法配制本发明的药物组合物。在本领域技术人员公知并容易获得的多种来源中描述了配制。例如Remington’s Pharmaceutical Science(Martin EW(1995)Easton Pennsylvania,Mack Publishing Company,第19版)描述了可以与本发明的相关配制。
本文所用的术语“个体”和“患者”可互换,指任何脊椎动物,例如人类和动物。优选地,患者是哺乳动物。可用于本发明公开的方法的哺乳动物包括但不限于:猿、黑猩猩、猩猩、人、猴;家养动物(例如,宠物),例如狗、猫、豚鼠、仓鼠、Vietnamese pot-bellied pig、兔和白鼬;驯养农畜,例如母牛、水牛、野牛、马、驴、猪、绵羊和山羊;通常可以在动物园中看到的珍奇动物,例如熊、狮、虎、豹、象、河马、犀牛、长颈鹿、羚羊、树懒、瞪羚、斑马、角马、草原土拨鼠、树袋熊、袋鼠、负鼠、浣熊、熊猫、鬣狗、海豹、海狮、海象、水獭、鼠海豚、海豚和鲸。人类或非人类动物患者的年龄可以从新生儿至老年。
根据本发明的另一实施方案,提供了一种治疗癌症的方法,包括对个体施用药学有效量的本发明药物组合物。
优选地,根据本发明的实施方案进行治疗的癌症选自前列腺癌、白血病、激素依赖型癌症、乳癌、结肠癌、肺癌、上皮癌、肝癌、食管癌、胃癌、脑癌和肾癌。
实施例1-鉴别GFB204,一种杯芳烃衍生物,其有效抑制了VEGF和PDGF-刺激的Flk-1和PDGF受体酪氨酸磷酸化
阻止生物学中重要的蛋白质-蛋白质相互作用(例如涉及生长因子与其受体的那些作用)的初期方法包括设计含有四个连接到杯[4]芳烃骨架上的合成肽环(loop)的分子(图1,反应(a))(Blaskovich,M.A.等人NatBiotechnol,2000,18:1065-70)。该肽环组分是以下述环状六肽为基础,所述环状六肽中两个残基被用5-氨基修饰的二肽拟态3-氨基甲基苯甲酸酯取代,以提供与杯芳烃空腔的连接键。这种设计可以合成环中具有不同肽序列并具有能够结合蛋白质表面的大表面积的杯芳烃衍生物文库。文库成员之一,GFB111,以亚微米级(subμM)浓度与PDGF结合并阻止其与PDGFR的结合,且该结合相对于其他生长因子是选择性的(Blaskovich,M.A.等人Nat Biotechnol,2000,18:1065-70)。GFB111中的四个肽环在序列GDGY中含有负电性和疏水性残基(图1,反应(a)),它们与同型二聚的PDGF的环I、II和III中的正性和疏水性氨基酸(它们对于与PDGFR的结合很重要)匹配很好(Oefner,C.等人Embo J,1992,11:3921-6;Andersson,M.等人Growth Factors,1995,12:159-64)。在2001年3月21日提交的美国公开申请US 2003/0118589和2001年3月21日提交的国际公开申请WO 01/70930中描述了GFB111和类似的化合物,其内容全部(包括所有的图和表)由此引入本文作为参考。为了改进这种设计,已经设计出第二代分子文库,其中不是将肽环,而是将用多种酸性和疏水性基团(R1和R2;图1,反应(b);和表1)官能化的简单的无环间苯二酸基团连接到杯[4]芳烃骨架上。
为了评测这种能够阻止PDGF和VEGF与其受体结合的分子文库,首先如“材料和方法”中所述测定它们破坏PDGF-和VEGF-刺激的受体酪氨酸磷酸化的能力。从文库GFB204中确定19种化合物(其中R1是羧酸且R2是苄酯),以190nM(PDGF)和480nM(VEGF)的IC50值作为VEGFR和PDGFR酪氨酸磷酸化(表1)的有效抑制剂。含有至少四个羧酸基团的所有文库成员都以低μM浓度(IC50≤6μM)抑制了PDGF信号传导,而唯一不含酸性团的化合物(GFB217)不具有明显的活性。表1中数据的分析显示,所有有效抑制剂(具有IC50≤0.6μM)均含有R1=COOH及R2=疏水性酯或酰胺。GFB211(其中R2=苄胺)具有仅略低于GFB204的活性(IC50=1.34±0.32μM),而GFB209(R2=甲酯)的效力较低(IC50=2.9±2.05μM)。这些数据表明,当疏水性取代基比甲基大时,其结构对于PDGF信号传导的抑制不是决定性的。具有芳族和脂族基团的化合物的活性相等,并且更稳定的酰胺具有与它们的酯类似物类似的活性。
