CN111148752A - 肽衍生物和包含其的药物组合物 - Google Patents
肽衍生物和包含其的药物组合物 Download PDFInfo
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- CN111148752A CN111148752A CN201880060749.1A CN201880060749A CN111148752A CN 111148752 A CN111148752 A CN 111148752A CN 201880060749 A CN201880060749 A CN 201880060749A CN 111148752 A CN111148752 A CN 111148752A
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Abstract
本发明提供一种肽,其包含将阻碍BIG3和PHB2的相互作用的BIG3的显性负性(Dominant negative)肽的一部分用至少2个钉合(Stapling)结构取代而成的结构。本发明的肽具有优异的细胞增殖抑制作用。此外,与单订书肽(Single stapled peptide)相比,该细胞增殖抑制作用持续时间更长。因此,具备在癌症的治疗中适合临床应用的特征。
Description
技术领域
本发明涉及在癌症治疗中有用的肽衍生物和包含其的药物组合物。
本申请主张于2017年7月19日申请的日本特愿2017-140101的优先权,通过参考将其全部内容组入本说明书中。
背景技术
雌激素受体α(Estrogen-receptor:ERα)在乳腺癌的发生和发展中起核心作用。近年的针对乳腺癌的内分泌疗法使用选择性ERα调节剂(例如,他莫昔芬和雷洛昔芬)、ERα下调剂(例如,氟维司群)和芳香化酶抑制剂(aromatase inhibitor:AI),将ERα信号传导作为主要靶标(非专利文献1~3)。在这些治疗法中,使用通过向ERα的竞争性结合而阻碍乳腺癌细胞的增殖的他莫昔芬的方法是针对ERα阳性乳腺癌患者的标准疗法。然而,他莫昔芬疗法存在经常无效的情况,患者也可能复发内分泌疗法耐性肿瘤而死亡(非专利文献4、5)。此外,与他莫昔芬相比,阻断雌激素合成的AI虽然带来良好的有效性、无复发生存期间的有意的延长和闭经女性中的复发期间的延长这样的实际临床效果,但是接受AI疗法的一部分的患者将发生复发(非专利文献6、7)。影响这些内分泌疗法的有效性的正确的分子现象尚未阐明。
作为癌症特异性蛋白质的布雷非德菌素A抑制鸟嘌呤核苷酸交换蛋白3(brefeldin A-inhibited guanine nucleotide-exchange protein 3:BIG3)与作为肿瘤抑制蛋白的抗增殖蛋白2(prohibitin 2:PHB2)形成的复合体在ERα阳性乳腺癌中的雌激素信号调节中起核心作用(非专利文献8、9)。BIG3与PHB2结合而阻碍抑制雌激素依赖性转录激活的PHB2的能力,带来恒定性的ERα活性。
基于这些发现,通过BIG3-PHB2相互作用的阻碍而使PHB2从与BIG3形成的复合体脱离、发挥PHB2的肿瘤抑制活性这样的策略,可以成为乳腺癌的新疗法。基于该策略,本发明人等以前开发了特异性地阻碍BIG3-PHB2相互作用的BIG3的显性负性(Dominantnegative)肽(专利文献1)。确认了,该肽通过重新激活PHB2的肿瘤抑制活性,而阻碍带来乳腺癌增殖的ERα信号通道,抑制乳腺癌增殖(专利文献1)。
现有技术文献
专利文献
专利文献1:WO2013/018690
非专利文献
非专利文献1:Johnston,S.R.,Clin.Cancer Res.16,1979-1987(2010).
非专利文献2:Fisher,B.et al.,J.Natl.Cancer Inst.97,1652-1662(2005).
非专利文献3:Jordan,V.C.,Nature Rev.Drug Discov.2,205-213(2003).
非专利文献4:Clarke,R.et al.,Pharmacol.Rev.53,25-71(2001).
非专利文献5:Fisher,B.et al.,J.Natl.Cancer Inst.93,684-690(2001).
非专利文献6:Chlebowski,R.et al.,Breast 2,S1-11(2009).
非专利文献7:Chumsri,S.et al.,J.Steroid Biochem.Mol.Biol.125,13-22(2011).
非专利文献8:Kim,J.W.et al.,Cancer Sci.100,1468-1478(2009).
非专利文献9:Yoshimaru,T.et al.,Nat.Commun.4,2443(2013).
非专利文献10:Yoshimaru,T.et al.,Sci Rep.7(1),1821(2017)
发明内容
发明所解决的技术问题
如上所述,阐明了基于BIG3的显性负性(Dominant negative)肽的乳腺癌细胞的增殖抑制作用。然而,公知的显性负性(Dominant negative)肽不能说具有较高的稳定性,对BIG3-PHB2相互作用的阻碍效果的持续时间不长。因此,本发明人等发现,通过将钉合(Stapling)结构(stapling structure;交联结构)导入所述显性负性(Dominantnegative)肽的分子内,而改善对BIG3-PHB2相互作用的阻碍效果的持续时间(PCT/JP2017/001187,Yoshimaru,T.et al.,SciRep.7(1),1821(2017))。确认了,导入了钉合(Stapling)结构的肽(订书肽(Stapled peptide);stERAP No.12等)表现出更稳定的乳腺癌增殖抑制效果。
所述订书肽(Stapled peptide)延长对BIG3-PHB2相互作用的阻碍效果的持续时间。然而,为了临床应用,期望其阻碍效果持续更长时间。
因此,本发明的目的是提供对BIG3-PHB2相互作用阻碍效果的持续时间更长的肽。
解决问题的技术手段
以前,本发明人等发现通过将钉合(Stapling)结构导入所述显性负性(Dominantnegative)肽的分子内,而改善对BIG3-PHB2相互作用的阻碍效果的持续时间,并且,发现通过增强分子内交联而提高稳定性,从而完成了本发明。即本发明提供以下的肽及其用途。
[1]、一种肽或其盐,其包含:在SEQ ID NO.4或SEQ ID NO.5所记载的氨基酸序列中,至少2对氨基酸残基被相同数量的钉合(Stapling)结构取代而成的氨基酸序列。
[2]根据[1]所述的肽或其盐,其中,
2对氨基酸残基被2个钉合(Stapling)结构取代。
[3]根据[1]或[2]所述的肽或其盐,其中,
2对氨基酸残基为以下的(a)和(b):
(a)从SEQ ID NO.4所记载的氨基酸序列的N末端起第3个和第7个氨基酸残基;
(b)从SEQ ID NO.4所记载的氨基酸序列的N末端起第8个和第12个氨基酸残基。
[4]根据[1]或[2]所述的肽或其盐,其中,
2对氨基酸残基为以下的(c)和(d):
(c)从SEQ ID NO.5所记载的氨基酸序列的N末端起第3个和第7个氨基酸残基;
(d)从SEQ ID NO.5所记载的氨基酸序列的N末端起第10个和第14个氨基酸残基。
[5]根据[1]~[4]中任一项所述的肽或其盐,其中,
钉合(Stapling)结构由下述式(I)表示:
[化学式1]
式中,实线和虚线的双划线表示单键或双键。
[6]根据[5]所述的肽或其盐,其中,
钉合(Stapling)结构由下述式(II)表示:
[化学式2]
式中,实线和虚线的双划线为单键或双键,
A1、A2、A3、A4和A5的组合从以下进行选择,
A1=QM,A2=SDL,A3=-,A4=QLR,A5=R
A1=QM,A2=SDL,A3=LQ,A4=RQR,A5=OH
此处“-”表示为肽键而没有氨基酸残基(即2个钉合(Stapling)结构相连接),并且,“OH”表示所述钉合(Stapling)结构的一端构成肽衍生物的C末端。
[7]根据[1]~[6]中任一项所述的肽或其盐,其中,
N末端和C末端的氨基酸残基的任一者或两者经过了修饰。
[8]根据[7]所述的肽或其盐,其中,
N末端和C末端的氨基酸残基的任一者或两者通过乙酰化、酰胺化和HA标签添加中的任一项或这些的组合而经过了修饰。
[9]根据[8]所述的肽或其盐,其中,
N末端的氨基酸残基被乙酰化,并且,C末端的氨基酸残基被酰胺化。
[10]根据[1]~[9]中任一项所述的肽或其盐,其中,
所有的氨基酸残基被D型的氨基酸残基所取代。
[11]一种肽或其盐,其是[1]~[9]中任一项所述的肽的逆反(Retro inverse)体。
[12]一种药物组合物,其包含:[1]~[11]中任一项所述的肽或其盐、和药学上允许的载体。
[13]根据[12]所述的药物组合物,其其用于癌症治疗。
[14]根据[13]所述的药物组合物,其中,
癌症为乳腺癌或前列腺癌。
[15]根据[13]或[14]所述的药物组合物,其中,
癌症为雌激素受体阳性的癌症。
或本发明提供一种癌症的治疗方法,其包含将所述[1]~[11]中任一项所述的肽或其盐对需要治疗的对象进行给药的工序。此外,本发明涉及所述[1]~[11]中任一项所述的肽或其盐在癌症的治疗用药物组合物的制造中的使用。此外,本发明涉及所述[1]~[11]中任一项所述的肽或其盐在癌症的治疗中的使用。此外,本发明涉及一种癌症的治疗用药物组合物的制造方法,其包含将所述[1]~[11]中任一项所述的肽或其盐与载体混合或配合的工序。
发明效果
如果根据本发明,则提供对BIG3-PHB2相互作用的阻碍效果的持续时间更长的肽。包含本发明的肽的药物组合物可以适用于癌症的治疗。
附图说明
[图1]图1表示双订书(Double stapled)ERAP(No.45h和No.46)的示意图。
[图2]图2表示双订书(Double stapled)ERAP长期稳定性地抑制雌激素依赖性的人乳腺癌细胞株的增殖。(图2A、B)用双订书(Double stapled)ERAP No.45(A)或双订书(Double stapled)ERAP No.46(B)对人乳腺癌细胞株MCF-7细胞进行处理,然后,立即用10nM雌激素进行刺激,通过MTT法(MTT assay)而每24小时对阻碍效果进行一次评价,直至96小时。数据表示3次独立的实验的平均值±标准差(SD)。(C)表示单订书(Singlestapled)ERAP(黑圆点●)、双订书(Double stapled)ERAP No.45(黑三角▲)或双订书(Double stapled)ERAP No.46(黑四角■)的肽浓度(0.01、0.05、0.1、0.5、1、5、10μM)与增殖抑制率的S型曲线(Sigmoid curve)。
[图3]图3表示双订书(Double stapled)ERAP的糜蛋白酶耐药性。表示双订书(Double stapled)ERAP和糜蛋白酶在37℃下进行24小时反应时的双订书(Doublestapled)ERAP No.45(A)和双订书(Double stapled)ERAP No.46(B)的色谱图。实验中,将双订书(Double stapled)ERAP和糜蛋白酶反应液提供至高效液相色谱法(反相柱,流速0.3mL/min,梯度洗脱;A液:0.1%三氟乙酸,B液:0.1%三氟乙酸/乙腈,A/B=90/10(0-20min)-40/60(20-80min))并在UV210nm下进行检测。
[图4]图4表示显示了在乳腺上皮细胞MCF-10A细胞的增殖中没有双订书(Doublestapled)ERAP No.46的效果的MTT法(MTT assay)的结果。将MCF-10A细胞用图中所示的浓度的双订书(Double stapled)ERAP进行处理直至96小时,每24小时对细胞增殖进行一次评价。
[图5]图5表示双订书(Double stapled)ERAP No.46阻碍BIG3和PHB2的相互作用。(A、B)对在MCF-7细胞中影响BIG3-PHB2相互作用的双订书(Double stapled)ERAP No.46的阻碍效果,通过蛋白质印迹法(Western Blot)而进行评价。将MCF-7细胞用1μM和10μM的双订书(Double stapled)ERAP No.46和单订书(Single stapled)ERAP进行处理,然后,立即用10nM雌激素进行24小时(A)和96小时(B)刺激。然后,使细胞溶解,使用抗BIG3抗体而进行免疫沉淀,进行使用了图中所示的抗体的免疫印迹分析。结合阻碍率表示为将非处理细胞中的PHB2的带(Band)面积设为100时的比例。
[图6]图6-8是订书(stapled)ERAP合成的示意图(scheme)。图6表示订书(stapled)ERAP合成中使用的氨基酸衍生物的合成示意图(scheme)。(i)~(vi)表示各反应中的试剂和氨基酸合成的条件:(i)2,4-二甲氧基苯甲醛,AcOH,MgSO4,CH2Cl2;(ii)NaBH4,MeOH,CH2Cl2,收率87%(两步);(iii)化合物2,EDC·HCl,DIPEA,CH2Cl2,收率76%;(iv)LiOH·H2O,THF,MeOH,H2O,收率92%;(v)TBSOTf,2,6-二甲基吡啶,CH2Cl2;(vi)Fmoc-OSu,Na2CO3,THF,H2O,收率90%(两步)。
[图7]图7表示闭环烯烃复分解引起的ERAP的钉合(Stapling)合成的示意图(scheme)。
[图8]图8表示通过分子内酰胺化进行的ERAP的钉合(Stapling)合成的示意图(scheme)。
[图9]图9表示ESR1变体的乳腺癌细胞株雌激素非依赖性地与PI3K进行结合。(A)表示在ESR1野生型的乳腺癌细胞株中在存在雌激素的情况下ERα和PI3K进行结合的免疫印迹。使转染了FLAG标签化ESR1(WT)的MCF-7细胞的溶解物通过抗FLAG抗体而进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。(B)表示当将转染了ESR1变体Y537S的MCF-7细胞用10μM stERAP进行处理时的PI3K、PKCα和PHB2的磷酸化的免疫印迹。将FLAG标签化ESR1变体(Y537S)转染在MCF-7细胞中之后,通过抗ERα抗体使随时间推移性而处理了10μMstERAP的细胞溶解物进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。
[图10-1]图10表示ESR1变体的乳腺癌细胞株雌激素非依赖性地具有高PKCα活性。(A)表示转染了ESR1变体的乳腺癌细胞株的PKCα活性。对转染了各ESR1变体的HEK293T细胞和MCF-7细胞用PKCα抑制剂星形孢菌素(staurosporine)进行24小时处理之后,通过抗PKCα抗体进行免疫沉淀,将包含Ser39的PHB2肽(YGVRE SVFTVE(SEQ ID NO.17))设为基质而对PKCα活性进行测定。此外,使用图中所示的抗体而对PKCα的免疫沉淀物进行免疫印迹分析。数据表示3次独立的实验的平均值±标准误差(SE)。***P<0.001。
[图10-2](B)表示转染了ESR1变体的乳腺癌细胞株的PKCα活性是PI3K依赖性的。对转染了各ESR1变体的MCF-7细胞用PI3K抑制剂渥曼青霉素(wortmannin)100nM进行24小时处理之后,通过抗PKCα抗体而进行免疫沉淀,对包含Ser39的PHB2肽的PKCα活性进行测定。数据表示3次独立的实验的平均值±标准误差(SE)。NS,无统计学意义,***P<0.001。(C)表示转染了ESR1变体的MCF-7细胞的磷酸化PKCα是PI3K依赖性的免疫印迹。对转染了各ESR1变体的MCF-7细胞用stERAP和渥曼青霉素(wortmannin)进行24小时处理之后,通过抗PKCα抗体而进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。
[图11-1]图11表示对于转染了ESR1变体的MCF-7细胞的增殖的、stERAP和抗雌激素剂的组合使用性的抑制效果。对使10μM stERAP、作为抗雌激素剂的1μM他莫昔芬(TAM)、2μM氟维司群(Fluv)和作为mTOR抑制剂的0.5μM依维莫司(Ever)在转染了各ESR1变体的MCF-7细胞中进行96小时反应时的细胞增殖进行评价。数据表示3次独立的实验的平均值±标准误差(SE)。*P<0.05,**P<0.01,***P<0.001。
[图11-2]是表示图11-1的后续的图。
[图12]图12表示对于转染了ESR1变体的MCF-7细胞在雌激素共存下的增殖的、stERAP的抑制效果。对在各雌激素浓度(0.1、1、10nM)的共存下使转染了各ESR1变体的MCF-7细胞与10μM stERAP进行24小时反应时的细胞增殖进行评价。数据表示3次独立的实验的平均值±标准误差(SE)。*P<0.05,**P<0.01,***P<0.001。
[图13]图13表示对于转染了ESR1变体的MCF-7细胞的ERα转录活性在雌激素共存下的、stERAP的抑制效果。在各雌激素浓度(0.1、1、10nM)的共存下使转染了各ESR1变体的MCF-7细胞与10μM stERAP进行24小时反应,对ERE-萤光素酶活性(ERα转录活性)进行测定。数据表示3次独立的实验的平均值±标准误差(SE)。
[图14]图14对下述细胞增殖进行了评价:在图中(横轴)各浓度的stERAP单独和存在10nM雌激素的情况下使将敲入了ESR1的Y537S的MCF-7细胞进行24小时反应时的细胞增殖。数据表示3次独立的实验的平均值±标准误差(SE)。
[图15]图15表示HER2阳性乳腺癌细胞株中的BIG3作为AKAP发挥功能。(A)表示HER2阳性乳腺癌细胞株中的BIG3的表达。通过实时PCR而求出Luminal型乳腺癌细胞株(MCF-7细胞)、HER2阳性乳腺癌细胞株(BT-474细胞、SK-BR-3细胞、KPL-4细胞)和正常乳腺细胞株(MCF-10A细胞)的BIG3的mRNA水平。数据通过β2-MG含量而进行标准化,以将MCF-10A细胞中的值设为1.0时的比例而进行表示,表示3次独立的实验的平均值±标准误差(SE)。(B)表示结合了BIG3、PKA、PP1Cα和PHB2的免疫印迹。使SK-BR-3细胞和KPL-4细胞溶解,使用抗BIG3抗体和大鼠IgG抗体而使细胞溶解物进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。数据是3次独立的实验的代表例。(C)表示BIG3的激酶活性和磷酸酶活性。使将SK-BR-3细胞用10μM H-89、100μg/mL曲妥珠单抗和10nM拉帕替尼进行了24小时处理而得到的细胞溶解物通过抗BIG3抗体而进行免疫沉淀,将CREBtide和p-NPB作为基质而算出其PKA活性和PP1Cα活性。此外,作为阴性对照,使用使SK-BR-3细胞的溶解物通过大鼠抗IgG抗体进行免疫沉淀而得到的物质。数据表示3次独立的实验的平均值±SE。***P<0.001。
[图16]图16表示HER2阳性乳腺癌细胞株中的BIG3的激活机理。BIG3表示通过介由HER2信号的PKA而被磷酸化的免疫印迹。使将SK-BR-3细胞和KPL-4细胞用10μM H-89、100μg/mL曲妥珠单抗和10nM拉帕替尼进行了30分钟处理而得到的细胞溶解物通过抗BIG3抗体而进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。
[图17]图17表示HER2阳性乳腺癌细胞株中的BIG3控制PHB2的抑制活性。(A)表示BIG3与PHB2结合而控制其磷酸化的免疫印迹。使将SK-BR-3细胞和KPL-4细胞用1μM stERAP进行了24小时处理而得到的细胞溶解物通过抗BIG3抗体和抗PHB2抗体而进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。(B)表示PHB2通过EGFR信号而使Ser39磷酸化的免疫印迹。使通过siRNA法而抑制PKA的表达之后用1μM stERAP进行了24小时处理的SK-BR-3细胞和在1μM stERAP存在下用100μg/mL曲妥珠单抗和10nM拉帕替尼进行了24小时处理的SK-BR-3细胞分别溶解,通过抗PHB2抗体而进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。
[图18]图18表示PKCα依赖性PHB2(Ser39)的磷酸化。(A)表示在HER2阳性乳腺癌细胞株中PKCα依赖性地PHB2(Ser39)被磷酸化的免疫印迹。将通过siRNA法而抑制了PKCα的表达的SK-BR-3细胞用1μM stERAP进行24小时处理之后,通过抗PHB2抗体而使其细胞溶解液进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。(B)表示SK-BR-3细胞的EGFR信号带来的PKCα活性。使将SK-BR-3细胞在1μM stERAP和stERAP存在下用10nM拉帕替尼进行了24小时处理而得到的细胞溶解物通过抗PKCα抗体而进行免疫沉淀,将CREBtide作为基质而算出PKCα活性。数据表示3次独立的实验的平均值±标准误差(SE)。
[图19]图19表示磷酸化PHB2(Ser39)抑制核内的转录活性。(A)表示转录抑制因子NcoR和HDAC1与PHB2(ser39)的磷酸化结合的免疫印迹。将HA标签化了的PHB2构建体(WT)、Ser39的丙氨酸变体(S39A)、Ser39的谷氨酸变体(S39E)转染至通过siRNA法而抑制了PHB2的表达的SK-BR-3细胞中,在48小时后用1μM stERAP进行24小时处理。通过比重离心而使核部分分离之后,通过抗HA抗体而使其核提取液进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。(B)表示PHB2(Ser39)的磷酸化不能抑制HER2信号的免疫印迹。使将SK-BR-3细胞在1μM stERAP存在下用100μg/mL曲妥珠单抗和10nM拉帕替尼进行了24小时处理而得到的细胞溶解物通过抗HER2抗体而进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。
[图20]图20表示PHB2的苏氨酸·磷酸化及其激活机理。(A)表示在HER2阳性乳腺癌细胞株中PKCα非依赖性地诱导PHB2的苏氨酸·磷酸化的免疫印迹。将通过siRNA法而抑制了PKCα的表达的SK-BR-3细胞用1μM stERAP和100μg/mL曲妥珠单抗进行24小时处理之后,通过抗PHB2抗体而使其细胞溶解物进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。(B)表示通过TTK和MK5而使PHB2进行苏氨酸·磷酸化的免疫印迹。将通过siRNA法而抑制了TTK、CHK1和MK5的表达的SK-BR-3细胞用1μM stERAP进行24小时处理之后,使该细胞溶解并使用图中所示的抗体而进行免疫印迹分析。
[图21]图21表示TTK和MK5引起的PHB2的苏氨酸·磷酸化对HER2信号的影响。(A、B)表示TTK和MK5引起的PHB2的苏氨酸·磷酸化阻碍HER2-HER3与HER2-Shc的结合的免疫印迹。将通过siRNA法而抑制了TTK、MK5和CHK1的表达的SK-BR-3细胞(A)和KPL-4细胞(B)用1μM stERAP进行24小时处理之后,使该细胞溶解并通过抗HER2抗体而进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。(C)表示通过TTK抑制剂而避免基于PHB2的HER2-HER3与HER2-Shc的结合阻碍的免疫印迹。将SK-BR-3细胞用2μM AZ3146和1μM stERAP进行24小时处理之后,通过抗HER2抗体而使其细胞溶解液进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。
[图22]图22表示PHB2的苏氨酸·磷酸化部位的鉴定。(A)表示对PHB2的苏氨酸·磷酸化部位是Thr42和Thr169进行了评价的免疫印迹。将HA标签化了的PHB2构建体、Thr42的丙氨酸变体(T42A)、Thr169的丙氨酸变体(T169A)、Thr42和Thr169的双丙氨酸变体(T42A+T169A)转染至通过siRNA法而抑制了PHB2的表达的SK-BR-3细胞中,在48小时后用1μMstERAP进行24小时处理。然后,使细胞溶解,通过抗HA抗体而进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。(B)表示PHB2的Thr42和Thr169的磷酸化阻碍HER2-HER3和HER2-Shc的结合的免疫印迹。将HA标签化了的PHB2构建体、Thr42的丙氨酸变体(T39A)、Thr169的丙氨酸变体(T169AE)、Thr42和Thr169的双丙氨酸变体(T42+T169)转染至通过siRNA法而抑制了PHB2的表达的SK-BR-3细胞中,在48小时后用1μM stERAP进行24小时处理。然后,使细胞溶解,通过抗HER2抗体和抗BIG3抗体而进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。
[图23]图23表示TTK和MK5引起的PHB2的苏氨酸·磷酸化。(A)表示PHB2和TTK进行结合的免疫印迹。将SK-BR-3细胞用1μM stERAP进行24小时处理之后,使该细胞溶解,通过抗PHB2抗体、抗TTK抗体和兔IgG抗体而进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。(B、C)表示使用了对TTK和MK5引起的PHB2的苏氨酸·磷酸化进行评价的Phos-tag的免疫印迹。改变PHB2的摩尔比,使重组PHB2与重组TTK(B)和重组MK5(C)在ATP存在下在30℃下,进行30分钟反应之后,使用图中所示的抗体而进行基于Phos-tag的免疫印迹分析。
[图24]图24表示影响HER2阳性乳腺癌细胞株的增殖的、stERAP的抑制效果。表示对HER2阳性乳腺癌细胞株的增殖中的stERAP的阻碍效果进行了评价的MTT法(MTT assay)的结果。使SK-BR-3细胞、BT-474细胞、KPL-4细胞与stERAP进行24小时反应。数据表示3次独立的实验的平均值±SE。*P<0.05,**P<0.01,***P<0.001。
[图25]图25表示stERAP阻碍HER2-HER3和HER2-Shc的相互作用。表示stERAP对HER2阳性乳腺癌细胞株的HER2-HER3和HER2-Shc的相互作用进行阻碍的免疫印迹。将HER2阳性乳腺癌细胞株(SK-BR-3细胞、BT-474细胞、KPL-4细胞)用各浓度的stERAP和100μg/mL曲妥珠单抗进行24小时处理之后,通过抗HER2抗体而使其细胞溶解物进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。
[图26]图26表示对于曲妥珠单抗耐药性HER2阳性乳腺癌细胞株,stERAP的抑制效果。(A)表示对曲妥珠单抗耐药性HER2阳性乳腺癌细胞株的增殖中的stERAP的阻碍效果进行了评价的MTT法(MTT assay)的结果。使曲妥珠单抗耐药性SK-BR-3细胞与stERAP和曲妥珠单抗进行24小时反应。数据表示3次独立的实验的平均值±SE。*P<0.05,**P<0.01,***P<0.001。(B)表示stERAP阻碍曲妥珠单抗耐药性HER2阳性乳腺癌细胞株的HER2-HER3和HER2-Shc的相互作用的免疫印迹。将SK-BR-3细胞和曲妥珠单抗耐药性SK-BR-3细胞用20μMstERAP和100μg/mL曲妥珠单抗进行24小时处理之后,通过抗HER2抗体使其细胞溶解物进行免疫沉淀,使用图中所示的抗体而进行免疫印迹分析。
[图27]图27表示对于曲妥珠单抗耐药性HER2阳性乳腺癌细胞株的NF-κB信号的、stERAP的影响。表示stERAP抑制曲妥珠单抗耐药性HER2阳性乳腺癌细胞株的NF-κB的核易位和IκBα的磷酸化的免疫印迹。将SK-BR-3细胞和曲妥珠单抗耐药性SK-BR-3细胞用20μMstERAP和100μg/mL曲妥珠单抗进行24小时处理之后,使该细胞溶解,使用图中所示的抗体而进行免疫印迹分析。
[图28]图28表示对于曲妥珠单抗耐药性HER2阳性乳腺癌细胞株的细胞周期的、stERAP的影响。表示显示出细胞周期中的stERAP的效果的FACS分析。将曲妥珠单抗耐药性SK-BR-3细胞用20μM stERAP和100μg/mL曲妥珠单抗进行24小时处理之后,使细胞固定化,用碘化丙啶使细胞染色而通过流式细胞技术(flow cytometry)而进行分析。
[图29]图29表示曲妥珠单抗耐药性HER2阳性乳腺癌细胞中的stERAP的体内(invivo)抗肿瘤效果。表示对于KPL-4细胞和曲妥珠单抗耐药性SK-BR-3细胞的原位移植小鼠模型中的肿瘤增殖的、stERAP的阻碍效果。左图是每7日投与150μg/kg的stERAP的组的肿瘤直径变动,右图表示小鼠的体重变动。图表中的各符号分别表示以下内容,黑圆点:未处理,白圆点:150μg/kg stERAP。肿瘤直径和体重的数据表示各组的平均±标准误差(SE)(n=5,***P<0.001)。
[图30]图30表示调查对于3种乳腺癌细胞株(SK-BR-3、BT-20、MDA-MB-231)和滑膜肉瘤细胞株SW982,3种stERAP(单stERAP、双stERAP#45、双stERAP#46)给细胞增殖带来的影响的结果。单stERAP和双stERAP#46从20μM开始以3倍系列稀释而添加共计11种浓度的肽。双stERAP#45从50μM开始以2倍系列稀释而添加共计8种浓度的肽。在肽添加96小时后对活细胞数进行测定,基于未添加肽的阴性对照细胞而算出相对值并制成图表。对于SW982细胞株,未实施双stERAP#45的实验。
[图31-1]图31表示调查对于SK-BR-3细胞(图31A)和MDA-MB-231细胞(图31B),2种stERAP(单stERAP、双stERAP#46)给细胞周期带来的影响的结果。以5μM浓度而添加各肽,在96小时后用碘化丙啶(Propidium Iodide,PI)对细胞进行染色,通过流式细胞仪(Flowcytometer)而对各细胞的荧光强度进行测定并制作直方图。表示图表内各细周期(SubG1期、G1期、S期、G2/M期、>2N细胞)的细胞数的比例。
[图31-2]使表示图31-1的后续的图。
具体实施方式
虽然当实施或试验本发明的方式时,可以使用与本说明书所述的方法和材料类似的或同等的任意的方法和材料,但这里记载方法、装置和材料为优选的。然而,应该理解,在对本发明的材料和方法进行记载之前,本说明书所述的特定的大小、形状、尺寸、材料、方法论、步骤可以根据惯例性的实验法和最佳化而进行变更,因此,本发明不限于此。本记载中所使用的专业术语仅用于说明特定的类型或方式,并且应该理解,本发明的范围不仅限于由附加的权利要求书所限定的本发明的范围。
定义
本说明书中使用的“1个(a)”、“1个(an)”和“该(the)”这样的词语,除非特别说明,否则意味着“至少1个”。
在本说明书中,除非特别说明,否则用大写字母记载的氨基酸代表L-氨基酸。另一方面,用小写字母记载的氨基酸代表D-氨基酸。此外,在本说明书中所记载的L-氨基酸和D-氨基酸可以包含氨基、羧基和侧链中的任一项经过修饰的物质。作为优选的修饰的实例,可举出:氨基的乙酰化、羧基的酰胺化和FLAG标签、HA标签等的标签肽的添加等。
此外,在本说明书中,除非特别说明,否则表示氨基酸序列中的氨基酸残基的位置的编号将N末端的氨基酸残基设为1而在C末端方向上依次分配。
本说明书中使用的“BIG3”这样的术语是指布雷非德菌素A抑制鸟嘌呤核苷酸交换蛋白3(brefeldin A-inhibited guanine nucleotide-exchange protein)。BIG3通过与PHB2形成复合体,而阻碍抑制雌激素依赖性转录激活的PHB2的功能。BIG3也称为“ARFGEF3(ARFGEF family member 3)”或“A7322”。人BIG3基因的代表性的碱基序列的实例示于SEQID NO.6(GenBank Accession No.NM_020340.4)中,并且由其编码的氨基酸序列示于SEQID NO.7中。本发明中,BIG3不限于所述碱基序列中编码的物质,还包含这些的同工型、变体。
本说明书中使用的“PHB2”这样的术语是指抗增殖蛋白2(prohibitin 2)。PHB2与雌激素受体结合而阻碍雌激素受体信号传达途径、抑制雌激素依赖性细胞增殖。PHB2也称为“REA(Repressor of Estrogen Activity)”。人PHB2基因的代表性的碱基序列的实例分别示于SEQ ID NO.8(GenBank Accession No.NM_001144831.1)和SEQ ID NO.10(GenBankAccession No.NM_001267700.1)中,并且由其编码的氨基酸序列分别示于SEQ ID NO.9和SEQ ID NO.11中。在本发明中,PHB2不限于所述碱基序列中编码的物质,还包含这些的同工型、变体。
本说明书中使用的“PHB2肽”这样的术语是指阻碍BIG3和PHB2的结合的、源自PHB2的肽。具体而言,包含SEQ ID NO.17所示的氨基酸序列(YGVRE SVFTVE)。
本说明书中使用的“雌激素受体”这样的术语包括雌激素受体α(ERα)和雌激素受体β(ERβ)两者。当结合雌激素时,雌激素受体易位至核内,与DNA上的作为增强子序列的ERE结合而引起与细胞增殖有关的基因的转录激活。由此,诱导雌激素依赖性细胞增殖。ERα和ERβ分别由ESR1基因和ESR2基因编码。代表性的人ESR1基因的碱基序列示于SEQ ID NO.12(GenBank Accession No.NM_000125.3)中。此外,代表性的人ESR2基因的碱基序列示于SEQID NO.14(GenBank Accession No.NM_001437.2)中。在本发明中,ERα和ERβ不限于所述碱基序列中编码的物质,还包含这些的同工型、变体。在本发明的优选的方式中,雌激素受体为ERα。
本说明书中使用的“ERAP”这样的术语是指包含SEQ ID NO.4或SEQ ID NO.5所记载的氨基酸序列的肽。SEQ ID NO.4或SEQ ID NO.5所记载的氨基酸序列是包含BIG3的氨基酸序列(SEQ ID NO.7)的第165~177个或第165~178个氨基酸残基的序列,并包含在与PHB2的结合中重要的氨基酸残基(SEQ ID NO.7所记载的氨基酸序列中第165个的谷氨酰胺(Q)、第169个的天门冬氨酸(D)和第173个的谷氨酰胺(Q))。ERAP具有与PHB2的结合能力,通过竞争性地与PHB2进行结合,而阻碍BIG3与PHB2形成复合体。
本说明书中使用的“钉合(Stapling)结构”这样的术语是指,构成肽的氨基酸序列中2个(1对)氨基酸残基交联而成的结构。并且,在本说明书中,将由1个或多个钉合(Stapling)结构取代原本的氨基酸残基而成的肽称为“订书肽(Stapled peptide)”。例如,订书(stapled)ERAP(stERAP,stapled ERAP)是指,包含SEQ ID NO.4或SEQ ID NO.5所记载的氨基酸序列的肽(ERAP)中至少1对氨基酸残基被钉合(Stapling)结构取代而成的肽。此外,短订书(short stapled)ERAP是指,包含SEQ ID NO.4或5所记载的氨基酸序列的部分序列的肽(短ERAP)中至少1对氨基酸残基被钉合(Stapling)结构取代而成的肽。在本说明书中,短订书(short stapled)ERAP也表示为“sh订书(stapled)ERAP”。
将由1个钉合(Stapling)结构取代原本的氨基酸残基而成的肽称为“单订书肽(Single stapled peptide)”或“单交联肽”,将由2个钉合(Stapling)结构取代原始的氨基酸残基而成的肽称为“双订书肽(Stapled peptide)”或“双交联肽”。例如,单订书(Singlestapled)ERAP(单stERAP,单stapled ERAP)是指,包含SEQ ID NO.4或SEQ ID NO.5所记载的氨基酸序列的肽(ERAP)中1对氨基酸残基被钉合(Stapling)结构取代而成的肽,双订书(Double stapled)ERAP(dsERAP,双stERAP,双stapled ERAP)是指,包含SEQ ID NO.4或SEQID NO.5所记载的氨基酸序列肽(ERAP)中2对氨基酸残基被钉合(Stapling)结构取代而成的肽。
由于这些订书肽(Stapled peptide)具有其一部分被人为性地取代而成的结构,因此,可以称为肽衍生物或肽类似物。
本说明书中使用的“治疗”这样的术语包括:缓和·改善由目标疾病引起的至少1种症状、抑制疾病的恶化和抑制疾病部位的扩大等。例如,“癌症的治疗”包括:癌症细胞的增殖抑制、癌症的恶化抑制、癌症的消退·缓解的诱导、癌症所伴随的症状的缓和·改善、癌症的转移的抑制、术后的复发抑制和生存期间延长的诱导等。
本发明的肽
本发明的肽是包含在SEQ ID NO.4或SEQ ID NO.5所记载的氨基酸序列中,n对(n为自然数)氨基酸残基被n个钉合(Stapling)结构取代的氨基酸序列的肽。N优选为3以下,更优选为2。因此,在本发明中,n对氨基酸残基是指,通常1~3对,或1对或2对,优选为2对氨基酸残基。
在本发明的肽中,虽然被钉合(Stapling)结构取代的氨基酸残基没有特别限定,但由于从SEQ ID NO.4或从SEQ ID NO.5所记载的氨基酸序列的N末端起第1个的谷氨酰胺(Q)、第5个的天门冬氨酸(D)和第9个的谷氨酰胺(Q)是在与PHB2的结合中重要的氨基酸残基,因此,从与PHB2的结合亲和性的观点出发,优选选自从SEQ ID NO.4(QMLSDLTLQLRQR)或SEQ ID NO.5(QMLSDLTLQLRQRQ)所记载的氨基酸序列的N末端起第1个的谷氨酰胺(Q)、第5个的天门冬氨酸(D)和第9个的谷氨酰胺(Q)以外的氨基酸残基。
例如,可以通过在构成肽的氨基酸残基中,将钉合(Staple)结构导入亮氨酸残基(L)中,而赋予糜蛋白酶耐药性。例如,优选包含选自SEQ ID NO.4或5的氨基酸序列中的第3个、第6个、第8个和第10个中的至少1个L的至少2对氨基酸残基作为被钉合(Staple)结构取代的位置。
作为被钉合(Stapling)结构取代的氨基酸残基的实例,例如可举出以下的氨基酸残基对;
(a)从SEQ ID NO.4所记载的氨基酸序列的N末端起第3个(L)和第7个氨基酸残基(T):
(b)从SEQ ID NO.4所记载的氨基酸序列的N末端起第8个(L)和第12个氨基酸残基(Q);
(c)从SEQ ID NO.5所记载的氨基酸序列的N末端起第3个(L)和第7个氨基酸残基(T);和
(d)从SEQ ID NO.5所记载的氨基酸序列的N末端起第10个(L)和第14个氨基酸残基(Q)。
特别优选所述(a)和(b)、或(c)和(d)的氨基酸残基被钉合(Stapling)结构取代。
在本发明的肽中,钉合(Stapling)结构没有特别限定。由于肽的钉合(Stapling)技术是公知的(例如,Blakwell,H.E.et al.,Angew.Chem.,Int.Ed.37,3281-3284(1994);Aihara,K.et al.,Tetrahedron 71,4183-4191(2015)等),因此,可以使用这些公知的钉合(Stapling)技术而形成钉合(Stapling)结构。例如,可以通过导入具有烯基等的取代基的氨基酸衍生物、固相合成等而合成肽,在所述氨基酸衍生物的取代基间进行烯烃复分解反应、分子内酰胺化反应,从而形成钉合(Stapling)结构。用于形成钉合(Stapling)结构的氨基酸衍生物可以使用市售的物质。
在本发明的肽中,作为优选的钉合(Stapling)结构的实例,例如可举出下述式(I)表示的结构。
[化学式3]
式中,实线和虚线的双划线表示单键或双键。
所述式(I)的钉合(Stapling)结构的形成,例如图7的示意图(scheme)(以下“示意图(scheme)(I)”)是通过烯烃复分解反应而形成钉合(Stapling)结构的实例。另一方面,图8所示的示意图(scheme)(以下“示意图(scheme)(II)”)是通过分子内酰胺化反应而形成钉合(Stapling)结构的实例。
在通过示意图(scheme)(I)所示的烯烃复分解反应而形成钉合(Stapling)结构的情况下,作为用于钉合(Stapling)的氨基酸衍生物,可以使用下述式(III)表示的谷氨酰胺衍生物(4-{烯丙基-[2-(叔丁基-二甲基-硅烷氧基)-4-甲氧基-苄基]-羰基}-2-(9H-芴-9-基甲氧基羰基氨基)-丁酸)。
[化学式4]
式(III)的谷氨酰胺衍生物,例如,可以根据以下的示意图(scheme)(III)而合成(Aihara,K.et al.,Tetrahedron 71,4183-4191(2015))。
示意图(scheme)(III)
[化学式5]
在所述示意图(scheme)(III)中,(i)~(vi)分别表示以下:(i)3-氨基-1-丙烯、AcOH、MgSO4、CH2Cl2;(ii)NaBH4、MeOH、CH2Cl2;(iii)化合物2、DCC、CH2Cl2;(iv)LiOH·H2O、THF、MeOH、H2O;(v)TBSOtf、2,6-二甲基吡啶;(vi)Fmoc-OSu、Na2CO3、THF、H2O。
如示意图(scheme)(III)所示,使2-羟基-4-甲氧基苯甲醛(化合物1)通过3-氨基-1-丙烯而还原性地氨基化,得到2-烯丙基氨基甲基-5-甲氧基-苯酚(化合物2)。接着,使化合物2与N-α-(叔丁氧基羰基)-L-谷氨酸α甲酯(化合物3)偶联,得到4-[烯丙基-(2-羟基-4-甲氧基-苄基)氨基甲酰基]-2-叔丁氧基羰基氨基-丁酸甲基酯(化合物4)。接下来,使化合物4的甲基酯水解,得到4-[烯丙基-(2-羟基-4-甲氧基-苄基)-氨基甲酰基]-2-叔丁氧基羰基氨基-丁酸(化合物5)。此外,用Fmoc基取代化合物5的Boc基,用TBS保护Hmb基的酚部分,从而可以得到式(III)的谷氨酰胺衍生物。需要说明的是,示意图(scheme)(III)的实施中需要的试剂种类都可以使用市售的物质。
另一方面,基于示意图(scheme)(I)的、订书(stapled)ERAP的合成,可以使用所述式(III)的谷氨酰胺衍生物,例如,通过以下的方式进行。首先,在SEQ ID NO.4或SEQ IDNO.5所记载的氨基酸序列中,分别用式(III)的谷氨酰胺衍生物取代待形成钉合(Stapling)结构的位置的氨基酸残基对,通过标准性的Fmoc固相肽合成而合成肽。接着,使Fmoc保护的肽N末端脱保护和乙酰化后,将乙酰化肽用Hoveyda-Grubbs第2代催化剂进行处理而进行烯烃复分解反应。此外,使用TFA/间甲酚/硫代苯甲醚/1,2-乙二硫醇/H2O混合物,进行酸不稳定保护基的脱保护和肽从树脂的分离。由此,可以得到具有式(I)的钉合(Stapling)结构(实线和虚线的双划线为双键)的订书(stapled)ERAP或sh订书(stapled)ERAP。需要说明的是,在通过示意图(scheme)(I)而合成的订书(stapled)ERAP或sh订书(stapled)ERAP中,介于钉合(Stapling)结构之间的氨基酸残基的数量没有特别限定,通常,优选为3残基。即,将夹有3残基的1对氨基酸残基用1个钉合(Stapling)结构取代而成的结构是本发明中的优选的钉合(Stapling)结构的实例。夹有3残基的钉合(Stapling)结构在保持肽的α螺旋结构方面是有效的。
此外,在通过示意图(scheme)(II)所示的分子内酰胺化反应而形成钉合(Stapling)结构的情况下,作为用于钉合(Stapling)的氨基酸衍生物,可以使用下述式(IV)表示的N-α-(9-芴基甲氧基羰基)-L-谷氨酸γ烯丙基酯和下述式(V)表示的(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)5-((4-(((烯丙基氧基)羰基)氨基)丁基)(2,4-二甲氧基苄基)氨基)-5-氧代戊酸。
[化学式6]
此外,在所述2种氨基酸衍生物中,式(IV)的谷氨酸衍生物可以使用市售的物质。此外,式(V)的谷氨酰胺衍生物,例如可以根据图6所示的示意图(scheme)(以下“示意图(scheme)(IV)”)而合成。如示意图(scheme)(IV)所示,使烯丙基(4-氨基丁基)氨基甲酸酯(化合物1)与2,4-二甲氧基苯甲醛偶联,得到烯丙基[4-{(2,4-二甲氧基苄基)氨基}丁基]氨基甲酸酯(化合物2)。接着,使化合物2与N-α-(叔丁氧基羰基)-L-谷氨酸α甲基酯(化合物3)偶联,得到(S)-甲基-5-{(4-[{(烯丙基氧基)羰基}氨基]丁基)(2,4-二甲氧基苄基)氨基}-2-{(叔丁氧基羰基)氨基}-5-氧代戊酸甲酯(化合物4)。接下来,使化合物4的甲基酯水解,得到(S)-5-{(4-[{(烯丙基氧基)羰基}氨基]丁基)(2,4-二甲氧基苄基)氨基}-2-{(叔丁氧基羰基)氨基}-5-氧代戊酸(化合物5)。此外,可以通过用Fmoc基取代化合物5的Boc基,而得到式(V)的谷氨酰胺衍生物。需要说明的是,示意图(scheme)(IV)的实施中需要的试剂种类可以都使用市售的物质。
另一方面,基于示意图(scheme)(II)的订书(stapled)ERAP的合成可以使用所述式(IV)的谷氨酸衍生物和式(V)的谷氨酰胺衍生物,例如,通过以下的方式进行。首先,在SEQ ID NO.4或SEQ ID NO.5所记载的氨基酸序列中,分别用式(IV)的谷氨酸衍生物和式(V)的谷氨酰胺衍生物取代待形成钉合(Stapling)结构的位置的氨基酸残基对,通过标准性的Fmoc固相肽合成而合成肽。接着,将Fmoc保护的肽与四(三苯基膦)钯(Pd(PPh3)4)的CHCl3/AcOH/N-甲基吗啉溶液进行混合,使谷氨酰胺衍生物残基的取代基还原。接着,使用N,N-二异丙基碳二亚胺(DIPCDI)和1-羟基-1H-苯并三唑水合物(HOBt·H2O)而使谷氨酰胺衍生物残基偶联,从而进行分子内酰胺化。此外,使用TFA/间甲酚/硫代苯甲醚/1,2-乙二硫醇/H2O混合物,而进行酸不稳定保护基的脱保护和肽从树脂的分离。由此,可以得到具有式(I)的钉合(Stapling)结构(实线和虚线的双划线为单键)的订书(stapled)ERAP或sh订书(stapled)ERAP。需要说明的是,在通过示意图(scheme)(II)而合成的订书(stapled)ERAP或sh订书(stapled)ERAP中,介于钉合(Stapling)结构之间的氨基酸残基的数量没有特别限定,通常,优选为3残基。
可以在导入最初(即,第1对)的钉合(Stapling)结构后,通过重复同样的反应而合成肽链,直至导入下一对(即,第2对)钉合(Staple)结构的位置。并且,通过第2次分子内交联反应,而带来第2对钉合(Stapling)结构。在进一步增加交联结构的情况下,可以通过重复同样的反应而得到目标结构。或者,可以使导入了1个钉合(Stapling)结构的2个(或其以上)肽片段连接,形成导入了2个(或其以上)的钉合(Stapling)结构的肽。
因此,在某些方式中,被钉合(Stapling)结构取代的2对氨基酸残基至少相邻,或经由1个以上的氨基酸残基而独立定位。即,通常,介于1个钉合(Stapling)结构的内部的氨基酸残基不用别的钉合(Stapling)结构取代。例如,在导入2对钉合(Stapling)结构的情况下,介于钉合(Stapling)结构之间的氨基酸残基的数量,例如可以设为0(即,相邻)、1、2或3。当考虑如上的条件时,在SEQ ID NO.4或5的氨基酸序列中,N末端侧的1对氨基酸残基和夹有0~3残基并位于其C末端侧的第2对氨基酸残基分别被钉合(Stapling)结构取代而成的肽,具有本发明中的优选的结构。并且,通过将构成各氨基酸对的氨基酸残基中至少1个设为L,而能够期待肽对糜蛋白酶的作用的耐药性。
作为本发明的肽的具体结构的实例,例如可举出具备至少2个下述式(II)表示的钉合(Stapling)结构的结构。
[化学式7]
式中,实线和虚线的双划线为单键或双键;
A1、A2、A3、A4和A5的组合从以下进行选择:
A1=QM,A2=SDL,A3=-,A4=QLR,A5=R
A1=QM,A2=SDL,A3=LQ,A4=RQR,A5=OH
此处“-”表示为肽键而没有氨基酸残基(即2个钉合(Stapling)结构相连接);
并且,“OH”表示所述钉合(Stapling)结构的一端构成肽衍生物的C末端。
具备2个所述式(II)表示的钉合(Stapling)结构的肽可以说是下述肽:在包含SEQID NO.4(QMLSDLTLQLRQR)所记载的氨基酸序列的肽中,以下的(a)和(b)的2对氨基酸残基分别被式(I)的钉合(Staple)结构取代而成的肽;
(a)从SEQ ID NO.4所记载的氨基酸序列的N末端起第3个(L)和第7个氨基酸残基(T);和
(b)从SEQ ID NO.4所记载的氨基酸序列的N末端起第8个(L)和第12个氨基酸残基(Q);
或,在包含SEQ ID NO.5(QMLSDLTLQLRQRQ)所记载的氨基酸序列的肽中,以下的(c)和(d)的2对氨基酸残基被式(I)的钉合(Staple)结构取代而成的肽;
(c)从SEQ ID NO.5所记载的氨基酸序列的N末端起第3个(L)和第7个氨基酸残基(T);和
(d)从SEQ ID NO.5所记载的氨基酸序列的N末端起第10个(L)和第14个氨基酸残基(Q)。
在具备至少2个式(II)表示的钉合(Stapling)结构的肽中,作为特别优选的肽,可举出:(II)的式中,A1,A2,A3,A4和A5的组合从以下进行选择的肽:
A1=QM,A2=SDL,A3=-,A4=QLR,A5=R
A1=QM,A2=SDL,A3=LQ,A4=RQR,A5=OH
此处“-”表示为肽键而没有氨基酸残基(即2个钉合(Stapling)结构相连接);
并且,“OH”表示所述钉合(Stapling)结构的一端构成肽衍生物的C末端。
这些肽对应于以下的肽:
(i)在包含SEQ ID NO.4(QMLSDLTLQLRQR)所记载的氨基酸序列的肽中,以下的(a)和(b)的2对氨基酸残基分别被式(I)的钉合(Staple)结构取代而成的肽;
(a)从SEQ ID NO.4所记载的氨基酸序列的N末端起第3个(L)和第7个氨基酸残基(T);和
(b)从SEQ ID NO.4所记载的氨基酸序列的N末端起第8个(L)和第12个氨基酸残基(Q);或,
(ii)在包含SEQ ID NO.5(QMLSDLTLQLRQRQ)所记载的氨基酸序列的肽中,以下的(c)和(d)的2对氨基酸残基分别被式(I)的钉合(Staple)结构取代而成的肽;
(c)从SEQ ID NO.5所记载的氨基酸序列的N末端起第3个(L)和第7个氨基酸残基(T);和
(d)从SEQ ID NO.5所记载的氨基酸序列的N末端起第10个(L)和第14个氨基酸残基(Q)。
需要说明的是,本发明的肽还包括N末端和C末端的氨基酸残基的任一者或两者经过了修饰的肽。修饰的种类没有特别限定,优选不影响对PHB2的亲和性和细胞渗透性的。作为优选的修饰的实例,例如可举出:N末端的氨基酸残基的乙酰化、C末端的氨基酸残基的酰胺化、和HA标签、FLAG标签等的标签肽的添加等。此外,作为本发明的肽的特别优选的实例,可举出:在所述式(II)表示的肽中,N末端的氨基酸残基被乙酰化、C末端的氨基酸残基被酰胺化的肽。需要说明的是,优选N末端和C末端的氨基酸残基以外的氨基酸残基未经过修饰。