相反,含有氨基酸取代基的杯芳烃衍生物(也就是GFB202、GFB203、GFB205、GFB206、GFB207和GFB208)大体表现出较低的活性(IC50在1-6μM范围内)。这可能是由于骨架上离子基与疏水基比率的改变(这些衍生物具有8-16个羧酸和仅0-4个疏水性取代基),或由于它们之间的非最佳距离。此外,间苯二酸间隔基(spacer)上酸性团的存在似乎比疏水性取代基的存在更重要:GFB201、GFB202、GFB203和GFB206在R1和R2位置不含疏水基,但是效力高于不含羧酸酯基团的GFB217。间苯二酸基团本身可能提供与PDGF的受体结合域的疏水性区域相互作用的疏水性面。
最后,重要的是注意到,该研究中的多数活性化合物在与之前鉴别出GFB111的研究(Blaskovich,M.A.等人Nat Biotechnol,2000,18:1065-70)相一致的骨架内的四个间苯二酸组分上正好具有一个羧酸和一个疏水基。SAR研究还表明,这一系列材料用于抑制VEGF-刺激的Flk-1酪氨酸磷酸化时所必需的特性苛刻很多。实际上,除GFB204(IC50=0.48±0.31μM)外,其他有效化合物中只有一种,GFB213以0.85±0.44μM的IC50值(表1)抑制了Flk-1酪氨酸磷酸化。从表1的数据难以推断确定抑制VEGF信号传导活性的因素。
GFB204与PDGF及VEGF均结合。通过荧光滴定曲线证实了GFB204与VEGF和PDGF均结合的能力。VEGF和PDGF都含有在294nM处激发334nM荧光的色氨酸。图2D和2E表明递增浓度的GFB-204以浓度相关方式降低了PDGF和VEGF发出荧光的能力。
实施例2--GFB204抑制了PDGF和VEGF但是不能抑制EGF与它们各自受体的结合
GFB204抑制PDGF和VEFG刺激的受体酪氨酸磷酸化的能力表明,GFB204破坏了配体/受体结合、受体二聚作用或受体酪氨酸激酶的活性。因此,测定了GFB204是否抑制了PDGF和VEGF及其各自受体之间的相互作用,但是不涉及其他生长因子。为此,如在“材料和方法”中所述,本发明人在NIH 3T3细胞(PDGF)、超表达人类Flk-1(VEGF)的NIH3T3细胞和人类EGFR(EGF)上评测了GFB204阻止[I-125]-PDGF、[I-125]-VEGF和[I-125]EGF与其受体结合的能力。GFB204分别以154+/-1.0nM和469+/-94nM的IC50值有效抑制了[I-125]PDGF和[I-125]-VEGF与其受体的结合(图2A-2C)。相反,[I-125]EGF与其受体的结合不受浓度高达100μM的GFB204的影响。因此,GFB204对于PDGF和VEGF的选择性高于EGF。
实施例3--GFB204破坏了PDGF-和VEGF-刺激的而不是EGF-、bFGF-或IGF-1刺激的Erk1、Erk2、Akt和STAT3磷酸化
为了进一步证明GFB204对PDGF和VEGF的选择性高于其他生长因子,本发明人测定了GFB204阻止生长因子刺激的激酶Erk1、Erk2和Akt及STAT3转录的信号转导物和激活剂的能力。为此,使NIH 3T3细胞(PDGF和bFGF)或超表达Flk-1(VEGF)、EGFR(EGF)或IGF-IR(IGF-1)的NIH 3T3细胞饥饿,并在存在或不存在GFB204的情况下用相应的生长因子刺激,如“材料和方法”中所述处理细胞以进行抗-磷酸酪氨酸(PDGF和VEGF)和进行抗-磷酸-Erk1/2、Akt和STAT3(PDGF、VEGF、EGF、bFGF和IGF-1)蛋白免疫印迹。图3A表明,如表1所述,用PDGF或VEGF处理饥饿细胞导致对受体酪氨酸磷酸化的有效刺激,并且用GFB204的处理分别以190nM和480nM的IC50值抑制这种刺激。类似地,也以类似的IC50值抑制了PDGF-和VEGF-刺激的Erk1和Erk2。此外,这种抑制的选择性在于,GFB204阻止了PDGF-和VEGF-刺激的Erk1、Erk2、Akt和STAT3磷酸化,但是对EGF-、bFGF-和IGF-1-刺激的Erk1、Erk2、Akt和STAT3磷酸化几乎没有影响(图3B)。
实施例4--GFB204抑制了体外和体内血管生成并抑制了裸鼠内人类肿瘤的生长。