本发明的肽不限于由L-氨基酸构成的物质,可以是包含1个以上的D-氨基酸的物质。肽中的L-氨基酸与D-氨基酸的构成比没有特别限定,优选为了保持α螺旋结构,所有氨基酸残基为L型(以下“L型肽”),或所有氨基酸残基为D型(以下“D型肽”)。因此,在任一所述本发明的肽中,所有氨基酸残基均被D型的氨基酸残基取代而成的肽也可作为本发明的肽的优选的方式而举出。在本发明的肽为D型肽的情况下,作为优选的肽,例如可举出:在式(II)表示的肽中,所有氨基酸残基均被D型的氨基酸残基取代而成的肽。
此外,本发明的肽可以是任一所述本发明的肽的逆反(Retro inverse)体。在逆反(Retro inverse)体的情况下,原本的肽的氨基酸序列颠倒,所有氨基酸残基被D型的氨基酸残基取代。即,逆反(Retro inverse)体是具有与原本的肽反向的氨基酸序列的D型肽。因此,作为任一所述本发明的肽的逆反(Retro inverse)体的肽,也可作为本发明的肽的优选的方式而举出。在本发明的肽为逆反(Retro inverse)体的情况下,作为优选的肽,例如可举出:作为式(II)表示的肽的逆反(Retro inverse)体的肽。
本发明的肽为D型肽的情况下,在如上所述的方法中,可以通过使用D-氨基酸代替L-氨基酸,而合成D型的订书(stapled)ERAP或sh订书(stapled)ERAP。需要说明的是,在D型的订书(stapled)ERAP或sh订书(stapled)ERAP的合成中,用于钉合(Stapling)结构形成的氨基酸衍生物也使用D型的。由于钉合(Stapling)结构形成中使用的一些D型氨基酸衍生物是市售的,因此,可以使用这些市售的D型氨基酸衍生物。
此外,在通过图7的示意图(scheme)(I)而合成D型的订书(stapled)ERAP的情况下,作为用于钉合(Stapling)的氨基酸衍生物,可以使用式(III)表示的谷氨酰胺衍生物的D型光学异构体(以下“式(III)的D-谷氨酰胺衍生物”)。式(III)的D-谷氨酰胺衍生物可以通过在所述示意图(scheme)(III)中使用N-α-(叔丁氧基羰基)-D-谷氨酸α甲基酯代替N-α-(叔丁氧基羰基)-L-谷氨酸α甲基酯(化合物3)而合成。并且,在SEQ ID NO.4或SEQ ID NO.5所记载的氨基酸序列中,分别用式(III)的D-谷氨酰胺衍生物取代待形成钉合(Stapling)结构的位置的氨基酸残基对,使用D-氨基酸并通过标准性的Fmoc固相肽合成而合成D型肽,根据示意图(scheme)(I)而进行烯烃复分解反应,从而能够得到D型的订书(stapled)ERAP。需要说明的是,在合成订书(stapled)ERAP或sh订书(stapled)ERAP的逆反(Retroinverse)体的情况下,基于SEQ ID NO.4或5所记载的氨基酸序列或其部分序列的反向的氨基酸序列,进行肽固相合成即可。此时,与所述同样,待形成钉合(Stapling)结构的位置的氨基酸残基对分别用式(II)的D-谷氨酰胺衍生物取代,在肽合成后,进行烯烃复分解反应。
在通过图8中所示示意图(scheme)(II)而合成D型的订书(stapled)ERAP的情况下,作为用于钉合(Stapling)的氨基酸衍生物,使用式(IV)表示的谷氨酸衍生物的D型光学异构体(以下“式(IV)的D-谷氨酸衍生物”)和式(V)表示的谷氨酰胺衍生物的D型光学异构体(以下“式(V)的D-谷氨酰胺衍生物”)即可。式(IV)的D-谷氨酸衍生物可以使用市售的物质。此外,式(V)的D-谷氨酰胺衍生物可以通过在图1A所示的示意图(scheme)(IV)中使用N-α-(叔丁氧基羰基)-D-谷氨酸α甲基酯代替N-α-(叔丁氧基羰基)-L-谷氨酸α甲基酯(化合物3)而合成。并且,在SEQ ID NO.4或SEQ ID NO.5所记载的氨基酸序列中,分别用式(IV)的D-谷氨酸衍生物和式(V)的D-谷氨酰胺衍生物取代待形成钉合(Stapling)结构的位置的氨基酸残基对,使用D-氨基酸并通过标准性的Fmoc固相肽合成而合成D型肽,根据示意图(scheme)(II)而进行分子内酰胺化反应,从而能够得到D型的订书(stapled)ERAP。需要说明的是,在合成订书(stapled)ERAP的逆反(Retro inverse)体的情况下,基于SEQ ID NO.4或SEQ ID NO.5所记载的氨基酸序列的反向的氨基酸序列,进行肽固相合成即可。此时,与所述同样,分别用式(IV)的D-谷氨酸衍生物和式(V)的D-谷氨酰胺衍生物取代待形成钉合(Stapling)结构的位置的氨基酸残基对,在肽合成后,进行分子内酰胺化反应。
此外,本发明的肽可以是盐的形态。盐的形态没有特别限定,优选是药学上允许的盐。需要说明的是,在本说明书中“药学上允许的盐”是指保持肽的药理学性或药学性的有效性和特性的盐。作为盐的优选的实例,可举出:碱金属(锂、钾、钠等)的盐、碱土金属(钙、镁等)的盐、其它金属(铜、铁、锌、锰等)的盐、有机碱基的盐、胺的盐、有机酸(乙酸、甲酸、丙酸、富马酸、马来酸、琥珀酸、酒石酸、柠檬酸、苹果酸、草酸、苯甲酸、甲磺酸等)的盐和无机酸(盐酸、磷酸、溴化氢酸、硫酸、硝酸等)的盐等。这些盐可以根据公知的方法而制备。
药物组合物
本发明的肽或其盐可以与药学上允许的载体一同作为药物组合物而制剂化。
本发明的肽具有对PHB2的结合能力,竞争性地阻碍BIG3-PHB2相互作用。BIG3-PHB2复合体的形成使雌激素依赖性转录活性提高,导致癌症细胞的增殖。因此,阻碍BIG3-PHB2相互作用而抑制BIG3-PHB2复合体的形成的本发明的肽,作为用于治疗癌症的药物组合物特别有用。
BIG3-PHB2复合体的形成导致的雌激素依赖性转录活性的提高,主要发生在雌激素受体阳性细胞中。因此,本发明的肽作为用于治疗雌激素受体阳性的癌症的药物组合物特别有用。作为这样的雌激素受体阳性的癌症的实例,可举出:乳腺癌、子宫内膜癌、卵巢癌、前列腺癌(Nelles JL,et al.,Expert Rev Endocrinol Metab.2011May;6(3):437-451.)、肺癌(特别是非小细胞肺癌症)(Stabile LP,et al.,Cancer Res.2005Feb 15;65(4):1459-70.;Marquez-Garban DC,et al.,Steroids.2007Feb;72(2):135-43.)等,但是不限于此。需要说明的是,适用本发明的药物组合物的癌症优选表达BIG3和PHB2,通常而言,雌激素受体阳性的癌症表达BIG3和PHB2。癌症是否为雌激素受体阳性可以通过ELISA法、免疫组织化学染色法等的公知的方法而进行确认。
此外,本发明的肽对于他莫昔芬耐药性的雌激素受体阳性的癌症也具有增殖抑制效果。因此,本发明的药物组合物可以适用于他莫昔芬耐药性的雌激素受体阳性的癌症。作为适用本发明的药物组合物的他莫昔芬耐药性的雌激素受体阳性的癌症的实例,例如可举出:他莫昔芬耐药性雌激素受体阳性乳腺癌。因此,作为本发明的药物组合物的优选的给药对象的实例,可举出具有他莫昔芬疗法不应性的雌激素受体阳性乳腺癌的患者。
此外,本发明的肽在雌激素受体(ESR1)中具有变异的乳腺癌细胞中也显示出增殖阻碍作用。ESR1的变异被认为是获得对激素疗法的抵抗性的机理之一。此外,在三阴性的乳腺癌细胞中,本发明的肽也显示出优异的细胞增殖抑制作用(图30)。通常,三阴性是指乳腺癌细胞欠缺作为主要的药物治疗的靶标因子的HER2、雌激素受体和孕激素受体的表达。因此,通常,三阴性的乳腺癌对药物治疗具有抵抗性。或者,本发明人等发现,本发明的肽对通常认为恶性度高的乳腺癌的HER2阳性的乳腺癌细胞,也具有高的细胞增殖抑制效果。因此,本发明的肽作为用于对这些治疗抵抗性或恶性的乳腺癌的患者进行给药的药物组合物是有用的。
即,本发明提供包含本发明的肽的药物组合物,其是用于对药物疗法抵抗性的乳腺癌患者和恶性的乳腺癌的任一者或两者进行给药的药物组合物。此外,本发明涉及用于在药物疗法抵抗性的乳腺癌患者和恶性的乳腺癌的任一者或两者的治疗中使用的本发明的肽。进一步,本发明涉及本发明的肽的、用于药物疗法抵抗性的乳腺癌患者和恶性的乳腺癌的任一者或两者的治疗的药物组合物的制造中的使用。或者,本发明还提供乳腺癌的治疗方法,其包含下述工序:对具有药物疗法抵抗性的乳腺癌患者和恶性的乳腺癌的任一者或两者的患者进行选择的工序和对所选择的患者投与本发明的肽的工序。
药物疗法抵抗性的乳腺癌患者可以通过在通常性的药物疗法后,对其治疗成绩进行观察而确定。具体而言,在通过治疗而未明确地观察到病灶的退缩的情况下,可以知道为治疗抵抗性。需要说明的是,阻止病灶的扩大的状态包含在病灶的退缩中。或者,预测乳腺癌的恶性度的标记是公知的。在检测出这些标记的情况下,知道患者具有恶性度高的乳腺癌。例如,HER2是乳腺癌的恶性度的指标之一。此外,三阴性的乳腺癌患者也对药物疗法具有抵抗性。三阴性是指具有下述特征的乳腺癌:除了前文所述的HER2之外,还欠缺雌激素受体和孕激素受体的表达。这些恶性度、药物疗法抵抗性的标记可以通过免疫染色、基因表达分析而进行定量性地评价。例如,在具有阴性对照同程度的表达水平的情况下,判断为阴性。阴性对照可以使用欠缺这些标记的表达的治疗抵抗性的癌症细胞株。
本发明的药物组合物可以通过将本发明的肽或其盐和药学上允许的载体进行混合,使用公知的制剂化技术而进行制造。需要说明的是,本说明书中“药学上允许的载体”是指,用作药物的稀释剂或溶剂的不活泼的物质。本发明的药物组合物中使用的药学上允许的载体可以根据要制备的药物组合物的剂形,而适宜选择通常性的药品中使用的载体即可。
本发明的药物组合物的剂形没有特别限定,可以适宜选择液剂、片剂、瓶装剂(ELIXIR)、胶囊剂、颗粒剂、散剂等的药品中通常使用的剂形。此外,可以根据选择的剂形,而适宜添加赋形剂、稳定剂、悬浮液、防腐剂、表面活性剂、增溶剂、pH调整剂、凝聚抑制剂等的添加物。
本发明的药物组合物包含药学性有效量的本发明的肽或其盐。药学性有效量可以根据药物组合物的剂形、给药间隔、给药对象的年龄、性别、体重、体表面积、疾病的种类等而适宜选择。例如,作为本发明的药物组合物中的本发明的肽或其盐的含量的实例,可举出:0.001mg~1000mg、0.01mg~100mg、0.1mg~30mg、0.1mg~10mg等,但不限于此。
此外,本发明的药物组合物可以任意包含其他药剂。作为其他药剂的实例,可举出:抗炎症剂、镇痛剂、解热剂、其他癌症治疗剂等。可以在本发明的药物组合物中使用的其他癌症治疗剂没有特别限定,在雌激素阳性的癌症中使用的情况下,可举出:选择性ERα调节剂(例如,他莫昔芬和雷洛昔芬)、ERα下调剂(例如,氟维司群)、芳香化酶抑制剂、LH-RH激动剂制剂、孕激素制剂等的激素疗法剂。此外,这些药剂可以以前体药物、药学上允许的盐的形式而进行混合。
本发明的药物组合物可以根据剂形,适宜选自适当的给药途径,对对象进行给药。给药途径没有特别限定,例如可举出:口服给药和皮内、皮下、肌肉内、骨内、腹膜和静脉内注射等。此外,可以是全身给药和向疾病部位附近的局部给药中的任一种,优选局部给药。更具体而言,可以通过注射等的手段而将本发明的药物组合物给药至癌症组织及其附近。或者,本发明的药物组合物可以外科性地给药至癌症组织内及其附近。本发明的药物组合物可以通过与适当的载体进行混合而成为缓释制剂。
本发明的药物组合物的给药间隔也可以根据给药对象的年龄、性别、体重、体表面积、疾病的种类等和本药物组合物的剂形和给药途径等而进行适宜选择。作为给药间隔的实例,例如可举出:每日、每4日、每7日等,但不限于此。
本发明的药物组合物的用量也可以根据给药对象的年龄、性别、体重、体表面积、疾病的种类等和本药物组合物的剂形和给药途径等而进行适宜选择。
作为本发明的肽或其盐的用量的实例,例如可举出:0.001~1000mg/kg/日、0.005~500mg/kg/日、0.01~250mg/kg/日等,但不限于此。
本发明的药物组合物可以根据给药对象的状态而与其他药品组合使用。组合使用的药品没有特别限定,在雌激素受体阳性的癌症中使用的情况下,可举出:选择性ERα调节剂(例如,他莫昔芬和雷洛昔芬)、ERα下调剂(例如,氟维司群)、芳香化酶抑制剂、LH-RH激动剂制剂、孕激素制剂等的激素疗法剂。在这些激素疗法剂中,作为特别优选的物质,可举出他莫昔芬和氟维司群。
在使用本发明的药物组合物用于癌症的治疗的情况下,可以在给药前调查治疗对象的癌症是否表达BIG3和PHB2。治疗对象的癌症是否表达BIG3和PHB2,可以通过在从对象采集的样品中对这些基因的转录产物、翻译产物进行检测而确认。检测方法可以使用公知的方法,例如,可以使用:通过基因探针、PCR法而对转录产物进行检测的方法(例如,cDNA微阵列法、Northern印迹杂交法、RT-PCR法等)和通过抗体等而对翻译产物进行检测的方法(例如,蛋白质印迹法(Western Blot)法、免疫染色法等)等。
本发明还提供包含本发明的药物组合物的制品或试剂盒。本发明的制品或试剂盒可以包含容纳本发明的药物组合物的容器。作为适当的容器的实例,可举出:瓶、管形瓶和试验管,但不限于此。容器可以由玻璃或塑料等的各种材料形成。容器上可以贴附标签,标签上可以记载应该使用本发明的药学性组合物的疾病或疾病的状态。标签还可以显示出与给药等有关的指示。
除了容纳本发明的药物组合物的容器之外,本发明的制品或试剂盒可以进一步包含任意容纳药学上允许的稀释剂的第2容器。本发明的制品或试剂盒可以进一步包含其他缓冲液、稀释剂、过滤器、注射针、注射器和记载了使用说明的附加文书等的从商业上的观点和使用者的观点出发优选的其它材料。
本发明的药物组合物根据需要还可以提供:可以包含含有1个或多个有效成分的单元剂形的包装或分发装置。该包装例如可以包含泡罩包装这样的金属箔或塑料箔。包装或分发装置可以附加与给药有关的说明书。
在别的方式中,本发明还提供以下的使用和方法等:
(a)用于治疗癌症的药物组合物的制造中的、本发明的肽或其盐的使用;
(b)在癌症的治疗中使用的本发明的肽或其盐;
(c)一种用于制造用于治疗癌症的药物组合物的方法或工序,其包含使本发明的肽或其盐和药学上允许的载体制剂化的阶段;
(d)一种用于制造用于治疗癌症的药物组合物的方法或工序,其包含使本发明的肽或其盐与药学上允许的载体进行混合的阶段;和
(e)包含将本发明的肽或其盐对对象进行给药的用于治疗癌症的方法。
以下,参照实施例而对本发明进行更详细地描述。然而,虽然以下的材料、方法和实施例可以在本发明的某种方式的制备和使用中用于支援本领域技术人员,但只是用于对本发明的某方面进行说明,因此,绝不旨在限定本发明的范围。本领域技术人员可以在本发明的实施或试验中使用与本说明书所述的类似或同等的方法和材料。
需要说明的是,本说明书中引用的所有现有技术文献作为参照而组入本说明书中。
实施例
实施例1双订书肽(Stapled peptide)的合成
双订书(Double stapled)ERAP No.45(SEQ ID NO.2)和订书(stapled)ERAP
No.46(SEQ ID NO.3)的合成
使用Rink Amide AM树脂(content:0.62mmol胺/g),通过Fmoc型固相合成法而进行肽链的延伸。在双订书(Double stapled)ERAP No.45的前体序列QMX1SDLX2X1QLRX2R、双订书(Double stapled)ERAP No.46的前体序列QMX1SDLX2LQX1RQRX2的钉合(Staple)化所需的位点导入非天然氨基酸X(X1=Fmoc-Glu(OAllyl)-OH;X2=Fmoc-Glu(N(DMB)-CH2CH2CH2CH2-NH-Alloc)-OH。对于天然型氨基酸,分别使用相对于树脂为3当量的Fmoc-Gln(Trt)-OH、Fmoc-Met-OH、Fmoc-Ser(tBu)-OH、Fmoc-Asp(OtBu)-OH、Fmoc-Leu-OH、Fmoc-Arg(Pbf)-OH。在N,N-二甲基甲酰胺(DMF)中使用O-苯并三氮唑-N’,N’,N’,N’-四甲基脲六氟磷酸酯(HBTU;相对于氨基酸为0.99当量)、N,N-二异丙基乙胺(DIPEA;相对于氨基酸为2当量),在室温下进行30秒激活后,对于固相树脂上的氨基而在室温下进行2小时反应。对于非天然氨基酸X,利用相对于树脂为1.5当量的氨基酸,同样,将HBTU作为激活剂而在室温下进行2小时反应。需要说明的是,Fmoc基的切断通过20%哌啶DMF溶液而在室温下进行10分钟的处理。
对于钉合(Staple)化,在从C末端侧导入一组X1和X2的时间点进行。即,使Nα-Fmoc保护肽树脂在Ar氛围下在N-甲基吗啉(10当量)/AcOH/CHCl3(0.5:2:37.5(v/v))的混合溶剂中,添加Pd(PPh3)4(3当量)并在室温下进行12小时搅拌(进行2次),进行烯丙基和烯丙氧羰(Alloc)基的除去。就除去保护基后的树脂的清洗而言,按照CHCl3、DMF、1M二甲基二硫代氨基甲酸钠/DMF(氨基脲溶液)、CHCl3、DMF、1M 1-羟基苯并三唑(HOBt)·H2O/NMP(仅第2次脱保护后)的顺序清洗树脂后,在N-甲基-2-吡咯烷酮(NMP)中添加1M HOBt·H2O/NMP(10当量)、DIPCI(10当量)并在室温下进行24小时反应,进行分子内酰胺键形成。需要说明的是,对于第2个钉合(Staple)化而言,在树脂的延伸结束后,对Nα-乙酰化树脂进行与所述同样的手法。此外,N末端的乙酰化使用(AcO)2O(相对于氨基酸为10当量)、DIPEA(相对于氨基酸为10当量)而进行。
使结束了氨基酸的延伸和侧链钉合(Staple)化的树脂在TFA-硫代苯甲醚-间甲酚-1,2-乙二硫醇(EDT)-H2O(80:5:5:5:5(v/v),相对于树脂为1mg的脱保护反应液50μL)中,在室温下进行2小时处理而进行侧链保护基的切断。使反应液浓缩后,添加Et2O,使粗肽沉淀,进行3次Et2O清洗,得到HPLC纯化用样品。肽的纯化条件和质量分析结果如下。
双订书(Double stapled)ERAP No.45
柱:Cosmosil 5C18(10x250mm);溶剂:
A 0.1%TFA-H2O,B 0.1%TFA in CH3CN,
B(10%-45%over 30min)in solvent A;
流速:3.0mL/min;检测:220nm,
保留时间24.5min
MS m/z calcd for C76H130N26O23S[M+2H]+904.5,
found 904.6
双订书(Double stapled)ERAP No.46
柱:Cosmosil 5C18(10x250mm);溶剂:
A 0.1%TFA-H2O,
B 0.1%TFA in CH3CN,B(10%-45%over 30min)in solvent A;
流速:3.0mL/min;检测:220nm,
保留时间19.8min
MS m/z calcd for C81H138N28O25S[M+2H]+968.5,
Found 968.6
非天然氨基酸X1和X2的结构(X1=Fmoc-Glu(OAllyl)-OH;X2=Fmoc-Glu(N(DMB)-CH2CH2CH2CH2-NH-Alloc)-OH)
[化学式8]
实施例2对于雌激素依赖性乳腺癌细胞的双订书(Double stapled)ERAP的效果
材料和方法
细胞株和培养条件
人乳腺癌细胞株MCF-7从JCRB细胞库(大阪,日本)购入,乳腺上皮细胞株MCF-10A从American Type Culture Collection(ATCC,Manassas,VA,USA)购入。全部的细胞株均在适当的培养基中,在5%CO2、37℃的条件下维护细胞。
在细胞增殖测试中,使用48孔板(2×104cells/200μL)而接种各细胞,在免疫沉淀法中,使用10cm皿(dish)(2×106cells/10mL)而接种各细胞。
MCF-7细胞接种在补充有10%FBS(NICHIREI BIOSCIENCES,东京,日本)、1%抗生素/抗真菌溶液(antibiotic/antimycotic solution)(Thermo Fisher Scientific,Waltham,MA,USA)、0.1mM NEAA(Thermo Fisher Scientific)、1mM丙酮酸钠(ThermoFisher Scientific)和10μg/mL胰岛素(Sigma,St.Louis,MO,USA)的MEM(Thermo FisherScientific)中。MCF-10A细胞接种在补充有Single Quots试剂盒(BPE,氢化可的松,hEGF,胰岛素,庆大霉素/两性霉素B)(Lonza,Walkersville,MD,USA)和100ng/mL霍乱毒素的MEBM(Lonza)中。对于MCF-7细胞,由于17β-雌二醇(雌激素,Sigma)刺激,因此,在接种的第二天将培养基变更为补充有10%FBS、1%抗生素/抗真菌溶液(antibiotic/antimycoticsolution)、0.1mM NEAA、1mM丙酮酸钠和10μg/mL胰岛素的无酚红的DMEM/F12(ThermoFisher Scientific)。在24小时后,用仅10nM雌激素或10nM雌激素与肽(单订书(Singlestapled)ERAP,双订书(Double stapled)ERAP)对细胞进行处理。
细胞增殖测试
MCF-7和MCF-10A中的细胞增殖测试使用Cell Counting Kit-8(CCK-8,DOJINDO,熊本,日本)而进行。数据表示为3次独立的实验的平均±标准差(SD)。
糜蛋白酶抵抗性
就糜蛋白酶抵抗性而言,将1μg糜蛋白酶(#C7761,Sigma)和5μg的双订书(Doublestapled)ERAP添加至缓冲液(50mM Tris-HCl;pH8.0,10mM CaCl2)中,在37℃下进行24小时反应,通过高效液相色谱法(HPLC)而对总量进行分析。就HPLC而言,使用反相柱(InertsilPeptides C18 250x3.0mm I.D.,GL SCIENCES,东京,日本),以流速0.3mL/min对A液(0.1%三氟乙酸)和B液(0.1%三氟乙酸/乙腈)进行梯度洗脱(A/B=90/10(0-20min),90/10-40/60(20-80min)),通过UV210nM对各双订书(Double stapled)ERAP的色谱图进行检测。
抗体和免疫印迹分析
就免疫印迹分析而言,在SDS-PAGE后,用4%Block Ace溶液(大日本制药,大阪,日本)对印迹有蛋白质的膜(Membrane)进行3小时封闭后,与针对BIG3(1:1000)和PHB2(1:1000,Abcam,Cambridge,UK)的抗体进行12小时反应。然后,使其与HRP标记二抗(BIG3为抗大鼠IgG-HRP,1:5000,PHB2为抗兔IgG-HRP,1:1000,Santa Cruz Biotechnology,Dallas,TX,USA)进行1小时反应,通过增强化学发光(ECL)系统(GE Healthcare,Buckinghamshire,UK)而展开印迹,使用Image Reader LAS-3000mini(FUJIFILM,东京,日本)而进行扫描。
免疫沉淀
就免疫沉淀分析而言,使用大鼠IgG抗体和rec-Protein G Sepharose 4B(ThermoFisher Scientific)而使溶解在细胞溶解缓冲液(50mM Tris-HCl;pH8.0,150mM NaCl,0.1%NP-40,和0.5%CHAPS,0.1%蛋白酶抑制剂混合液(protease inhibitor cocktail)III)中的细胞溶解物在4℃下进行3小时预清除。然后,使上清液与针对BIG3的抗体5μg在4℃下进行12小时反应。接下来,使用rec-Protein G Sepharose 4B使抗原抗体复合体在4℃下进行1小时沉淀。用细胞溶解缓冲液对进行了免疫沉淀的蛋白质复合体进行4次清洗,进行SDS-PAGE和免疫印迹分析。
结果
双订书(Double stapled)ERAP的合成(参照实施例1双订书(Double stapled)
ERAP合成方法)
单订书(Single stapled)ERAP(SEQ ID NO.1)能够长期稳定性地抑制雌激素依赖性的肿瘤增殖,通过使分子内交联的数量增加,而尝试稳定性的进一步提高。就分子内交联的位置而言,考虑对糜蛋白酶的抵抗性而以使亮氨酸残基交联的方式进行设计,除了单订书(Single stapled)ERAP的位置(167L和171T)之外,还合成具有172L与175Q的交联(图1,双订书(Double stapled)ERAP No.45)和174L与178Q的交联(图1,双订书(Doublestapled)ERAP No.46)的双订书(Double stapled)ERAP。
双订书(Double stapled)ERAP对于雌激素依赖性增殖的长期稳定性
单订书(Single stapled)ERAP的96小时处理对雌激素依赖性的MCF-7细胞的增殖进行浓度依赖性抑制,其IC50为0.88μM。就双订书(Double stapled)ERAP No.45而言,虽然通过10μM的96小时处理而持续大致完全的抑制效果,但至1μM时不能对雌激素依赖性的细胞增殖进行大部分抑制,其抑制效果比单订书(Single stapled)ERAP差(IC50=2.32μM,图2A),暗示了连续的钉合(Stapling)立体结构影响了膜渗透性等的可能性。另一方面,双订书(Double stapled)ERAP No.46与双订书(Double stapled)ERAP No.45不同,对雌激素依赖性增殖的抑制效果比单订书(Single stapled)ERAP强,即使1μM时也显示出81%的抑制率(图2B,单订书(Single stapled)ERAP:51%的抑制率,双订书(Double stapled)ERAPNo.45:21%的抑制率),IC50为0.43μM且比单订书(Single stapled)ERAP提升2倍(图2C)。