GFB204有效和选择性地抑制PDGF和VEGF/配体受体结合和随后信号传导的能力促使本发明人测定该试剂是否可以在体外和体内抑制血管生成并随后抑制肿瘤生长。首先,如“材料和方法”中所述,评测GFB204抑制VEGF诱导的人脑内皮毛细血管网生成的能力,从而测定GFB204是否抑制了体外的血管生成。GFB204以700nM的IC50值高度有效地抑制了VEGF诱发的毛细血管网生成(图4C)。接着,如“材料和方法”中所述测定GFB204抑制人脑内皮细胞移动的能力。GFB204以600nM的IC50值抑制了VEGF诱导的内皮细胞通过matrigel孔移动到下室中(图4B)。
GFB204抑制VEGF和PDGF与其受体结合和随后信号传导的能力,结合它们的抑制VEGF诱导的内皮细胞移动和毛细血管网生成的能力,表明GFB204可以在所有动物中抑制血管生成和肿瘤生成。因此,接着通过在裸鼠中皮下注射植入人类肺癌A-549细胞,评测GFB204是否能够在体内抑制肿瘤生长和血管生成。当肿瘤达到100立方毫米的平均尺寸时,用载体或GFB204处理小鼠,并在3周后取出肿瘤,如“材料和方法”中所述进行处理,进行CD31免疫染色,从而测定GFB204的抗血管生成作用。来自对照动物的肿瘤生长至749±111立方毫米的平均尺寸(图6)。相反,来自GFB204处理的动物的肿瘤仅分别生长至650±114立方毫米(GFB204;1毫克/千克)和284±108立方毫米(GFB204;5毫克/千克)的平均尺寸。因此,用GFB204进行的处理以5毫克/千克(73%)而非1毫克/千克(15%)造成统计上显著(p<0.05)的肿瘤生长抑制。来自GFB204处理的动物的肿瘤切片表现出对CD31染色的明显抑制(图5A-5C)。当场(at field)放大(400X)的微血管量化表明,来自载体处理的小鼠的肿瘤含有11.3±1.9条微血管,而来自GFB204(5毫克/千克)处理的小鼠的肿瘤仅含有2.6±0.9条微血管。综上所述,该结果明显表明GFB204抑制了体内A-549异种移植的肿瘤的生长和血管生成。
肿瘤生长对血管生成的严格要求和高度依赖性已经促使许多研究者设计通过干扰血管生成(从而夺取癌症细胞的营养物并基本使肿瘤饿死)来治疗癌症的方案(Zhang,W.等人Angiogenesis,2002,5:35-44;Ferrara,N.Semin Oncol,2002,29:10-4;Jain,R.K.Semin Oncol,2002,29:3-9;Morin,M.J.Oncogene,2000,19:6574-83;Miao,R.Q.等人Blood,2002,100:3245-52;Laird,A.D.等人Cancer Res,2000,60:4152-60;Wedge,S.R.等人Cancer Res,2000,60:970-5;Relf,M.等人Cancer Res,1997,57:963-9;Huang,J.等人Proc Natl Acad Sci美国,2003,100:7785-90;Blaskovich,M.A.等人Nat Biotechnol,2000,18:1065-70)。尽管数十年前就提出靶向血管生成的癌症治疗法,但仅在最近FDA才批准了第一种靶向血管生成的复杂过程中的一个步骤的药物(Ferrara,N.Semin Oncol,2002,29:10-4)。实际上,AVASTIN,人源化的抗-VEGF单克隆抗体已经表现出对转移性结肠癌的活性。尽管这种方法对于证实在人类中靶向血管生成的概念是关键性的,但这种方法还没有充分开发。此后寻求的一种改进是设计同时靶向血管生成过程中的不同步骤的方法(Bergers,G.等人J ClinInvest,2003,111:1287-95;Relf,M.等人Cancer Res,1997,57:963-9;Huang,J.等人Proc Natl Acad Sci美国,2003,100:7785-90)。本发明人已经开发出一种新型的合成药剂,其抑制了VEGF和PDGF(它们是分别表现出对介导新血管生成和维持作用的生长因子)两者的作用。(Bergers,G.等人JClin Invest,2003,111:1287-95;Dvorak,H.F.J Clin Oncol,2002,20:4368-80;Ferrara,N.Curr Top Microbiol Immunol,1999,237:1-30;Dvorak,H.F.等人Curr Top Microbiol Immunol,1999,237:97-132;Eriksson,U.和Alitalo,K.Curr Top Microbiol Immunol,1999,237:41-57)。