双订书(Double stapled)ERAP的糜蛋白酶耐药性
对双订书(Double stapled)ERAP No.45和No.46的对于24小时的糜蛋白酶处理的抵抗性进行研究。糜蛋白酶处理引起的蛋白质的分解用图3中的黑箭头表示。其结果,双订书(Double stapled)ERAP No.45的情况下,观察到一些糜蛋白酶处理引起的分解(图3A),与之相对,就双订书(Double stapled)ERAP No.46的糜蛋白酶处理而言,几乎没有观察到其分解(图3B)。认为对糜蛋白酶处理引起的蛋白质分解的抵抗性暗示在生物体内ERAP不易被分解,反映了雌激素依赖性细胞增殖的长期稳定性的抑制效果的保持。
双订书(Double stapled)ERAP对乳腺上皮细胞的增殖的影响
研究使用双订书(Double stapled)ERAP No.46的1μM和10μM,对MCF-10A细胞的增殖的影响。MCF-10A细胞是ERα、BIG3同时为阴性的正常的乳腺上皮细胞。其结果,就双订书(Double stapled)ERAP No.46而言,虽然在作为ERα、BIG3同时阳性的乳腺癌细胞MCF-7中,在1μM和10μM的情况下96小时后,雌激素依赖性的细胞增殖显示为79%、91%的抑制率(图2B),但是MCF-10A细胞的增殖直至10μM都几乎没有受到影响(图4),这暗示双钉合(Stapling)结构不参与正常的乳腺上皮细胞的功能。
双订书(Double stapled)ERAP No.46的BIG3-PHB2相互作用的结合阻碍
研究当对双订书(Double stapled)ERAP No.46的1μM和10μM进行24、96小时处理时,对BIG3和PHB2的相互作用的阻碍效果。其结果,在24小时处理的情况下,双订书(Doublestapled)ERAP在1μM的情况下大致完全地对BIG3与PHB2的结合进行阻碍(图5A),与之相对,虽然单订书(Single stapled)ERAP在10μM的情况下具有大致完全的阻碍效果,但是在1μM的情况下减弱为46%的阻碍率(图5A)。此外,虽然在96小时处理的情况下,双订书(Doublestapled)ERAP No.46在1μM的情况下为60%,在10μM的情况下为95%的阻碍率与24小时处理相比稍微减弱(图5B),但是持续了强抑制效果。另一方面,单订书(Single stapled)ERAP在1μM情况下,几乎没有观察到抑制效果,在10μM的情况下为81%(图5B)。从以上的事实判断,双订书(Double stapled)ERAP No.46能够以比单订书(Single stapled)ERAP更低的浓度而对BIG3和PHB2的结合进行阻碍,其结果,可以在更低浓度下抑制增殖。
实施例3stERAP对于ESR1变体的乳腺癌细胞的效果
材料和方法
细胞株
MCF-7细胞和HEK293T细胞从American Type Culture Collection(ATCC,Manassa,VA,USA)购入。Y537S敲入MCF-7细胞由Laki Buluwela博士(Imperial CollegeLondon,UK)提供。全部的细胞株均在各个保藏者的推荐的条件下进行培养。
细胞培养
MCF-7细胞在添加了10%FBS(NICHIREI BIOSCIENCES,东京,日本)、1%抗生素/抗真菌溶液(antibiotic/antimycotic solution)(Thermo Fisher Scientific,Waltham,MA,USA)、0.1mM NEAA(Thermo Fisher Scientific)、1mM丙酮酸钠(Thermo FisherScientific)和10μg/mL胰岛素(Sigma,St.Louis,MO,USA)的MEM(Thermo FisherScientific)中进行培养,HEK293T细胞在添加了10%FBS和1%抗生素/抗真菌溶液(antibiotic/antimycotic solution)的DMEM(Sigma)中进行培养,Y537S敲入MCF-7细胞在添加了10%FBS、1%抗生素/抗真菌溶液(antibiotic/antimycotic solution)和0.1mMNEAA的DMEM(Sigma)中进行培养。各细胞接种在48孔板(2×104cells/0.2mL)、6孔板(5×105cells/2mL)、10cm皿(dish)(2×106cells/10mL)中,在5%CO2、37℃的条件下进行培养(Incubate),在24小时后用stERAP等的抑制剂进行处理。
化合物和抑制剂
BIG3-PHB2的结合阻碍肽使用WO2017/12646中记载的单订书(stapled)ERAP(stERAP,stapled ERAP)。他莫昔芬从Sigma购入,氟维司群从LKT laboratories公司(St.Paul,MN,USA)购入,依维莫司从Cell Signaling Technol ogy(Danvers,MA,USA)购入,星形孢菌素(staurosporine)和渥曼青霉素(wort mannin)由ONCO THERAPY SCIENCE公司(神奈川,日本)和佐佐木拓也博士(德岛大学,德岛,日本)提供。
蛋白质印迹法(Western Blot)分析
通过包含0.1%蛋白酶抑制剂混合液(protease inhibitor cocktail)III(Calbiochem,San Diego,CA,USA)的溶解缓冲液(50mM Tris-HCl:pH8.0,150m M NaCl,0.1%NP-40,0.5%CHAPS)使细胞溶解。使细胞溶解物进行电泳,在硝基纤维素膜(Membrane)上进行印迹,用4%BlockAce solution(大日本制药,大阪,日本)进行3小时封闭。在抗FLAG标签抗体(M2)(Sigma);抗PHB2抗体(Abcam,Cambridge,UK);抗PKCα抗体(H-7)、抗PI3-kinase p85α(U13)(Santa Cruz Biotechnology,Santa Cruz,CA,USA);抗磷酸化PI3K p85/p55抗体(Tyr458/Tyr199)、抗磷酸化PKCα/βII抗体(Thr638/Thr641)(Cell SignalingTechnology);抗ERα抗体(SP1)(Thermo Fisher Scientific);抗磷酸化PHB2纯化抗体(Ser39)(株式会社SCRUM,东京,日本)的存在下对膜(Membrane)进行12小时培养(Incubate)。在HRP结合二抗(Santa Cruz Biotechnology)的存在下进行1小时培养(Incubate)后,通过增强化学发光(ECL)系统(GE Healthcare,Buckinghamshire,UK)而使膜(Membrane)展开。印迹使用Image Read er LAS-3000mini(FUJIFILM,东京,日本)进行扫描。
免疫沉淀
如“蛋白质印迹法(Western Blot)分析”的项中所述,通过0.1%NP-40溶解缓冲液使细胞溶解,使用Normal IgG和rec-Protein G Sepharose 4B(Thermo FisherScientific),在4℃下3小时,对细胞溶解物进行预清洗。离心分离后,使上清液在5μg的抗PKCα抗体,抗ERα抗体,和抗FLAG标签抗体的存在下在4℃下进行12小时培养(Incubate)。然后,在4℃下添加rec-Protein G Sepharose 4B,进行1小时培养(Incubate),从而使抗原-抗体复合体沉淀。用溶解缓冲液对进行了免疫沉淀的蛋白质复合体进行3次清洗,通过SDS-PAGE而进行分离。然后,进行蛋白质印迹法(Western Blot)分析。
PKCα(Protein Kinase C alpha)活性
PKCα的活性通过下述方式进行测定:使PKCα的免疫沉淀物在激酶缓冲液(25mMHepes,pH7.2,25mM MgCl2,5mM EDTA,5mM EGTA,0.25mM DTT)下与包含基质Ser39的PHB2肽(YGVRE SVFTVE(SEQ ID NO.17))和0.5mM ATP在30℃下进行30分钟反应,使用ADP-Glokinase assay Kit(Promega,Fitchburg,WI,USA)而进行测定。
细胞增殖测试
使用Cell-Counting Kit-8(CCK-8,DOJINDO,熊本,日本)而进行细胞增殖测试。将细胞以2×104cells/well接种至48孔板中,通过在5%CO2存在下的培养箱(Incubator)(37℃)而进行保持。在指示的时间点,添加10倍稀释的CCK-8溶液并进行30分钟培养(Incubate),对450nm的吸光度进行测定而对生存细胞的数量进行计算。
萤光素酶报告基因测试(Luciferase reporter assay)
为了ERE报告基因测试,将ERE报告基因(SABiosciences,Frederick,MD,USA)转染至MCF-7细胞中16小时后,将培养基替换成测试培养基(Opti-MEM,10%FBS,0.1mM NEAA,1mM丙酮酸钠,10μg/mL胰岛素),8小时后,用雌激素和stERAP进行24小时处理。使用Promegadual luciferase reporter assay(PROMEGA,东京,日本)对细胞溶解物的萤光素酶活性和Renilla-萤光素酶活性进行评价。考虑到转染效率,所有数据通过Renilla-萤光素酶活性而进行标准化。
统计分析
使用用于确定试验组间的差异的统计学意义的t检验,在P值<0.05的情况下被认为是显著的。
结果
ESR1变体的乳腺癌细胞株雌激素非依赖性地与PI3K结合
乳腺癌的70%表达雌激素受体(ERα),其大部分对ERα的抑制具有感受性。然而,在ERα阳性的晚期乳腺癌的情况下,在配体结合域中发现ERα基因(ESR1)的突然变异,这样的基因变异激活配体非依赖性,暗示可能对内分泌疗法具有抵抗性(Nat Genet,45,1439,2013,Nat Genet,45,1446,2013)。此外,报告了在ERα阳性乳腺癌的情况下,除了雌激素信号之外,PI3K(phosphatidylinositol 3-kinase)/AKT(protein kinase B)/mTOR(mammalian target of rapamycin)途径也发挥极其重要的作用,参与内分泌疗法的耐性机理(Cancer Discov.2011Sep;1(4):338-51,Nature,e2012 Oct 4;490(7418):61-70,Cancer Lett.2012Oct 1;323(1):77-87,Clin Breast Cancer.2015Jun;15(3):197-203)。首先,研究了ESR1的野生型(WT)和变异型(Y537S)是否与PI3K进行结合。其结果,转染了WT的MCF-7细胞在雌激素未处理的情况下没有观察到ERα与PI3K的结合,在雌激素存在下的情况下观察到ERα与PI3K的结合和PI3K的磷酸化(图9A)。另一方面,在转染了Y537S的MCF-7细胞的情况下,与WT不同,即使在未处理的情况下,PI3K与Y537S结合并被磷酸化,也观察到PKCα的激活(Thr638/Thr641的磷酸化)(图9B)。这暗示,ESR1的变异引起的结构变化使得雌激素非依赖性的ESR1变体与PI3K的结合成为可能,可能是获得耐药性的主要因素。此外,当用10μM stERAP进行处理时,从BIG3脱离的PHB2即使在不存在雌激素的情况下也与Y537S进行重新结合,在stERAP处理后1小时观察到最大的PHB2量的结合,之后,PI3K和PKCα的磷酸化减少(图9B)。有趣的是,PHB2的Ser39的磷酸化在stERAP处理后马上被诱导,直至3小时时显示出最大的磷酸化强度,之后的强度因PI3K磷酸化的减少而减弱(磷酸化PHB2的负控制,图9B)。然而,与PI3K和PKCα的磷酸化强度相比,从PHB2(Ser39)的磷酸化保持在某种程度的强度的方面出发(图9B),认为stERAP对ERα-Y537S的耐药性细胞具有抑制效果。
ESR1变体的乳腺癌细胞株雌激素非依赖性地具有高PKCα活性
认为由于ESR1变体与PI3K结合,因此,使作为PI3K的下游分子的PKC被激活(Biochem Biophys Res Commun,310,720,2004)。此外,已知在ERα阳性乳腺癌的情况下,借助雌激素刺激的PKCα的激活使PHB2的Ser39磷酸化(Nat Commun,8,15427,2017),由此对ESR1变体的乳腺癌细胞株中的PKCα的活性状态进行评价。就实验而言,用PKCα抑制剂星形孢菌素(staurosporine)对转染了各ESR1变体的HEK293T细胞和MCF-7细胞进行24小时处理之后,通过抗PKCα抗体而进行免疫沉淀,将包含Ser39的PHB2肽(YGVRE SVFTVE(SEQ IDNO.17))作为基质而对PKCα活性进行测定。其结果,ESR1变体细胞与mock、WT比较而显示出显著的PKCα活性(图10A),与之相对,星形孢菌素(staurosporine)处理大致完全地抑制其活性(图10A),因此,认为ESR1变体细胞的PKCα活性可能源自PI3K。
因此,对于转染了各ESR1变体的MCF-7细胞,评价当用PI3K抑制剂渥曼青霉素(wortmannin)进行24小时处理时的PKCα活性和磷酸化PI3K。其结果,转染了各ESR1变体的细胞的PKCα的活性通过渥曼青霉素(wortmannin)处理而显著地被抑制(图10B)。此外,就转染了ESR1变体的细胞而言,PKCα和PI3K的磷酸化比WT更显著地被诱导,但是其各磷酸化被渥曼青霉素(wortmannin)大致完全地阻碍(图10C),因此,暗示PI3K的下游存在PKCα的激活。此外,各ESR1变体细胞株的PKCα活性与磷酸化PKCα的强度大致相关,转染了Y537S的细胞株当然显示高PKCα的激活和磷酸化。
stERAP和抗雌激素剂的组合使用对ESR1变体的乳腺癌细胞株的增殖的效果
对stERAP与现存的激素剂(他莫昔芬,氟维司群)和分子靶向药物(mTOR抑制剂依维莫司)的组合使用对使ESR1变体过表达的MCF-7细胞的增殖的效果,通过96小时反应而进行研究。就实验而言,在不存在雌激素的情况下转染了各ESR1变体之后,进行10μM stERAP、1μM他莫昔芬、2μM氟维司群和0.5μM依维莫司处理。其结果,96小时的stERAP单独处理显著地抑制ESR1变体的转染细胞的增殖,特别是,在Y537S的变体的情况下显示出49%的抑制率(图11)。此外,他莫昔芬、氟维司群和依维莫司的组合使用能够相乘性地抑制ESR1变体的细胞增殖,对全部的变体细胞株的增殖显示出80%以上的抑制率(图11)。
stERAP对雌激素存在下的ESR1变体的乳腺癌细胞株的增殖的抑制效果
对于转染了ESR1变体的细胞株的增殖,stERAP处理在不存在雌激素的情况下显示出40~50%的抑制率(图11),因此,研究是否在雌激素存在的情况下,stERAP的抑制效果提高。其结果,在不存在雌激素的情况下,stERAP的单独处理几乎不抑制mock与WT的细胞增殖,与之相对,在S463P、Y537S、D538G、S463P/D538G的变体的细胞增殖的情况下各显示出24%、44%、39%、40%的抑制率(图12)。另一方面,在存在雌激素的情况下,stERAP处理能够在mock和WT的情况下大致完全地抑制雌激素刺激引起的增殖,在各ESR1变体的情况下,通过1nM以上的雌激素共存而使得stERAP的抑制效果相乘性地提高,在S463P、Y537S、D538G、S463P/D538G的情况下各显示出62%、80%、75%、77%的抑制率(图12)。此外,观察到在10nM雌激素共存下,抑制率进一步提高至76%、82%、84%、83%(图12)。认为可能通过追加雌激素信号,而使得stERAP的作用点增加,引起相乘性的抑制效果。
stERAP对ESR1变体的乳腺癌细胞株的ERα转录活性的抑制效果
对stERAP对ESR1变体(S463P、Y537S、D538G、S463P+D538G)的ERα转录活性的抑制效果进行研究。就实验而言,对在各雌激素浓度(0.1、1、10nM)的共存下用stERAP对ERE-萤光素酶和转染了各FLAG标签化ESR1变体的MCF-7细胞进行24小时处理时的ERE-萤光素酶活性(ERα转录活性)进行测定。其结果,在用WT的FLAG标签化ERα进行了转染的细胞情况下,虽然ERE-萤光素酶活性在0.1nM以上的雌激素的情况下浓度依赖性地增加,但是该活性通过stERAP处理而大致完全地被抑制(图13)。另一方面,在各ESR1变体的转染细胞的情况下,即使在不存在雌激素的情况下ERE-萤光素酶活性也显著地被诱导(S463P:2.3倍,Y537S:7.5倍,D538G:5.0倍,S463P/D538G:6.6倍),特别是,Y537S的转染细胞被诱导出与WT的10nM雌激素刺激同程度的激活(图13)。此外,与WT的雌激素刺激同样,stERAP即使在任一条件下都可以显著地抑制ERE-萤光素酶性。
stERAP对Y537S敲入MCF-7细胞的增殖的抑制效果
使用敲入了ESR1的Y537S的MCF-7细胞,研究24小时的stERAP处理对细胞增殖的影响。其结果,stERAP处理即使在不存在雌激素的情况下也浓度依赖性地对细胞增殖进行抑制,在10μM的情况下显示出显著的抑制效果(图14),IC50(50%阻碍浓度)为1.57μM。此外,在存在雌激素的情况下,通过雌激素信号的追加而使得stERAP的抑制率显著地提高,IC50为0.78μM。
实施例4曲妥珠单抗耐药性HER2阳性乳腺癌细胞中的stERAP的效果
材料和方法
细胞株
人乳腺癌细胞株(MCF-7,BT-474,SK-BR-3)从American Type CultureCollection(ATCC,Rockville,MD,USA)购入。KPL-4由红林淳一博士(川崎医科大学,冈山,日本)根据材料移动协议(Material Transfer Agreement)而提供,曲妥珠单抗耐药性SK-BR-3由神崎浩孝博士(冈山大学,冈山,日本)提供。全部的细胞株均在各个保藏者的推荐的条件下进行培养。
细胞培养
SK-BR-3细胞在添加了10%FBS(NICHIREI BIOSCIENCES,东京,日本)和1%抗生素/抗真菌溶液(antibiotic/antimycotic solution)(Thermo Fisher Scientific,Fremont,CA,USA)的McCoy’A(Thermo Fisher Scientific)中进行培养,KPL-4细胞、BT-474细胞、曲妥珠单抗耐药性SK-BR-3细胞在添加了10%FBS和1%抗生素/抗真菌溶液(antibiotic/antimycotic solution)的DMEM(Sigma,St.Louis,MO,USA)中进行培养。就细胞的接种而言,接种在48孔板(2×104cells/0.2mL)、6孔板(5×105cells/2mL)、10cm皿(dish)(2×106cells/10mL)。细胞在5%CO2、37℃的条件下进行培养(Incubate),在24小时后用stERAP等的抑制剂进行处理。
化合物和抑制剂
BIG3-PHB2的结合阻碍肽使用WO2013/018690中记载的单订书(stapled)ERAP(stERAP)。重组PHB2从Abnova(Taipei,Taiwan)购入,重组TTK和重组MK5从SignalChem(Richmond,Canada)购入,TTK抑制剂AZ3146从Santa Cruz Biotechnology购入。
蛋白质印迹法(Western Blot)分析
通过包含0.1%蛋白酶抑制剂混合液(protease inhibitor cocktail)III(Calbiochem,San Diego,CA,USA)的溶解缓冲液(50mM Tris-HCl:pH8.0,150mM NaCl,0.1%NP-40,0.5%CHAPS)而使细胞溶解。使细胞溶解物进行电泳,在硝基纤维素膜(Membrane)进行印迹,用4%BlockAce solution(大日本制药,大阪,日本)进行3小时封闭。在抗BIG3纯化抗体(抗hA7322(His13),Sigma);抗HA标签抗体(3F10,Roche,Mannheim,Germany);抗PHB2抗体、抗NcoR抗体(Abcam,Cambridge,UK);抗PKAαcat抗体(C-20)、抗PKCα抗体(H-7)、抗PP1Cα抗体(FL-18)、抗HDAC1抗体(H-51)(Santa Cruz Biote chnology,Santa Cruz,CA,USA);抗HER2抗体(Merck,Darmstadt,Germany);抗HER3抗体(1B2E)、抗TTK抗体(D-8)、抗MK5抗体(D70A10)、抗CHK1抗体(G-4)、抗磷酸化Shc(Y239/Y240)、抗p38抗体、抗磷酸化p38抗体(T180/Y182)、抗NF-κB p65抗体、抗IκB抗体(L35A5)、抗磷酸化IκB抗体(S32/S36、5A5)(Cell Signaling Technology,Danvers,MA,USA);抗Shc抗体(BD,FranklinLakes,NJ,USA);抗磷酸化PHB2纯化抗体(Ser39)、抗磷酸化BIG3纯化抗体(Ser305)、抗磷酸化BIG3抗体(Ser1208,株式会社SCRUM,东京,日本);抗磷酸化苏氨酸抗体(Thermo FisherScientific)的存在下,对膜(Membrane)进行12小时培养(Incubate)。在HRP结合二抗(Santa Cruz Biotechno logy)的存在下进行1小时培养(Incubate)后,通过增强化学发光(ECL)系统(GE Healthcare,Buckinghamshire,UK)而使膜(Membrane)展开。印迹使用ImageReader LAS-3000mini(FUJIFILM,东京,日本)进行扫描。
Phos-tag SDS-PAGE
为了对激酶引起的PHB2的直接的磷酸化进行评价,使用precast SuperSep gels(50μM phos-tag acrylamide and 100μM ZnCl2,WAKO CHEMICAL,大阪,日本)而进行Phos-tag SDS-PAGE。分子量标记使用WIDE-VIEW Prestained Protein Size Marker III(WAKOCHEMICAL)。磷酸化效率通过相对于总PHB2带的磷酸化PHB2带的比例而算出。
免疫沉淀
如“蛋白质印迹法(Western Blot)分析”的项所述,通过0.1%NP-40溶解缓冲液使细胞溶解,使用Normal IgG和rec-Protein G Sepharose 4B(Thermo FisherScientific),在4℃下3小时,对细胞溶解物进行预清洗。离心分离后,使上清液在5μg的抗BIG3抗体、抗PHB2抗体、抗HER2抗体、抗PKCα和抗HA标签抗体的存在下在4℃下,进行12小时培养(Incubate)。然后,添加rec-Protein G Sepharose 4B在4℃下进行1小时培养(Incubate),从而使抗原-抗体复合体沉淀。用溶解缓冲液对进行了免疫沉淀的蛋白质复合体进行3次清洗,通过SDS-PAGE而进行分离。然后,进行蛋白质印迹法(Western Blot)分析。
体内(in vivo)肿瘤增殖阻碍
使KPL-4细胞悬浮液和曲妥珠单抗耐药性SK-BR-3细胞悬浮液(1×107cells/mouse)与等量的Matrigel(BD)混合,注射在5周大的雌性BALB/c裸鼠(CHARLES RIVERLABORATORIES,东京,日本)的乳房脂肪体中。小鼠以12小时明期/12小时暗期的循环饲养在无菌的隔离设施中,随意喂养啮齿动物饲料和水。使肿瘤发育一周直至达到约100mm3(作为1/2×(宽度×长度2)算出)的尺寸。然后,将小鼠随机划分为各实验群(5个体/群)。stERAP处理通过每7日尾静脉注射150μg/kg,而对小鼠进行给药。肿瘤体积使用游标卡尺而每4日进行测定,持续4周。全部的试验根据德岛大学的动物设施的指导方针而进行。
激酶反应
PKA(Protein Kinase A)和PKCα(Protein Kinase C alpha)的活性通过下述方式进行测定:使BIG3和PKCα的免疫沉淀物在激酶缓冲液(25mM Hepes,pH7.2,25mM MgCl2,5mMEDTA,5mM EGTA,0.25mM DTT)下与合成基质CREBtide(KRREILSRRPSYR)和0.5mM ATP在30℃下进行30分钟反应,使用ADP-Glo kinase assay Kit(Promega,Fitchburg,WI,USA)而进行测定。
PP1Cα活性
PP1Cα的磷酸酶活性使用Protein Phosphatase Assay Kit(AnaSpec,Frem ont,CA,USA)而进行。使细胞溶解液与基质(对硝基苯磷酸酯;p-Nitrophenyl phosphate)在室温下进行60分钟培养(Incubate)后,使反应停止,对405nm的吸光度进行测定。PP1Cα活性(μmole/min)定义为每分钟催化1μmole的基质的酶量。
细胞增殖测试
使用Cell-Counting Kit-8(CCK-8,DOJINDO,熊本,日本)而进行细胞增殖测试。收获细胞,以2×104cells/well接种至48孔板中,通过在5%CO2存在下的培养箱(Incubator)(37℃)而进行保持。在指示的时间点,添加10倍稀释的CCK-8溶液并进行30分钟培养(Incubate),对450nm的吸光度进行测定而对生存细胞的数量进行计算。
实时PCR
通过实时PCR而对BIG3的表达进行评价。使用NucleoSpin RNA(Macherey-Nagel,Germany)而从各细胞提取总RNA,使用Superscript II reverse transcriptase(ThermoFisher Scientific)、oligo dT primer(Thermo Fisher Scientific)和25mM dNTPMixture(Thermo Fisher Scientific)而逆转录为cDNA。通过使用了SYBR Premix Ex Taq(Thermo Fisher Scientific)的7500Real Time PCR System(Thermo FisherScientific)的实时PCR而对cDNA进行分析。各样品通过β2-MG的mRNA含量而标准化。用于扩增的引物如下:
BIG3:5’-CTTGACAAGGCCTTTGGAGT-3’(SEQ ID NO.18)和
5’-CAATATGCTTTTCCCGCTTT-3’(SEQ ID NO.19),
β2-MG:5’-AACTTAGAGGTGGGGAGCAG-3’(SEQ ID NO.20)和
5’-CACAACCATGCCTTACTTTATC-3’(SEQ ID NO.21)。
细胞质与核的分离
细胞质部分和核部分使用NE-PER nuclear and cytoplasmic extractionreagent(Thermo Fisher Scientific)而进行分离。
细胞周期
通过冷70%乙醇使细胞固定,通过20μg/mL碘化丙啶(Sigma)和1mg/mL核糖核酸酶A(Sigma)使细胞染色,通过FACSCalibur(BD,Franklin Lakes,NJ,USA)而进行分析,使用CellQuest software(BD,Franklin Lakes,NJ,US A)对细胞周期进行评价。
统计分析
使用用于确定试验组间的差异的统计学意义的t检验,在P值<0.05的情况下被认为是显著的。
结果
HER2阳性乳腺癌细胞株中的BIG3作为AKAP而发挥功能
本发明人等在WO2013/018690和Nat Commun.2017May 30;8:15427中报告了在雌激素受体(ERα)阳性的乳腺癌细胞的情况下BIG3作为AKAP(Akinase anchor protein)而发挥功能,这次研究即使在HER2(human epidermal growth factor receptor 2)阳性乳腺癌细胞株的情况下,BIG3是否也作为AKAP而发挥功能。首先,通过实时PCR对HER2阳性乳腺癌细胞株中的BIG3的表达进行评价。其结果,各HER2阳性乳腺癌细胞株(BT-474细胞、SK-BR-3细胞、KPL-4细胞)的情况下观察到BIG3的显著的表达提高(图15A),表现出比ERα阳性乳腺癌细胞的MCF-7细胞更高的表达。
因此,认为即使在HER2阳性乳腺癌细胞的情况下也与ERα阳性乳腺癌细胞同样,BIG3可能作为AKAP而发挥功能。其结果,明确了HER2阳性乳腺癌细胞株的SK-BR-3细胞和KPL-4细胞对于BIG3的免疫沉淀物而与PKA、PP1Cα、PHB2进行强结合(图15B),认为BIG3即使在HER2阳性乳腺癌细胞的情况下也与PKA和蛋白磷酸酶(protein phosphatase)形成复合体,从而可能作为AKAP而发挥功能。
接下来,为了对HER2阳性乳腺癌细胞中的BIG3的激活机理进行评价,研究在HER2信号和EGFR(Epidermal Growth Factor Receptor)信号的下游PKA和PP1Cα是否存在,而使用HER2抑制剂曲妥珠单抗和EGFR抑制剂拉帕替尼而研究BIG3对PKA活性和PP1Cα活性的影响。其结果,通过PKA抑制剂H-89和曲妥珠单抗处理而使得BIG3的免疫沉淀物显示出PKA活性分别为100%、88%的抑制率,PP1Cα活性分别为96%、88%的抑制率(图15C)。另一方面,从观察到拉帕替尼处理仅对PKA活性和PP1Cα活性减少约15%的方面出发(图15C),暗示BIG3通过HER2信号而进行激活。
HER2阳性乳腺癌细胞株中的BIG3的激活机理
由于BIG3的激活需要Ser305和Ser1208的磷酸化(Nat Commun,8,15427,2017),因此,对HER2阳性乳腺癌细胞中的BIG3的磷酸化进行研究。其结果,观察到在SK-BR-3细胞和KPL-4细胞的情况下BIG3的各磷酸化(Ser305和Ser1208)恒定性地被诱导(图16),认为在HER2阳性乳腺癌细胞的情况下BIG3可能总是被激活。另一方面,对PKA抑制剂H-89、HER2抑制剂曲妥珠单抗和EGFR抑制剂拉帕替尼带来的影响进行研究,其结果为,在SK-BR-3细胞和KPL-4细胞中被激活的BIG3的各磷酸化(Ser305和Ser1208)通过H-89和曲妥珠单抗处理而大致完全地被抑制,与之相对,拉帕替尼处理未明显参与BIG3磷酸化的抑制(图16),由此出发,暗示BIG3可能通过源自HER 2信号的PKA而被激活。
HER2阳性乳腺癌细胞株中的BIG3控制PHB2的抑制活性
迄今为止,本发明人等已经发现,通过PKA而被激活的BIG3的磷酸化使PP1Cα的磷酸酶活性提高,使与作为PP1Cα的调节单元的BIG3结合的癌症抑制因子PHB2(Prohibitin2)的Ser39的磷酸化进行脱磷酸化,从而显著地参与乳腺癌细胞的增殖(Nat Commun,8,15427,2017)。此外,本发明人设计了作为以BIG3和PHB2的相互作用为靶标的显性负性肽的ERAP(Nat Commun,4,2443,2013),以对长期稳定性、BIG3-PHB2相互作用的阻碍具有高感受性的方式而尝试了生物学性的改善,制备了订书(stapled)ERAP(stERAP)(Sci Rep,7,1821,2017)。实际上,显示当将stERAP对乳腺癌细胞株进行给药时,BIG3和PHB2的结合完全地被阻碍,从BIG3脱离的PHB2迅速地使Ser39磷酸化,从而具有抑制活性(Sci Rep,7,1821,2017)。因此,对stERAP对HER2阳性乳腺癌细胞的BIG3和PHB2的影响进行研究。其结果,当对SK-BR-3细胞和KPL-4细胞进行stERAP处理时,观察到BIG3和PHB2的相互作用大致完全地被阻碍(图17A)。此外,观察到通过stERAP处理而从BIG 3脱离的PHB2迅速地诱导Ser39和苏氨酸的磷酸化(图17A),暗示BIG3控制PHB2的磷酸化(抑制激活)。
接下来,对HER2阳性乳腺癌细胞中的PHB2的激活机理进行评价。就实验而言,使用用于抑制BIG3的激活的基于siRNA法的PKA的表达抑制和HER2抑制剂曲妥珠单抗和EGFR抑制剂拉帕替尼而对PHB2的磷酸化进行研究。其结果,PHB2(Ser39)的磷酸化在siPKA处理和曲妥珠单抗处理的情况下几乎没有观察到减少倾向,与之相对,通过拉帕替尼处理而大致完全地被抑制(图17B),由此出发,认为PHB2(Ser39)的磷酸化主要是EGFR信号引起的。
另一方面,从PHB2的苏氨酸·磷酸化是HER2信号和EGFR信号非依赖性的方面出发(图17B),认为存在与Ser39的磷酸化完全不同的激活机理。
PKCα依赖性PHB2(Ser39)的磷酸化
迄今为止,由于已知在ERα阳性乳腺癌的情况下PKCα使PHB2的Ser39磷酸化(NatCommun,8,15427,2017),因此,对siRNA法引起的PKCα的表达抑制对PHB2(Ser39)的磷酸化的影响进行研究。其结果,通过stERAP处理而被诱导的PHB2(Ser39)的磷酸化在siPKCα处理中被显著地抑制(图18A)。此外,从SK-BR-3细胞中的PKCα的免疫沉淀物的PKCα活性通过拉帕替尼处理而显示出约80%的活性阻碍的方面出发(图18B),暗示PHB2(Ser39)通过EGFR信号引起的PKCα的激活而被磷酸化。
磷酸化PHB2(Ser39)抑制核内的转录活性
就PHB2(Ser39)的磷酸化参与转录活性的抑制而言,使用PHB2的磷酸化变体进行评价。就实验而言,将HA标签化了的PHB2构建体和Ser39的丙氨酸变体(S39A)转染至通过siRNA法而抑制PHB2的表达的SK-BR-3细胞中,48小时后,进行24小时的stERAP处理,分离该核部分而用HA抗体进行免疫沉淀。其结果,通过stERAP处理而易位至核内的HA标签化PHB2显著地观察到转录抑制因子NcoR与HDAC1的结合(图19A),暗示可能能够抑制转录活性。另一方面,在转染了S39A的细胞中,针对HA标签化S39A的NcoR和HDAC1的结合被减弱(图19A;NcoR:82%,HDAC1:54%的减少率),由此出发,暗示PHB2的丝氨酸·磷酸化,特别是Ser39的磷酸化显著地参与转录活性的抑制。此外,使用S39E的疑似磷酸化质粒,对Ser39的磷酸化对转录活性的抑制的影响进行研究,其结果为,在转染了S39E的疑似磷酸化的细胞中,与WT相同,NcoR和HDAC1具有强结合(图19A),认为PHB2的Ser39的磷酸化对转录活性的抑制是重要的。
接下来,研究PHB2(Ser39)的磷酸化对HER2-HER3和HER2-Shc的相互作用的影响。其结果,观察到通过stERAP单独处理而从BIG3脱离的PHB2的Ser39被磷酸化,显示通过与HER2结合而对HER2与HER3、HER2与Shc的相互作用同时进行阻碍至83%(图19B)。另一方面,虽然在stERAP存在下的拉帕替尼处理,与所述同样(图17B),几乎没有观察到PHB2(Ser39)的磷酸化,但是能够分别以62%、74%而显著地阻碍HER2-HER3和HER2-Shc的相互作用,认为PHB2(Ser39)的磷酸化不影响HER2信号的抑制。另一方面,观察到PHB2也通过stERAP处理而诱导苏氨酸·磷酸化(图19B),该磷酸化是对HER2信号和EGFR信号非依赖性的(图17B,图19B),由此出发,暗示PHB2的苏氨酸·磷酸化可能显著地参与HER2信号的抑制。
PHB2的苏氨酸·磷酸化及其激活机理
对PHB2的苏氨酸·磷酸化的激活机理进行研究。首先,假设与Ser39的磷酸化同样的PKCα的参与,对通过siRNA法而对PKCα进行表达抑制时的PHB2的苏氨酸·磷酸化进行评价,其结果为,通过stERAP处理而被诱导的PHB2的苏氨酸·磷酸化即使在经过曲妥珠单抗处理和siPKCα处理的细胞中也得到较强保持(图20A),暗示PHB2的苏氨酸·磷酸化通过PKCα以外的激酶而被激活。
暗示通过stERAP处理而从BIG3脱离的PHB2除了Ser39的磷酸化之外还诱导苏氨酸·磷酸化(图17B,图19B),因此,从公共数据库预测PHB2的苏氨酸·磷酸化部位。其结果,在NetPhos 3.1(http://www.cbs.dtu.dk/services/Net Phos/)中Thr155和Thr169显示较高分数(分别为0.849、0.992;表1A),同时存在于PHB2的ERα转录活性的抑制域(19-49aa,150-174aa;Proc Natl Acad Sci USA,96,6947,1999)中,暗示Thr169的磷酸化可能是PKC以外的激酶引起的。
[表1]
接下来,使用Group-based Prediction System(GPS3.0;http://gps.biocuckoo.org/),对与PHB2的苏氨酸残基的磷酸化有关的激酶进行预测,其结果为,对于Thr42的磷酸化的TKK与其他相比显著地显示更高的分数(62.64)(表1B)。根据以上的预测结果,预测PHB2的Thr42和Thr169为苏氨酸·磷酸化部位,Thr42着眼于TTK,Thr169着眼于CHK1和MK5作为其激酶。
因此,对通过siRNA法而抑制TTK、CHK1和MK5的表达并进行stERAP处理时的PHB2的苏氨酸·磷酸进行评价。其结果,通过stERAP处理而被诱导的PHB2的苏氨酸·磷酸化通过siTTK处理和siMK5处理而显示出79%和74%的抑制效果(图20B)。此外,判断虽然siCHK1处理也对PHB2的苏氨酸·磷酸化具有33%的抑制率,但是TTK和MK5显著地参与PHB2的苏氨酸·磷酸化。
有趣的是,从报告p38作为TTK的基质的方面出发(JP4647456B2),对TTK和p38的关系进行调查,其结果为,p38的磷酸化通过siTTK处理而被抑制至约25%(图20B),暗示TTK的下游存在p38。此外,从p38激活MK5的方面出发(Cell Signal,22,1185,2010),暗示存在通过TTK激活的p38而激活MK5的途径。根据以上的结果,认为TTK控制PHB2的Thr42和Thr169的磷酸化,并且MK5参与Thr169的磷酸化。
TTK和MK5引起的PHB2的苏氨酸·磷酸化对HER2信号的影响
为了调查TTK、MK5和CHK1对HER2-HER3和HER2-Shc的相互作用的影响,分别通过siRNA而进行表达抑制之后,通过HER2抗体而进行免疫沉淀。其结果,当对SK-BR-3细胞进行1μM stERAP处理时,HER3和Shc对于HER2的结合被阻碍至93%、90%,与之相对,当对TTK和MK5的表达进行抑制时其结合阻碍被避免(图21A;siTTK:阻碍率23%和9%,siMK5:阻碍率48%和31%)。此外,TTK和MK5的表达抑制分别抑制stERAP处理引起的PHB2的苏氨酸·磷酸化各87%,46%(图21A)。从其他HER2阳性乳腺癌细胞株KPL-4细胞也得到同样的结果的方面出发(图21B),认为TTK和MK5引起的PHB2的苏氨酸·磷酸化对HER2信号级联的控制很重要。另一方面,在SK-BR-3细胞和KPL-4细胞中CHK1的表达抑制不能避免stERAP处理引起的HER2-HER3和HER2-Shc的结合阻碍,由此出发,认为几乎不参与HER2信号。
接下来,使用TTK抑制剂AZ3146,研究PHB2的苏氨酸·磷酸化和HER 2信号的影响。其结果,再现了通过stERAP单独处理而显著地阻碍HER2-HER3和HER2-Shc的相互作用(各96%、91%的阻碍率),与之相对,AZ3146大致完全地消除其阻碍效果(图20C)。此外,AZ3146阻碍23%的PHB2的苏氨酸·磷酸化(图20C),由此出发,暗示TTK的激活引起的PHB2的苏氨酸·磷酸化参与HER2信号的阻碍。
PHB2的苏氨酸·磷酸化部位的鉴定
研究了PHB2的苏氨酸·磷酸化部位为Thr42和Thr169。就实验而言,将HA标签化了的PHB2构建体(WT)、Thr42的丙氨酸变体(T42A)、Thr169的丙氨酸变体(T169A)、以及Thr42和Thr169的双丙氨酸变体(T42A+T169A)转染至通过siRNA法而对内源性PHB2进行了表达抑制的SK-BR-3细胞中,在进行24小时的stERAP处理之后,通过抗HA抗体而进行免疫沉淀。其结果,在WT的转染细胞中通过stERAP处理而被诱导的PHB2的苏氨酸·磷酸化在T42A和T169A的情况下观察到各50%、20%的减弱,在T42A+T169A的双变体的情况下76%的苏氨酸·磷酸化被抑制(图22A)。
接下来,研究PHB2的Thr42和Thr169的各磷酸化对HER2信号的抑制的影响。就实验而言,在将各HA标签化PHB2(野生型WT、Ser39的丙氨酸变体S39A、Thr42和Thr169的双丙氨酸变体T42A+T169A)转染至通过siRNA法而对内源性PHB2进行了表达抑制的SK-BR-3细胞中之后,进行24小时的stERAP处理,通过抗HER2抗体和抗BIG3抗体而进行免疫沉淀。其结果,即使在stERAP的未处理的情况下各HA标签化PHB2也直接与HER2结合,但是通过stERAP处理而大致完全地阻碍BIG3和各HA标签化PHB2的结合(图22B,BIG3的免疫沉淀物),伴随这些,与HER2结合的HA标签化PHB2的结合量增加,由此出发,判断在stERAP处理下,HA标签化PHB2不与BIG3结合的条件成立。
因此,在该条件下,对各HA标签化PHB2对HER2-HER3和HER2-Shc的相互作用的影响进行评价,其结果为,与HER2结合的PHB2-WT大致完全地阻碍HER2-HER3和HER2-Shc的相互作用(图22B;HER2-HER3:98%,HER2-Shc:93%的阻碍率),与之相对,PHB2-S39A的变体分别以95%、85%阻碍与HER3和Shc的结合(图22B),与WT的阻碍效果几乎相同。另一方面,在T42A+T169A的苏氨酸·双变体的情况下,尽管PHB2的Ser39被磷酸化,但是PHB2的抑制功能显著地丧失(HER2-HER3:15%,HER2-Shc:15%的阻碍率),暗示Thr42和Thr169的各磷酸化显著地参与PHB2对HER2信号的抑制功能。
TTK和MK5引起的PHB2的苏氨酸·磷酸化
通过用抗TTK抗体和抗PHB2抗体对进行了24小时的stERAP处理的SK-BR-3细胞进行免疫沉淀而研究TTK和PHB2是否发生结合。其结果,通过两抗体引起的免疫沉淀而发现TTK和PHB2发生强相互作用(图23A),暗示TTK直接使PHB2磷酸化。
接下来,TTK和MK5使PHB2直接苏氨酸·磷酸化的可能性,通过使用了Phos-tag的SDS-PAGE而进行评价。就实验而言,在重组PHB2与重组TTK或者重组MK5与ATP存在下在30℃下进行30分钟反应之后,进行Phos-tag SDS-PAGE。其结果,在重组TTK与PHB2的摩尔比1:1时稍微确认了磷酸化带(28%的磷酸化),在PHB2:TTK=1:2以上的摩尔比的情况下显著地检测出75%的磷酸化带(图23B)。此外,通过抗磷酸化苏氨酸抗体而进行免疫印迹也在大致相同位置观察到磷酸化带(图23B)。此外,对针对磷酸化Thr42和磷酸化Thr169的免疫血清进行免疫印迹,其结果为,磷酸化Thr42的检测具有高感受性,但是根据PHB2与TTK的摩尔比而显著地观察到各磷酸化带(图23B),暗示TTK可能使PHB2的Thr42和Thr169直接磷酸化。
重组MK5在摩尔比PHB2:MK5=1:0.25的情况下稍微确认了磷酸化带(6.5%的磷酸化),根据摩尔比而使磷酸化效率增加,在PHB2:MK=1:2以上的摩尔比的情况下检测到75%的磷酸化带,具有与抗磷酸化苏氨酸抗体的免疫印迹相同的位置(图23C)。此外,以与所述同样的方式,对免疫血清进行免疫印迹,其结果为,磷酸化Thr42的血清也发生轻微反应,磷酸化Thr169血清显示与抗磷酸化苏氨酸抗体大致相同磷酸化的行动,强烈暗示Thr169为MK5带来的PHB2的磷酸化部位。
stERAP对HER2阳性乳腺癌细胞株的增殖的抑制效果
对HER2阳性乳腺癌细胞株中的stERAP的增殖抑制效果进行研究(图24)。其结果,观察到stERAP对各HER2阳性乳腺癌细胞株(SK-BR-3细胞、BT-474细胞、KPL-4细胞)的增殖具有容量依赖性的抑制效果,各细胞株对应的IC50(50%阻碍浓度)为0.054μM、0.58μM、0.02μM。此外,SK-BR-3细胞和KPL-4细胞是雌激素受体(ERα)阴性,由此出发,表明如果stERAP表达BIG3,则HER2阳性乳腺癌细胞和ERα阴性细胞中也显示出显著的增殖抑制效果。
stERAP阻碍HER2-HER3和HER2-Shc的相互作用
对使用stERAP对各HER2阳性乳腺癌细胞株的增殖的IC50和完全抑制浓度(SK-BR-3细胞:0.05μM和1μM,BT-474细胞:0.5μM和10μM,KPL-4细胞:0.01μM和1μM),对各细胞株的HER2-HER3和HER2-Shc的相互作用的影响和与曲妥珠单抗的组合使用效果进行研究。其结果,曲妥珠单抗几乎不能阻碍HER2与HER3和HER2与Shc的结合,与之相对,stERAP的单独处理能够得到较强的阻碍效果(图25),在针对细胞增殖的完全抑制浓度的情况下,可以大致完全地阻碍HER2-HER3和HER2-Shc的相互作用。此外,即使在stERAP的IC50的情况下,通过与曲妥珠单抗组合使用,而观察到戏剧性的阻碍率的提高(图25)。
此外,stERAP处理也对HER2(Y877)的磷酸化和Shc的磷酸化(Y239/Y240)显示出同样的阻碍效果(图25)。此外,stERAP处理浓度依赖性地诱导PHB2与HER2的结合量,但是与曲妥珠单抗组合使用也没有使PHB2的结合量变化(图25)。
stERAP对曲妥珠单抗耐药性HER2阳性乳腺癌细胞株的抑制效果
对曲妥珠单抗耐药性SK-BR-3细胞中的stERAP的增殖抑制效果进行研究。其结果,曲妥珠单抗的单独给药不能完全抑制曲妥珠单抗耐药性SK-BR-3细胞的增殖,与之相对,观察到stERAP处理对曲妥珠单抗耐药性SK-BR-3细胞的增殖具有容量依赖性的抑制效果,与曲妥珠单抗感受性SK-BR-3细胞的IC50(0.054μM,图24)相比,IC50高达10.64μM(图26A),暗示stERAP具有显著的抑制效果而与耐药性和感受性细胞无关。
接下来,对stERAP对曲妥珠单抗耐药性SK-BR-3细胞的HER2-HER3异源二聚体和HER2-Shc的结合的影响进行研究。其结果,stERAP可以大致完全地阻碍感受性和耐药性细胞株中的HER2-HER3和HER2-Shc的结合以及Shc的磷酸化(Y239/Y240)(图26B)。此外,观察到通过stERAP处理而从BIG3脱离的PHB与HER2结合,暗示PHB2参与HER2-HER3、HER2-Shc复合体的阻碍。另一方面,赫赛汀(注射用曲妥珠单抗)单独处理对HER2-HER3和HER2-Shc的结合几乎没有影响。
stERAP对曲妥珠单抗耐药性HER2阳性乳腺癌细胞株的NF-κB信号的影响
报告了HER2阳性乳腺癌细胞中的NF-κB信号的激活可能发生化学放射线疗法的耐性(Anticancer Res,26,4235,2006,Breast Cancer Res,13,221,2011)。因此,研究stERAP对HER2阳性乳腺癌细胞株的NF-κB信号的影响。其结果,与亲本菌株的SK-BR-3细胞相比,在曲妥珠单抗耐药性SK-BR-3细胞的情况下观察到大量的NF-κB p65易位至核内,暗示该信号参与对于曲妥珠单抗治疗的耐性(图27)。另一方面,stERAP的给药显著地阻碍曲妥珠单抗耐药性SK-BR-3细胞中的NF-κB p65的核易位(图27)。此外,发现stERAP通过大致完全地阻碍仅在曲妥珠单抗耐药性SK-BR-3细胞中激活的IκBα的磷酸化,而控制NF-κB p65的核易位(图27)。以上暗示,stERAP通过对IκBα的磷酸化和NF-κB p65的核易位进行抑制,而避免对曲妥珠单抗治疗的耐药性。
stERAP对曲妥珠单抗耐药性HER2阳性乳腺癌细胞株的细胞周期的影响(图28)
调查stERAP给药对曲妥珠单抗耐药性SK-BR-3细胞的细胞周期的影响。其结果,曲妥珠单抗耐药性SK-BR-3细胞的细胞周期显著地发展至G2/M期,但是曲妥珠单抗的给药不能使大部分细胞周期停止,与之相对,在stERAP的单独给药的情况下,观察到G0/G1期中的细胞周期的停止。此外,组合使用20μM stERAP和100μg/mL曲妥珠单抗,则发现sub-G1期的细胞显著增加,细胞死亡。通过以上发现,stERAP通过诱导G1期停止而指导细胞增殖抑制效果,通过与作用机理不同的曲妥珠单抗组合使用而促进细胞死亡。
曲妥珠单抗耐药性HER2阳性乳腺癌细胞中的stERAP的体内(in vivo)抗肿瘤效果
(图29)
对stERAP带来的体内(in vivo)抗肿瘤效果进行研究。将KPL-4和曲妥珠单抗耐药性SK-BR-3细胞原位移植至BALB/c裸鼠乳腺中,当肿瘤达到约100mm3时开始stERAP的尾静脉给药,以后,每7日给药并调查抗肿瘤效果。其结果,KPL-4肿瘤和曲妥珠单抗耐药性SK-BR-3肿瘤随时间推移性地增殖,与之相对,150μg/kg的stERAP在给药后立即观察到肿瘤直径的减少倾向,每7日的给药仍然持续显著的阻碍效果,28日后观察到肿瘤的缩小。此外,根据未观察到stERAP给药导致的毒性和显著的体重减少的方面,从治疗的观点出发暗示优异的治疗指数。
实施例5双stERAP的效果
材料和方法
细胞株和培养条件
3种人乳腺癌细胞株SK-BR-3、BT-20、MDA-MB-231和人滑膜肉瘤细胞株SW982从American Type Culture Collection(ATCC,Manassas,VA,USA)购入。
SK-BR-3细胞使用McCoy's 5A培养基(Thermo Fisher Scientific,Waltham,MA,USA)、BT-20使用EMEM培养基(Thermo Fisher Scientific),在5%CO2、37℃的条件下进行培养。MDA-MB-231细胞和SW982细胞使用Leibo vitz's L-15培养基(Thermo FisherScientific),在未调节CO2浓度、37℃的条件下进行培养。所有的培养基均补充有10%FBS(Thermo Fisher Scientific)、1%抗生素-抗真菌溶液(和光纯药,大阪,日本)而使用。
细胞增殖测试
就细胞接种而言,在SK-BR-3细胞、BT-20细胞、MDA-MB-231细胞的情况下,在48孔板中以1×104cells/200μL in well而进行,在SW982细胞的情况下以0.5×104cells/200μLin well而进行。48小时后,将各孔的培养基替换为添加了肽(单stERAP与双stERAP#46:从20μM开始以3倍的系列稀释,双stERAP#45:从50μM开始以2倍的系列稀释)的培养基,进一步进行96小时培养后,使用Cell Counting Kit-8(DOJINDO,熊本,日本)对细胞增殖水平进行测定。数据通过3次独立的实验而取得,使用图表制作·数据分析软件SigmaPlot(SystatSoftware,San Jose,CA,USA)而进行图表制作(平均±标准差(SD))和肽对细胞增殖的50%阻碍浓度(IC50)的计算。