这是第一次报导了同时抑制VEGF和PDGF与其受体结合并随后抑制酪氨酸磷酸化和下游信号传导途径(Erk、Akt和STAT3)的试剂。GFB204还有效阻止了内皮细胞移动的能力(IC50=600nM)以及它们在体外形成毛细血管的能力(IC50=700nM)。在体内,对携带人类肿瘤(皮下注射)的小鼠的处理抑制了肿瘤物质周围的血管生成以及抑制了肿瘤生长。尽管GFB204有效地同时抑制了VEGF和PDGF与其受体的结合(200-500nM),但其不是所有配体/受体结合的非特性破坏剂,因为在高达100μM的剂量下,EGF与其受体的结合不受影响。由于证明了GFB204通过PDGF和VEGF而非通过EGF、bFGF或1GF-1抑制了Erk1、Erk2、Akt和STAT3的活性,进一步证实了选择性。
鉴别能够同时阻碍VEGF和PDGF与其受体结合的杯[4]烯烃衍生物是一种靶向受体酪氨酸激酶信号传导的新方法。尽管抗-VEGF抗体AVASTIN也阻碍了VEGF与其受体的结合(Zhang,W.等人Angiogenesis,2002,5:35-44;Ferrara,N.Semin Oncol,2002,29:10-4),但明显没有其他试剂能够同时阻碍PDGF和VEGF与其受体的结合。此外,GFB204优于AVASTIN的优点在于,与产生治疗用抗体所包含的费力和昂贵方法不同,GFB204是可低成本简单合成的小得多的分子。尽管在本申请之前,还不存在VEGF和PDGF与其受体结合的双重抑制剂,但是已经制备了VEGF和PDGF受体酪氨酸激酶的双重抑制剂,并且一些用于临床试验(Kerbel,R.S.Carcinogenesis,2000,21:505-15;Jain,R.K.Semin Oncol,2002,29:3-9;Morin,M.J.Oncogene,2000,19:6574-83;Miao,R.Q.等人Blood,2002,100:3245-52;Laird,A.D.等人Cancer Res,2000,60:4152-60;Wedge,S.R.等人Cancer Res,2000,60:970-5)。
在这些ATP模拟物和GFB204之间存在明显差别。GFB204的靶标是在细胞外表面上胞外产生的配体/受体相互作用,而ATP模拟物靶向胞内的受体酪氨酸激酶域。因此,与GFB204不同,激酶抑制剂必须进入细胞来到达它们的靶标。此外,多数激酶抑制剂靶向ATP结合位点,其变异普遍存在于细胞中。因此,用GFB204治疗患者的结果与用ATP模拟物(其同时靶向PDGF和VEGF受体酪氨酸激酶)治疗患者的结果非常不同。在准备GFB204在人类中的I期试验的临床新药研究(IND)申请中,正在进行探索性临床前研究。
在与本说明书的明确教导一致的程度上,本文所参考或引用的所有专利、专利申请、临时申请和公开均全文(包括所有图和表)由此引入本文作为参考。
应该理解的是,本文描述的实施例和实施方案仅用于举例说明的目的,本领域技术人员可以想到的根据其进行的各种修改或变动均包含在本申请的宗旨和范围内。
Claims (7)
2.一种药物组合物,其包含一种或多种权利要求1的生长因子结合化合物或任何所述生长因子结合化合物的可药用盐及可药用载体。
3.根据权利要求2所述的药物组合物,其中每种所述生长因子结合化合物能够结合血小板衍生生长因子、血管内皮生长因子,或其两者的混合物。
4.根据权利要求2所述的药物组合物,其进一步包含生物活性剂。
5.至少一种权利要求1定义的化合物,或权利要求2-4中任一项定义的药物组合物在制备治疗下述疾病的药物中的用途,所述疾病包括PDGF和/或VEGF相关的过度细胞增殖、过度血管生成、肿瘤或上述任何疾病的组合。
6.至少一种权利要求1定义的化合物,或权利要求2-4中任一项定义的药物组合物在制备抑制PDGF和/或VEGF与细胞结合、抑制PDGF和/或VEGF刺激的磷酸化、抑制PDGF和/或VEGF相关的血管生成、抑制PDGF和/或VEGF相关的癌症生长、抑制PDGF和/或VEGF相关的肿瘤生长或用于上述用途的组合的药物中的用途。
7.至少一种权利要求1定义的化合物,或权利要求2-4中任一项定义的药物组合物在制备抑制了PDGF和/或VEGF刺激的Erk1、Erk2、Akt或STAT3的磷酸化的药物中的用途。
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