细胞周期分析
分别将SK-BR-3细胞和MDA-MB-231细胞接种在5×105cells/10cm皿(dish)中。72小时后,将培养基替换为添加了5μM的肽的新的培养基,48小时、72小时、96小时后通过胰蛋白酶处理而回收细胞,添加70%乙醇溶液而在-20℃下固定一晚以上。将细胞悬浮液的溶液从70%乙醇替换为碘化丙啶(Propidium Iodide,PI)/RNase Staining Solution(CellSignaling Technologies,Danvers,MA,USA),在室温、暗处的条件下进行15分钟反应后,通过细胞筛(BD biosciences,Franklin Lakes,NJ,USA)而除去细胞凝聚块。接下来,通过FACS array(BD biosciences)和分析软件FlowJo(FLOWJO LCC,Ashland,OR,USA)而对各细胞样品的细胞周期的比例进行分析。
结果
stERAP带来的乳腺癌细胞株和滑膜肉瘤细胞株的增殖抑制效果
对于3种乳腺癌细胞株(SK-BR-3、BT-20、MDA-MB-231)和滑膜肉瘤细胞株SW982,调查3种stERAP对细胞增殖的影响。其结果,在图30所示的所有的细胞株中,观察到各stERAP带来的浓度依赖性的细胞增殖抑制效果。此外,表2表示各肽的50%阻碍浓度(IC50)。在3种肽中,双stERAP#46的增殖阻碍效果最高,源自恶性度高的三阴性乳腺癌的细胞株(BT-20和MDA-MB-231)、源自滑膜肉瘤的细胞株SW982中也观察到较强的增殖抑制效果。
stERAP对乳腺癌细胞株(SK-BR-3とMDA-MB-231)的细胞周期的影响
对于2种乳腺癌细胞株(SK-BR-3和MDA-MB-231),通过流式细胞技术(flowcytometry)分析而研究细胞增殖抑制效果的明显的2种肽(单stERAP和双stERAP#46)对细胞周期的影响。其结果,如图31A所示,在SK-BR-3细胞中,与分别添加阴性对照的磷酸缓冲生理食盐水(PBS)相比,通过添加两肽而观察到G2/M期的细胞数的减少,另一方面,观察到G1期的细胞数的增加,由此出发,观察到G1期的细胞周期停止。在肽添加96小时后依然保持该效果。另一方面,在MDA-MB-231细胞中,如图31B所示,观察到G1期的细胞数减少并且S期的细胞数增加,观察到S期的细胞周期停止,在96小时后依然保持该效果。这些结果暗示,2种肽(单stERAP和双stERAP#46)带来的细胞增殖阻碍效果均可能导致细胞周期停止。
[表2]
stERAP肽的50%细胞增殖阻碍浓度(IC50,μM)
工业实用性
本发明提供对BIG3-PHB2相互作用的阻碍效果的持续时间更长的肽。包含本发明的肽或其盐的药物组合物可以用于治疗癌症,特别是雌激素受体阳性的癌症、雌激素受体阴性的乳腺癌和前列腺癌。
序列表
<110> 肿瘤疗法科学股份有限公司
国立大学法人德岛大学
<120> 肽衍生物和包含其的医药组合物
<130> ONC-A1701P
<150> JP 2017-140101
<151> 2017-07-19
<160> 21
<170> PatentIn version 3.5
<210> 1
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 源自BIG3的单订书PHB2结合肽
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> 用于钉合的谷氨酸类似物
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<221> MISC_FEATURE
<222> (7)..(7)
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<223> 源自BIG3的双订书PHB2结合肽
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<221> MISC_FEATURE
<222> (3)..(3)
<223> 用于钉合的谷氨酸类似物
<220>
<221> MISC_FEATURE
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<223> 用于钉合的谷氨酸类似物
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<223> 用于钉合的谷氨酸类似物
<220>
<221> MISC_FEATURE
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<223> 用于钉合的谷氨酸类似物
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Gly Tyr Trp Gly Ser Pro Glu Asp Asn Ser Leu Pro Leu Ile Thr Met
805 810 815
ctg acc gat att gac ggc tta gag agc agt gcc att ggt ggc cag ctg 2673
Leu Thr Asp Ile Asp Gly Leu Glu Ser Ser Ala Ile Gly Gly Gln Leu
820 825 830
atg gcc tcg gct gct aca gag tct cct ttc gcc cag agc agg aga att 2721
Met Ala Ser Ala Ala Thr Glu Ser Pro Phe Ala Gln Ser Arg Arg Ile
835 840 845 850
gat gac tcc aca gtg gca ggc gtg gca ttt gct cgc tat att ctg gtg 2769
Asp Asp Ser Thr Val Ala Gly Val Ala Phe Ala Arg Tyr Ile Leu Val
855 860 865
ggc tgc tgg aag aac ttg atc gat act tta tca acc cca ctg act ggt 2817
Gly Cys Trp Lys Asn Leu Ile Asp Thr Leu Ser Thr Pro Leu Thr Gly
870 875 880
cga atg gcg ggg agc tcc aaa ggg ctg gcc ttc att ctg gga gct gaa 2865
Arg Met Ala Gly Ser Ser Lys Gly Leu Ala Phe Ile Leu Gly Ala Glu
885 890 895
ggc atc aaa gag cag aac cag aag gag cgg gac gcc atc tgc atg agc 2913
Gly Ile Lys Glu Gln Asn Gln Lys Glu Arg Asp Ala Ile Cys Met Ser
900 905 910
ctc gac ggg ctg cgg aaa gcc gca cgg ctg agc tgc gct cta ggc gtt 2961
Leu Asp Gly Leu Arg Lys Ala Ala Arg Leu Ser Cys Ala Leu Gly Val
915 920 925 930
gct gct aac tgc gcc tca gcc ctt gcc cag atg gca gct gcc tcc tgt 3009
Ala Ala Asn Cys Ala Ser Ala Leu Ala Gln Met Ala Ala Ala Ser Cys
935 940 945
gtc caa gaa gaa aaa gaa gag agg gag gcc caa gaa ccc agt gat gcc 3057
Val Gln Glu Glu Lys Glu Glu Arg Glu Ala Gln Glu Pro Ser Asp Ala
950 955 960
atc aca caa gtg aaa cta aaa gtg gag cag aaa ctg gag cag att ggg 3105
Ile Thr Gln Val Lys Leu Lys Val Glu Gln Lys Leu Glu Gln Ile Gly
965 970 975
aag gtg cag ggg gtg tgg ctg cac act gcc cac gtc ttg tgc atg gag 3153
Lys Val Gln Gly Val Trp Leu His Thr Ala His Val Leu Cys Met Glu
980 985 990
gcc atc ctc agc gta ggc ctg gag atg gga agc cac aac ccg gac 3198
Ala Ile Leu Ser Val Gly Leu Glu Met Gly Ser His Asn Pro Asp
995 1000 1005
tgc tgg cca cac gtg ttc agg gtg tgt gaa tac gtg ggc acc ctg 3243
Cys Trp Pro His Val Phe Arg Val Cys Glu Tyr Val Gly Thr Leu
1010 1015 1020
gag cac aac cac ttc agc gat ggt gcc tcg cag ccc cct ctg acc 3288
Glu His Asn His Phe Ser Asp Gly Ala Ser Gln Pro Pro Leu Thr
1025 1030 1035
atc agc cag ccc cag aag gcc act gga agc gct ggc ctc ctt ggg 3333
Ile Ser Gln Pro Gln Lys Ala Thr Gly Ser Ala Gly Leu Leu Gly
1040 1045 1050
gac ccc gag tgt gag ggc tcg ccc ccc gag cac agc ccg gag cag 3378
Asp Pro Glu Cys Glu Gly Ser Pro Pro Glu His Ser Pro Glu Gln
1055 1060 1065
ggg cgc tcc ctg agc acg gcc cct gtc gtc cag ccc ctg tcc atc 3423
Gly Arg Ser Leu Ser Thr Ala Pro Val Val Gln Pro Leu Ser Ile
1070 1075 1080
cag gac ctc gtc cgg gaa ggc agc cgg ggt cgg gcc tcc gac ttc 3468
Gln Asp Leu Val Arg Glu Gly Ser Arg Gly Arg Ala Ser Asp Phe
1085 1090 1095
cgc ggc ggg agc ctc atg agc ggg agc agc gcg gcc aag gtg gtg 3513
Arg Gly Gly Ser Leu Met Ser Gly Ser Ser Ala Ala Lys Val Val
1100 1105 1110
ctc acc ctc tcc acg caa gcc gac agg ctc ttt gaa gat gct acg 3558
Leu Thr Leu Ser Thr Gln Ala Asp Arg Leu Phe Glu Asp Ala Thr
1115 1120 1125
gat aag ttg aac ctc atg gcc ttg gga ggt ttt ctt tac cag ctg 3603
Asp Lys Leu Asn Leu Met Ala Leu Gly Gly Phe Leu Tyr Gln Leu
1130 1135 1140
aag aaa gca tcg cag tct cag ctt ttc cat tct gtt aca gat aca 3648
Lys Lys Ala Ser Gln Ser Gln Leu Phe His Ser Val Thr Asp Thr
1145 1150 1155
gtt gat tac tct ctg gca atg cca gga gaa gtt aaa tcc act caa 3693
Val Asp Tyr Ser Leu Ala Met Pro Gly Glu Val Lys Ser Thr Gln
1160 1165 1170
gac cga aaa agc gcc ctc cac ctg ttc cgc ctg ggg aat gcc atg 3738
Asp Arg Lys Ser Ala Leu His Leu Phe Arg Leu Gly Asn Ala Met
1175 1180 1185
ctg agg att gtg cgg agc aaa gca cgg ccc ctg ctc cac gtg atg 3783
Leu Arg Ile Val Arg Ser Lys Ala Arg Pro Leu Leu His Val Met
1190 1195 1200
cgc tgc tgg agc ctt gtg gcc cca cac ctg gtg gag gct gct tgc 3828
Arg Cys Trp Ser Leu Val Ala Pro His Leu Val Glu Ala Ala Cys
1205 1210 1215
cat aag gaa aga cat gtg tct cag aag gct gtt tcc ttc atc cat 3873
His Lys Glu Arg His Val Ser Gln Lys Ala Val Ser Phe Ile His
1220 1225 1230
gac ata ctg aca gaa gtc ctc act gac tgg aat gag cca cct cat 3918
Asp Ile Leu Thr Glu Val Leu Thr Asp Trp Asn Glu Pro Pro His
1235 1240 1245
ttt cac ttc aat gaa gca ctc ttc cga cct ttc gag cgc att atg 3963
Phe His Phe Asn Glu Ala Leu Phe Arg Pro Phe Glu Arg Ile Met
1250 1255 1260
cag ctg gaa ttg tgt gat gag gac gtc caa gac cag gtt gtc aca 4008
Gln Leu Glu Leu Cys Asp Glu Asp Val Gln Asp Gln Val Val Thr
1265 1270 1275
tcc att ggt gag ctg gtt gaa gtg tgt tcc acg cag atc cag tcg 4053
Ser Ile Gly Glu Leu Val Glu Val Cys Ser Thr Gln Ile Gln Ser
1280 1285 1290
gga tgg aga ccc ttg ttc agt gcc ctg gaa aca gtg cat ggc ggg 4098
Gly Trp Arg Pro Leu Phe Ser Ala Leu Glu Thr Val His Gly Gly
1295 1300 1305
aac aag tca gag atg aag gag tac ctg gtt ggt gac tac tcc atg 4143
Asn Lys Ser Glu Met Lys Glu Tyr Leu Val Gly Asp Tyr Ser Met
1310 1315 1320
gga aaa ggc caa gct cca gtg ttt gat gta ttt gaa gct ttt ctc 4188
Gly Lys Gly Gln Ala Pro Val Phe Asp Val Phe Glu Ala Phe Leu
1325 1330 1335
aat act gac aac atc cag gtc ttt gct aat gca gcc act agc tac 4233
Asn Thr Asp Asn Ile Gln Val Phe Ala Asn Ala Ala Thr Ser Tyr
1340 1345 1350
atc atg tgc ctt atg aag ttt gtc aaa gga ctg ggg gag gtg gac 4278
Ile Met Cys Leu Met Lys Phe Val Lys Gly Leu Gly Glu Val Asp
1355 1360 1365
tgt aaa gag att gga gac tgt gcc cca gca ccc gga gcc ccg tcc 4323
Cys Lys Glu Ile Gly Asp Cys Ala Pro Ala Pro Gly Ala Pro Ser
1370 1375 1380
aca gac ctg tgc ctc ccg gcc ctg gat tac ctc agg cgc tgc tct 4368
Thr Asp Leu Cys Leu Pro Ala Leu Asp Tyr Leu Arg Arg Cys Ser
1385 1390 1395
cag tta ttg gcc aaa atc tac aaa atg ccc ttg aag cca ata ttc 4413
Gln Leu Leu Ala Lys Ile Tyr Lys Met Pro Leu Lys Pro Ile Phe
1400 1405 1410
ctt agt ggg aga ctt gcc ggc ttg cct cga aga ctt cag gaa cag 4458
Leu Ser Gly Arg Leu Ala Gly Leu Pro Arg Arg Leu Gln Glu Gln
1415 1420 1425
tca gcc agc agt gag gat gga att gaa tca gtc ctg tct gat ttt 4503
Ser Ala Ser Ser Glu Asp Gly Ile Glu Ser Val Leu Ser Asp Phe
1430 1435 1440
gat gat gac acc ggt ctg ata gaa gtc tgg ata atc ctg ctg gag 4548
Asp Asp Asp Thr Gly Leu Ile Glu Val Trp Ile Ile Leu Leu Glu
1445 1450 1455
cag ctg aca gcg gct gtg tcc aat tgt cca cgg cag cac caa cca 4593
Gln Leu Thr Ala Ala Val Ser Asn Cys Pro Arg Gln His Gln Pro
1460 1465 1470
cca act ctg gat tta ctc ttt gag ctg ttg aga gat gtg acg aaa 4638
Pro Thr Leu Asp Leu Leu Phe Glu Leu Leu Arg Asp Val Thr Lys
1475 1480 1485
aca cca gga cca ggg ttt ggt atc tat gca gtg gtt cac ctc ctc 4683
Thr Pro Gly Pro Gly Phe Gly Ile Tyr Ala Val Val His Leu Leu
1490 1495 1500
ctt cct gtg atg tcc gtt tgg ctc cgc cgg agc cat aaa gac cat 4728
Leu Pro Val Met Ser Val Trp Leu Arg Arg Ser His Lys Asp His
1505 1510 1515
tcc tac tgg gat atg gcc tct gcc aat ttc aag cac gct att ggt 4773
Ser Tyr Trp Asp Met Ala Ser Ala Asn Phe Lys His Ala Ile Gly
1520 1525 1530
ctg tcc tgt gag ctg gtg gtg gag cac att caa agc ttt cta cat 4818
Leu Ser Cys Glu Leu Val Val Glu His Ile Gln Ser Phe Leu His
1535 1540 1545
tca gat atc agg tac gag agc atg atc aat acc atg ctg aag gac 4863
Ser Asp Ile Arg Tyr Glu Ser Met Ile Asn Thr Met Leu Lys Asp
1550 1555 1560
ctc ttt gag ttg ctg gtc gcc tgt gtg gcc aag ccc act gaa acc 4908
Leu Phe Glu Leu Leu Val Ala Cys Val Ala Lys Pro Thr Glu Thr
1565 1570 1575
atc tcc aga gtg ggc tgc tcc tgt att aga tac gtc ctt gtg aca 4953
Ile Ser Arg Val Gly Cys Ser Cys Ile Arg Tyr Val Leu Val Thr
1580 1585 1590
gcg ggc cct gtg ttc act gag gag atg tgg agg ctt gcc tgc tgt 4998
Ala Gly Pro Val Phe Thr Glu Glu Met Trp Arg Leu Ala Cys Cys
1595 1600 1605
gcc ctg caa gat gcg ttc tct gcc aca ctc aag cca gtg aag gac 5043
Ala Leu Gln Asp Ala Phe Ser Ala Thr Leu Lys Pro Val Lys Asp
1610 1615 1620
ctg ctg ggc tgc ttc cac agc ggc acg gag agc ttc agc ggg gaa 5088
Leu Leu Gly Cys Phe His Ser Gly Thr Glu Ser Phe Ser Gly Glu
1625 1630 1635
ggc tgc cag gtg cga gtg gcg gcc ccg tcc tcc tcc cca agt gcc 5133
Gly Cys Gln Val Arg Val Ala Ala Pro Ser Ser Ser Pro Ser Ala
1640 1645 1650
gag gcc gag tac tgg cgc atc cga gcc atg gcc cag cag gtg ttt 5178
Glu Ala Glu Tyr Trp Arg Ile Arg Ala Met Ala Gln Gln Val Phe
1655 1660 1665
atg ctg gac acc cag tgc tca cca aag aca cca aac aac ttt gac 5223
Met Leu Asp Thr Gln Cys Ser Pro Lys Thr Pro Asn Asn Phe Asp
1670 1675 1680
cac gct cag tcc tgc cag ctc att att gag ctg cct cct gat gaa 5268
His Ala Gln Ser Cys Gln Leu Ile Ile Glu Leu Pro Pro Asp Glu
1685 1690 1695
aaa cca aat gga cac acc aag aaa agc gtg tct ttc agg gaa att 5313
Lys Pro Asn Gly His Thr Lys Lys Ser Val Ser Phe Arg Glu Ile
1700 1705 1710
gtg gtg agc ctg ctg tct cat cag gtg tta ctc cag aac tta tat 5358
Val Val Ser Leu Leu Ser His Gln Val Leu Leu Gln Asn Leu Tyr
1715 1720 1725
gac atc ttg tta gaa gag ttt gtc aaa ggc ccc tct cct gga gag 5403
Asp Ile Leu Leu Glu Glu Phe Val Lys Gly Pro Ser Pro Gly Glu
1730 1735 1740
gaa aag acg ata caa gtg cca gaa gcc aag ctg gct ggc ttc ctc 5448
Glu Lys Thr Ile Gln Val Pro Glu Ala Lys Leu Ala Gly Phe Leu
1745 1750 1755
aga tac atc tct atg cag aac ttg gca gtc ata ttc gac ctg ctg 5493
Arg Tyr Ile Ser Met Gln Asn Leu Ala Val Ile Phe Asp Leu Leu
1760 1765 1770
ctg gac tct tat agg act gcc agg gag ttt gac acc agc ccc ggg 5538
Leu Asp Ser Tyr Arg Thr Ala Arg Glu Phe Asp Thr Ser Pro Gly
1775 1780 1785
ctg aag tgc ctg ctg aag aaa gtg tct ggc atc ggg ggc gcc gcc 5583
Leu Lys Cys Leu Leu Lys Lys Val Ser Gly Ile Gly Gly Ala Ala
1790 1795 1800
aac ctc tac cgc cag tct gcg atg agc ttt aac att tat ttc cac 5628
Asn Leu Tyr Arg Gln Ser Ala Met Ser Phe Asn Ile Tyr Phe His
1805 1810 1815
gcc ctg gtg tgt gct gtt ctc acc aat caa gaa acc atc acg gcc 5673
Ala Leu Val Cys Ala Val Leu Thr Asn Gln Glu Thr Ile Thr Ala
1820 1825 1830
gag caa gtg aag aag gtc ctt ttt gag gac gac gag aga agc acg 5718
Glu Gln Val Lys Lys Val Leu Phe Glu Asp Asp Glu Arg Ser Thr
1835 1840 1845
gat tct tcc cag cag tgt tca tct gag gat gaa gac atc ttt gag 5763
Asp Ser Ser Gln Gln Cys Ser Ser Glu Asp Glu Asp Ile Phe Glu
1850 1855 1860
gaa acc gcc cag gtc agc ccc ccg aga ggc aag gag aag aga cag 5808
Glu Thr Ala Gln Val Ser Pro Pro Arg Gly Lys Glu Lys Arg Gln
1865 1870 1875
tgg cgg gca cgg atg ccc ttg ctc agc gtc cag cct gtc agc aac 5853
Trp Arg Ala Arg Met Pro Leu Leu Ser Val Gln Pro Val Ser Asn
1880 1885 1890
gca gat tgg gtg tgg ctg gtc aag agg ctg cac aag ctg tgc atg 5898
Ala Asp Trp Val Trp Leu Val Lys Arg Leu His Lys Leu Cys Met
1895 1900 1905
gaa ctg tgc aac aac tac atc cag atg cac ttg gac ctg gag aac 5943
Glu Leu Cys Asn Asn Tyr Ile Gln Met His Leu Asp Leu Glu Asn
1910 1915 1920
tgt atg gag gag cct ccc atc ttc aag ggc gac ccg ttc ttc atc 5988
Cys Met Glu Glu Pro Pro Ile Phe Lys Gly Asp Pro Phe Phe Ile
1925 1930 1935
ctg ccc tcc ttc cag tcc gag tca tcc acc cca tcc acc ggg ggc 6033
Leu Pro Ser Phe Gln Ser Glu Ser Ser Thr Pro Ser Thr Gly Gly
1940 1945 1950
ttc tct ggg aaa gaa acc cct tcc gag gat gac aga agc cag tcc 6078
Phe Ser Gly Lys Glu Thr Pro Ser Glu Asp Asp Arg Ser Gln Ser
1955 1960 1965
cgg gag cac atg ggc gag tcc ctg agc ctg aag gcc ggt ggt ggg 6123
Arg Glu His Met Gly Glu Ser Leu Ser Leu Lys Ala Gly Gly Gly
1970 1975 1980
gac ctg ctg ctg ccc ccc agc ccc aaa gtg gag aag aag gat ccc 6168
Asp Leu Leu Leu Pro Pro Ser Pro Lys Val Glu Lys Lys Asp Pro
1985 1990 1995
agc cgg aag aag gag tgg tgg gag aat gcg ggg aac aaa atc tac 6213
Ser Arg Lys Lys Glu Trp Trp Glu Asn Ala Gly Asn Lys Ile Tyr
2000 2005 2010
acc atg gca gcc gac aag acc att tca aag ttg atg acc gaa tac 6258
Thr Met Ala Ala Asp Lys Thr Ile Ser Lys Leu Met Thr Glu Tyr
2015 2020 2025
aaa aag agg aaa cag cag cac aac ctg tcc gcg ttc ccc aaa gag 6303
Lys Lys Arg Lys Gln Gln His Asn Leu Ser Ala Phe Pro Lys Glu
2030 2035 2040
gtc aaa gtg gag aag aaa gga gag cca ctg ggt ccc agg ggc cag 6348
Val Lys Val Glu Lys Lys Gly Glu Pro Leu Gly Pro Arg Gly Gln
2045 2050 2055
gac tcc ccg ctg ctt cag cgt ccc cag cac ttg atg gac caa ggg 6393
Asp Ser Pro Leu Leu Gln Arg Pro Gln His Leu Met Asp Gln Gly
2060 2065 2070
caa atg cgg cat tcc ttc agc gca ggc ccc gag ctg ctg cga cag 6438
Gln Met Arg His Ser Phe Ser Ala Gly Pro Glu Leu Leu Arg Gln
2075 2080 2085
gac aag agg ccc cgc tca ggc tcc acc ggg agc tcc ctc agt gtc 6483
Asp Lys Arg Pro Arg Ser Gly Ser Thr Gly Ser Ser Leu Ser Val
2090 2095 2100
tcg gtg aga gac gca gaa gca cag atc cag gca tgg acc aac atg 6528
Ser Val Arg Asp Ala Glu Ala Gln Ile Gln Ala Trp Thr Asn Met
2105 2110 2115
gtg cta aca gtt ctc aat cag att cag att ctc cca gac cag acc 6573
Val Leu Thr Val Leu Asn Gln Ile Gln Ile Leu Pro Asp Gln Thr
2120 2125 2130
ttc acg gcc ctc cag ccc gca gtg ttc ccg tgc atc agt cag ctg 6618
Phe Thr Ala Leu Gln Pro Ala Val Phe Pro Cys Ile Ser Gln Leu
2135 2140 2145
acc tgt cac gtg acc gac atc aga gtt cgc cag gct gtg agg gag 6663
Thr Cys His Val Thr Asp Ile Arg Val Arg Gln Ala Val Arg Glu
2150 2155 2160
tgg ctg ggc agg gtg ggc cgt gtc tat gac atc att gtg tag 6705
Trp Leu Gly Arg Val Gly Arg Val Tyr Asp Ile Ile Val
2165 2170 2175
ccgactcctg ttctactctc ccaccaaata acagtagtga gggttagagt cctgccaata 6765
cagctgttgc attttcccca ccactagccc cacttaaact actactactg tctcagagaa 6825
cagtgtttcc taatgtaaaa agcctttcca accactgatc agcattgggg ccatactaag 6885
gtttgtatct agatgacaca aacgatattc tgattttgca cattattata gaagaatcta 6945
taatccttga tatgtttcta actcttgaag tatatttccc agtgcttttg cttacagtgt 7005
tgtccccaaa tgggtcattt tcaaggatta ctcatttgaa aacactatat tgatccattt 7065
gatccatcat ttaaaaaata aatacaattc ctaaggcaat atctgctggt aagtcaagct 7125
gataaacact cagacatcta gtaccaggga ttattaattg gaggaagatt tatggttatg 7185
ggtctggctg ggaagaagac aactataaat acatattctt gggtgtcata atcaagaaag 7245
aggtgacttc tgttgtaaaa taatccagaa cacttcaaaa ttattcctaa atcattaaga 7305
ttttcaggta ttcaccaatt tccccatgta aggtactgtg ttgtaccttt atttctgtat 7365
ttctaaaaga agaaagttct ttcctagcag ggtttgaagt ctgtggctta tcagcctgtg 7425
acacagagta cccagtgaaa gtggctggta cgtagattgt caagagacat aagaccgacc 7485
agccaccctg gctgttcttg tggtgtttgt ttccatcccc aaggcaaaca aggaaaggaa 7545
aggaaagaag aaaaggtgcc ttagtccttt gttgcacttc catttccatg ccccacaatt 7605
gtctgaacat aaggtatagc atttggtttt taagaaaaca aaacattaag acgcaactca 7665
ttttatatca acacgcttgg aggaaaggga ctcagggaag ggagcaggga gtgtggggtg 7725
gggatggatt atgatgaaat cattttcaat cttaaaatat aatacaacaa tcttgcaaaa 7785
ttatggtgtc agttacacaa gctctagtct caaaatgaaa gtaatggaga aagacactga 7845
aatttagaaa attttgtcga tttaaaatat ttctcctatc taccaagtaa agttacccta 7905
tgtttgatgt ctttgcattc agaccaatat ttcaggtgga tatttctaag tattactaga 7965
aaatacgttt gaaagcttta tcttattatt tacagtattt ttatatttct tacattatcc 8025
taatgattga aaactcctca atcaagctta cttacacaca ttctacagag ttatttaagg 8085
catacattat aatctcccag ccccattcat aatgaataag tcacccttta aatataagac 8145
acaaattcta cagtattgaa ataaggattt aaaggggtat ttgtaaactt tgccctcctt 8205
gagaaatatg gaactacctt agaggttaag aggaaggcag tgttctgact tctttaggtg 8265
atctgaaaaa aacaccctta tcatccagtg taccatctag agatcaccac agaatccatt 8325
tttttcccag ttccacaaaa cactctgttt gccttcagtt tttactcact agacaataat 8385
tcaagtttag aaacaggtaa tcagctattt gatcttaaaa ggcaatgaat tgttgggata 8445
tcagtgaact atgttgtata cttttgaatt tttacatttt ataaatggaa ttgaaagttg 8505
gataactgct ttttttaaat tttccaacag aagtaacacc acagttgctt tgtttctttt 8565
tatagcttac ctgaggttca gttcttcttt gtgaacctgt gagtactcca cagtttactg 8625
ggggaaaagg cttcagtaaa gcagaggcta gaattacagt atttatacat agcaactttt 8685
cataaagtag aaaaattcaa aggaagctgt ctcaatttga gaataccagc tgggcacggt 8745
ggctcacgcc tgtaatccca gcacttactt tgggaggcca aggtgggcag ataacctgcg 8805
gtcaggagtt tgagaccagg ctggacaaca tggtgaaacc tcgtctctac taaaaataca 8865
aaaattagcc aggtgtggta ggatgcacct gtaatcccag ctacttagga ggccgagaca 8925
ggagaatcgc tcgaacccag gaggcggacg ttgcagtgag ccaagattgc accattgcac 8985
tccagactgg gtgacaagag tgaaactcca tctaaaaaaa aaaaaaaaaa aaagtgaata 9045
ctgtatccca aagtatgtta gttgtttgtt tggaaatcag cattctcccc gatgctctat 9105
tatgggatcc aaaattcttg aacataagtt taccctgtac tgtgtccaaa cactgttcta 9165
gttctagcct gattatgggt cccaagaata aaaggatgag taggtgtaca gagctcttga 9225
cctacaattt tttaagagtg ttttggtacc ttcccattgt cttctctata actcagtcct 9285
aacatactct gcactcgagt taccagccat ccacactgac atcagatttc aaccagaacc 9345
atcactgagt gacagcagta cttctcagag gtatttgcag cttgatgcaa agtagtctct 9405
aatgagtagg cattcaggtg gttcttccca gcaggtggag aagaaaggga ggagatgaag 9465
aacactgaga ggggagtggc accttcccag gctgcccagc tcagtctctt gccctgttcc 9525
tgtgactcag ctgcccactc ccccaacttt gtttccctcc ctcccagtct ctgaaagtgt 9585
caggtgtttc tctcctcaca gtctcttttg cagcaacagt aagacaaaat tcaaggcagc 9645
cttttaaagt tacgaacagt tattagcatg tatttacaga cctaagcaga atgagagttt 9705
atacattgtt tttagttgcc tgtatttata gccaaaagta tattacctta aagttgagat 9765
ctttctcttc ttttcctaaa ttttggtaaa gtgtgcttca tgaaacaaac atctggaaaa 9825
ctccaagtat aagagaccct ggactgatga tggcccagcc aagtatatgg agggacagag 9885
ttctctctgt cattaatgag gacatcggtt ttcacaattg aacctcatgc actgtccaca 9945
gcatctcacc tagctcctgt atctcctgat ctgcttttaa aaatagttag ttaggctgcc 10005
tttttacacc accttctctc tctccccttg tggtaatttt ccagccttcc ccatagatat 10065
aaaactagaa cacctttatg atttggggtc tatgtaatga ctgaccgata agaacccagg 10125
cagatgctaa catacttaac agctcgcatt aaaatacttt aaatcaggcg tgatggctca 10185
ttcctgtaat ctcaagcact ttgggaggct aaggtgggtg gatctcttga ggtcaggagt 10245
tcgagaccaa cctggccaac gtggtgaaac cccgtctcta ctaaaaatac aaaattagcc 10305
gggcatggtg gcagctgcct gtaatcccag ctactcggga agctgaggca ggagaattgc 10365
ttgaacctgg gaggtgggga ttgcagtcag ccaagattgt tctgcagcat gggtgacaaa 10425
gtgagacttc gtctcaagta aataaaacta aaatttttaa atcaaacatg acaaaaatgt 10485
taatataatt cagaagtacc ttgaaattga aacatatttg tgcaatgatc attaggcttt 10545
ttgtccttgt tgttttaaaa tgaggcttat acagagtgag ttgagagtca agtagccttc 10605
gctgtgagac ggtaatgcag ttatataata gatacccttg actttgccag attcatcaca 10665
atactgctta tacaggaaag ttttctcaga aaggaaaatc cattagtatc agtcccatca 10725
agccaaacag aatgaagacc tttgatagta atagcaagag gttacaaata gcagggagga 10785
ggcgagtagt gaatgtcact gtgattgcaa acccttacct gtattatcac acgtagtcct 10845
cacaacaacc ttgtgagaca agtgttgtgt tcctcatttt ttcagagggg aacacagacc 10905
cagagaggtt aagaaatttg cccaagataa caagtaaaag gcaaagttgg ttgcaaaaga 10965
ggtgtttctg aattcaaggg ccatactctc tctctgacaa catgctctaa gtccatagag 11025
taagcactct agtatgaaaa aaagtttcaa ggaacgaggc catgaaaatg agactatttg 11085
acatctcaga tctgtctggg atgttatgga ggtttttaaa aataaagttg aaaaaagaaa 11145
atgaatcatg tttatacata aaaaaatcac atgtaacaca tttcaagtgt ttgaaaataa 11205
aaccaaaatc taaactttag tcttcaagca gacattcagt gttactttag aaaactcact 11265
gaattaggtg gaaatgatgg aataatacta ttcatggcca gctattaaca cagaagaaca 11325
tggcagtgtg tgtctggaac ggcatgcaca atttgtaaac ctttttcaaa tatcatttaa 11385
tcaactcaga ataaagtgcc ctgtagccaa cagtgcctct ttacttgctt ctctgggaaa 11445
tacatggtac taaattagta gcacaaagtt tgggaatatg caaaataatg gataaccatt 11505
tttcaaaatg tacattctct gaagaggaag cagctggttg gacaggattt cttgaagagc 11565
caggtgctaa gggcatcagg tcgacatcca tagtaaccat gtgccataac atctacacat 11625
ttccacttgt tttacagaca aggtaacagg cagaaggaaa atccagagtc ttgcagtaag 11685
cagatgacaa aacttcaata tgcttgggca ccacttaggt gaccccaggg agatttagtg 11745
tggccttagg aaagcaaaag agcacttttt attggaaata tgagcttgtc actgggaaag 11805
atttgtaaaa ttgatcaaga acttgattta taattatgcc tcaaaaaaaa aagttctcat 11865
ttagtagtgg agcaatctag aaaacatacc ttttttgttt gtttggaaga tcctctttcc 11925
ctggctgtat tgtagtgttt gctatttgat gtggaaataa ctaataactt aagattttgg 11985
aacagaacac cctttagatt tccaaaacac aattcttatt tcagggaaga cagaccaaaa 12045
atatctcctg agatcattgg tttctttata aattgtggta ccactccatc attgaagaga 12105
aaccactacc acaccactag caccatacag aaccttttct ctgtatcttt gtacaatact 12165
acaaaggggt accagggagg agagagtggc tgaccacttt agtgacaaaa cagcactcca 12225
ctgctggtga atcccatcta attatggtcc ttccaccctt ttcaaccacc aacaactgtt 12285
cgtactgtta attcctatcc tgaaggttta accagtggtt gtctagtatc ttctgtcttt 12345
agaacagtgg ttctcaaact ttagtacaca tcagcatcac ctggagggcc tttttttaaa 12405
ataagacaca gattgctggg ctcatggtca gagttcccag ttaagtaaat caggaaattt 12465
gtatttctaa caagtttata ggtgaggcca atactgctgt tttgggaact atgctttgag 12525
aaccactgcc ttgaaaaaat ttccaacttc tacctttaag atcagcctga cttatcaaac 12585
gctagagaaa aactgaatct acccttgggc agatgacttg ggattggatt ctatacagca 12645
gtcttgctca atcttcccag tttccagttt tattatacca acaattggtt tttacaagct 12705
agaagacaat gaatgtataa gttctatgga acagtgagat aaatctaagc ttcttgtctt 12765
tgtatttaga aacattgatt ctatggatga tcatttgtat catgttgacc ctttgacttg 12825
tactgaaggt gattttaaat ttaagtatgt agtgtttgaa tttcttccat ccatgtcgtt 12885
ttaatgagat gtttccatgt cagctccttt acagccttgg ctcctggctt acagattttt 12945
gaatagttgt ttgcttgcca gttgttttac atctttcatt ggccaccaaa atattagcca 13005
tttgagatga gatgagacta cttgttgtac cttcatcttt catttaattt tctggcgtaa 13065
attaacattt taatttcata tatatctgta aagagtctac ccaaaggctt cacggaaatt 13125
tgcaaaatga actaattccc ttttaagcag caggtgtgcc tgtttttgac ttttcagtaa 13185
atatgttgtt tgtgcacata tctacatggt ggagaccata ttcattattt catcttccaa 13245
ataatgggaa aaatataaaa gtgaatcagt gtgctttggg aattcagtga aatcatgtta 13305
actcatatag agggggcctt agtttatctc ttctttactg aattaattag ttttggaaat 13365
tcttttacca ttaaaaaaaa ttaaggacca tacagagaat gatttaagaa aaaacaagtc 13425
acttaaaaat catcacctat ttataaactg tattaattac acataatgct tattgattca 13485
atgaggtttc tctaaagact tctgcttaat aaatatgctg acttcattta aattagttta 13545
gactattgta ggaatggaag gaaatgatta tatttactag aattagtgag atcagaaagc 13605
atatcagaat gttgatgata tcaaggagac aatctacaga gtttttgcct ctgtggatgg 13665
aaataagggt gttttttttt ggtttttttt ttactttagt ttcccataat ttttggaaat 13725
tatgtgtgca tttagttctt ttagtaacac tgattttaaa attaaatttc aaaagtcaat 13785
ctctaagagt aatttatttt tgttttacca accagtgcca aaaaggagag gagggaatcc 13845
aaaagccaat cttttgaacc aatgtgtaaa agattatgtt ttttcttaaa gttagggagg 13905
ctcgggccct gacactgcca gccccagtga gcatccctgg ctacctcggg attatgtgca 13965
agctgctttg tcctacattt ctttcatctg gttcttattg ggagtgcttc tctctaataa 14025
aaattgattt cccacaaaat aggcaaagct gaacaaagat gaatgctttt gataagttgg 14085
gtttcacttc agttgaaaca atgtgataga atatccaggt gtggcatgat ggggcaggag 14145
gaggtgccta gagggaaaag ttatttttgt ttcttagtgt tgtgttgtgg ggatgggaca 14205
gataagaata agatgtttat tgccctaatc atgctaagag actattattc aatatgcttt 14265
tcccgctttt ctaagaggaa taaacttaga caaattacat tataaacagt tcccctacta 14325
ctatctccca ctctagataa agccagtggg tggtatgggt ccttttattc cttatagtat 14385
tatgccaaag aatcaactta ttttcattga agattataaa taaatgaagc ttgttatagc 14445
cataatgatt tgagtcagta taccatttta cctataaaat gcaaaattca tccttgcaac 14505
cccattcacc aggagccttg aagcattttg tttactccaa aggccttgtc aaggaagcat 14565
aattttttgt tttgccttct tatttagtca gtttggtcat atttacttaa aaaaacaaac 14625
tgaaaatcac actcctttat atgttgatat aactgatttt atagaatctg tctgttcttt 14685
gtttaacagg tctctgtaag caagcttgca agtgtatttt gtgtacattt tatctgaggt 14745
ggaaatgaaa attctaaaga gaaaatattt taaaagatat tgtatttatg ttgcttgtgt 14805
tgtagaataa agattcaaat gcattaaaaa tctggtacat gaaacaattg tgtttactga 14865
ataaatatat ataaataaaa aaaaaaaaaa 14895
<210> 7
<211> 2177
<212> PRT
<213> 智人
<400> 7
Met Glu Glu Ile Leu Arg Lys Leu Gln Lys Glu Ala Ser Gly Ser Lys
1 5 10 15
Tyr Lys Ala Ile Lys Glu Ser Cys Thr Trp Ala Leu Glu Thr Leu Gly
20 25 30
Gly Leu Asp Thr Ile Val Lys Ile Pro Pro His Val Leu Arg Glu Lys
35 40 45
Cys Leu Leu Pro Leu Gln Leu Ala Leu Glu Ser Lys Asn Val Lys Leu
50 55 60
Ala Gln His Ala Leu Ala Gly Met Gln Lys Leu Leu Ser Glu Glu Arg
65 70 75 80
Phe Val Ser Met Glu Thr Asp Ser Asp Glu Lys Gln Leu Leu Asn Gln
85 90 95
Ile Leu Asn Ala Val Lys Val Thr Pro Ser Leu Asn Glu Asp Leu Gln
100 105 110
Val Glu Val Met Lys Val Leu Leu Cys Ile Thr Tyr Thr Pro Thr Phe
115 120 125
Asp Leu Asn Gly Ser Ala Val Leu Lys Ile Ala Glu Val Cys Ile Glu
130 135 140
Thr Tyr Ile Ser Ser Cys His Gln Arg Ser Ile Asn Thr Ala Val Arg
145 150 155 160
Ala Thr Leu Ser Gln Met Leu Ser Asp Leu Thr Leu Gln Leu Arg Gln
165 170 175
Arg Gln Glu Asn Thr Ile Ile Glu Asn Pro Asp Val Pro Gln Asp Phe
180 185 190
Gly Asn Gln Gly Ser Thr Val Glu Ser Leu Cys Asp Asp Val Val Ser
195 200 205
Val Leu Thr Val Leu Cys Glu Lys Leu Gln Ala Ala Ile Asn Asp Ser
210 215 220
Gln Gln Leu Gln Leu Leu Tyr Leu Glu Cys Ile Leu Ser Val Leu Ser
225 230 235 240
Ser Ser Ser Ser Ser Met His Leu His Arg Arg Phe Thr Asp Leu Ile
245 250 255
Trp Lys Asn Leu Cys Pro Ala Leu Ile Val Ile Leu Gly Asn Pro Ile
260 265 270
His Asp Lys Thr Ile Thr Ser Ala His Thr Ser Ser Thr Ser Thr Ser
275 280 285
Leu Glu Ser Asp Ser Ala Ser Pro Gly Val Ser Asp His Gly Arg Gly
290 295 300
Ser Gly Cys Ser Cys Thr Ala Pro Ala Leu Ser Gly Pro Val Ala Arg
305 310 315 320
Thr Ile Tyr Tyr Ile Ala Ala Glu Leu Val Arg Leu Val Gly Ser Val
325 330 335
Asp Ser Met Lys Pro Val Leu Gln Ser Leu Tyr His Arg Val Leu Leu
340 345 350
Tyr Pro Pro Pro Gln His Arg Val Glu Ala Ile Lys Ile Met Lys Glu
355 360 365
Ile Leu Gly Ser Pro Gln Arg Leu Cys Asp Leu Ala Gly Pro Ser Ser
370 375 380
Thr Glu Ser Glu Ser Arg Lys Arg Ser Ile Ser Lys Arg Lys Ser His
385 390 395 400
Leu Asp Leu Leu Lys Leu Ile Met Asp Gly Met Thr Glu Ala Cys Ile
405 410 415
Lys Gly Gly Ile Glu Ala Cys Tyr Ala Ala Val Ser Cys Val Cys Thr
420 425 430
Leu Leu Gly Ala Leu Asp Glu Leu Ser Gln Gly Lys Gly Leu Ser Glu
435 440 445
Gly Gln Val Gln Leu Leu Leu Leu Arg Leu Glu Glu Leu Lys Asp Gly
450 455 460
Ala Glu Trp Ser Arg Asp Ser Met Glu Ile Asn Glu Ala Asp Phe Arg
465 470 475 480
Trp Gln Arg Arg Val Leu Ser Ser Glu His Thr Pro Trp Glu Ser Gly
485 490 495
Asn Glu Arg Ser Leu Asp Ile Ser Ile Ser Val Thr Thr Asp Thr Gly
500 505 510
Gln Thr Thr Leu Glu Gly Glu Leu Gly Gln Thr Thr Pro Glu Asp His
515 520 525
Ser Gly Asn His Lys Asn Ser Leu Lys Ser Pro Ala Ile Pro Glu Gly
530 535 540
Lys Glu Thr Leu Ser Lys Val Leu Glu Thr Glu Ala Val Asp Gln Pro
545 550 555 560
Asp Val Val Gln Arg Ser His Thr Val Pro Tyr Pro Asp Ile Thr Asn
565 570 575
Phe Leu Ser Val Asp Cys Arg Thr Arg Ser Tyr Gly Ser Arg Tyr Ser
580 585 590
Glu Ser Asn Phe Ser Val Asp Asp Gln Asp Leu Ser Arg Thr Glu Phe
595 600 605
Asp Ser Cys Asp Gln Tyr Ser Met Ala Ala Glu Lys Asp Ser Gly Arg
610 615 620
Ser Asp Val Ser Asp Ile Gly Ser Asp Asn Cys Ser Leu Ala Asp Glu
625 630 635 640
Glu Gln Thr Pro Arg Asp Cys Leu Gly His Arg Ser Leu Arg Thr Ala
645 650 655
Ala Leu Ser Leu Lys Leu Leu Lys Asn Gln Glu Ala Asp Gln His Ser
660 665 670
Ala Arg Leu Phe Ile Gln Ser Leu Glu Gly Leu Leu Pro Arg Leu Leu
675 680 685
Ser Leu Ser Asn Val Glu Glu Val Asp Thr Ala Leu Gln Asn Phe Ala
690 695 700
Ser Thr Phe Cys Ser Gly Met Met His Ser Pro Gly Phe Asp Gly Asn
705 710 715 720
Ser Ser Leu Ser Phe Gln Met Leu Met Asn Ala Asp Ser Leu Tyr Thr
725 730 735
Ala Ala His Cys Ala Leu Leu Leu Asn Leu Lys Leu Ser His Gly Asp
740 745 750
Tyr Tyr Arg Lys Arg Pro Thr Leu Ala Pro Gly Val Met Lys Asp Phe
755 760 765
Met Lys Gln Val Gln Thr Ser Gly Val Leu Met Val Phe Ser Gln Ala
770 775 780
Trp Ile Glu Glu Leu Tyr His Gln Val Leu Asp Arg Asn Met Leu Gly
785 790 795 800
Glu Ala Gly Tyr Trp Gly Ser Pro Glu Asp Asn Ser Leu Pro Leu Ile
805 810 815
Thr Met Leu Thr Asp Ile Asp Gly Leu Glu Ser Ser Ala Ile Gly Gly
820 825 830
Gln Leu Met Ala Ser Ala Ala Thr Glu Ser Pro Phe Ala Gln Ser Arg
835 840 845
Arg Ile Asp Asp Ser Thr Val Ala Gly Val Ala Phe Ala Arg Tyr Ile
850 855 860
Leu Val Gly Cys Trp Lys Asn Leu Ile Asp Thr Leu Ser Thr Pro Leu
865 870 875 880
Thr Gly Arg Met Ala Gly Ser Ser Lys Gly Leu Ala Phe Ile Leu Gly
885 890 895
Ala Glu Gly Ile Lys Glu Gln Asn Gln Lys Glu Arg Asp Ala Ile Cys
900 905 910
Met Ser Leu Asp Gly Leu Arg Lys Ala Ala Arg Leu Ser Cys Ala Leu
915 920 925
Gly Val Ala Ala Asn Cys Ala Ser Ala Leu Ala Gln Met Ala Ala Ala
930 935 940
Ser Cys Val Gln Glu Glu Lys Glu Glu Arg Glu Ala Gln Glu Pro Ser
945 950 955 960
Asp Ala Ile Thr Gln Val Lys Leu Lys Val Glu Gln Lys Leu Glu Gln
965 970 975
Ile Gly Lys Val Gln Gly Val Trp Leu His Thr Ala His Val Leu Cys
980 985 990
Met Glu Ala Ile Leu Ser Val Gly Leu Glu Met Gly Ser His Asn Pro
995 1000 1005
Asp Cys Trp Pro His Val Phe Arg Val Cys Glu Tyr Val Gly Thr
1010 1015 1020
Leu Glu His Asn His Phe Ser Asp Gly Ala Ser Gln Pro Pro Leu
1025 1030 1035
Thr Ile Ser Gln Pro Gln Lys Ala Thr Gly Ser Ala Gly Leu Leu
1040 1045 1050
Gly Asp Pro Glu Cys Glu Gly Ser Pro Pro Glu His Ser Pro Glu
1055 1060 1065
Gln Gly Arg Ser Leu Ser Thr Ala Pro Val Val Gln Pro Leu Ser
1070 1075 1080
Ile Gln Asp Leu Val Arg Glu Gly Ser Arg Gly Arg Ala Ser Asp
1085 1090 1095
Phe Arg Gly Gly Ser Leu Met Ser Gly Ser Ser Ala Ala Lys Val
1100 1105 1110
Val Leu Thr Leu Ser Thr Gln Ala Asp Arg Leu Phe Glu Asp Ala
1115 1120 1125
Thr Asp Lys Leu Asn Leu Met Ala Leu Gly Gly Phe Leu Tyr Gln
1130 1135 1140
Leu Lys Lys Ala Ser Gln Ser Gln Leu Phe His Ser Val Thr Asp
1145 1150 1155
Thr Val Asp Tyr Ser Leu Ala Met Pro Gly Glu Val Lys Ser Thr
1160 1165 1170
Gln Asp Arg Lys Ser Ala Leu His Leu Phe Arg Leu Gly Asn Ala
1175 1180 1185
Met Leu Arg Ile Val Arg Ser Lys Ala Arg Pro Leu Leu His Val
1190 1195 1200
Met Arg Cys Trp Ser Leu Val Ala Pro His Leu Val Glu Ala Ala
1205 1210 1215
Cys His Lys Glu Arg His Val Ser Gln Lys Ala Val Ser Phe Ile
1220 1225 1230
His Asp Ile Leu Thr Glu Val Leu Thr Asp Trp Asn Glu Pro Pro
1235 1240 1245
His Phe His Phe Asn Glu Ala Leu Phe Arg Pro Phe Glu Arg Ile
1250 1255 1260
Met Gln Leu Glu Leu Cys Asp Glu Asp Val Gln Asp Gln Val Val
1265 1270 1275
Thr Ser Ile Gly Glu Leu Val Glu Val Cys Ser Thr Gln Ile Gln
1280 1285 1290
Ser Gly Trp Arg Pro Leu Phe Ser Ala Leu Glu Thr Val His Gly
1295 1300 1305
Gly Asn Lys Ser Glu Met Lys Glu Tyr Leu Val Gly Asp Tyr Ser
1310 1315 1320
Met Gly Lys Gly Gln Ala Pro Val Phe Asp Val Phe Glu Ala Phe
1325 1330 1335
Leu Asn Thr Asp Asn Ile Gln Val Phe Ala Asn Ala Ala Thr Ser
1340 1345 1350
Tyr Ile Met Cys Leu Met Lys Phe Val Lys Gly Leu Gly Glu Val
1355 1360 1365
Asp Cys Lys Glu Ile Gly Asp Cys Ala Pro Ala Pro Gly Ala Pro
1370 1375 1380
Ser Thr Asp Leu Cys Leu Pro Ala Leu Asp Tyr Leu Arg Arg Cys
1385 1390 1395
Ser Gln Leu Leu Ala Lys Ile Tyr Lys Met Pro Leu Lys Pro Ile
1400 1405 1410
Phe Leu Ser Gly Arg Leu Ala Gly Leu Pro Arg Arg Leu Gln Glu
1415 1420 1425
Gln Ser Ala Ser Ser Glu Asp Gly Ile Glu Ser Val Leu Ser Asp
1430 1435 1440
Phe Asp Asp Asp Thr Gly Leu Ile Glu Val Trp Ile Ile Leu Leu
1445 1450 1455
Glu Gln Leu Thr Ala Ala Val Ser Asn Cys Pro Arg Gln His Gln
1460 1465 1470
Pro Pro Thr Leu Asp Leu Leu Phe Glu Leu Leu Arg Asp Val Thr
1475 1480 1485
Lys Thr Pro Gly Pro Gly Phe Gly Ile Tyr Ala Val Val His Leu
1490 1495 1500
Leu Leu Pro Val Met Ser Val Trp Leu Arg Arg Ser His Lys Asp
1505 1510 1515
His Ser Tyr Trp Asp Met Ala Ser Ala Asn Phe Lys His Ala Ile
1520 1525 1530
Gly Leu Ser Cys Glu Leu Val Val Glu His Ile Gln Ser Phe Leu
1535 1540 1545
His Ser Asp Ile Arg Tyr Glu Ser Met Ile Asn Thr Met Leu Lys
1550 1555 1560
Asp Leu Phe Glu Leu Leu Val Ala Cys Val Ala Lys Pro Thr Glu
1565 1570 1575
Thr Ile Ser Arg Val Gly Cys Ser Cys Ile Arg Tyr Val Leu Val
1580 1585 1590
Thr Ala Gly Pro Val Phe Thr Glu Glu Met Trp Arg Leu Ala Cys
1595 1600 1605
Cys Ala Leu Gln Asp Ala Phe Ser Ala Thr Leu Lys Pro Val Lys
1610 1615 1620
Asp Leu Leu Gly Cys Phe His Ser Gly Thr Glu Ser Phe Ser Gly
1625 1630 1635
Glu Gly Cys Gln Val Arg Val Ala Ala Pro Ser Ser Ser Pro Ser
1640 1645 1650
Ala Glu Ala Glu Tyr Trp Arg Ile Arg Ala Met Ala Gln Gln Val
1655 1660 1665
Phe Met Leu Asp Thr Gln Cys Ser Pro Lys Thr Pro Asn Asn Phe
1670 1675 1680
Asp His Ala Gln Ser Cys Gln Leu Ile Ile Glu Leu Pro Pro Asp
1685 1690 1695
Glu Lys Pro Asn Gly His Thr Lys Lys Ser Val Ser Phe Arg Glu
1700 1705 1710
Ile Val Val Ser Leu Leu Ser His Gln Val Leu Leu Gln Asn Leu
1715 1720 1725
Tyr Asp Ile Leu Leu Glu Glu Phe Val Lys Gly Pro Ser Pro Gly
1730 1735 1740
Glu Glu Lys Thr Ile Gln Val Pro Glu Ala Lys Leu Ala Gly Phe
1745 1750 1755
Leu Arg Tyr Ile Ser Met Gln Asn Leu Ala Val Ile Phe Asp Leu
1760 1765 1770
Leu Leu Asp Ser Tyr Arg Thr Ala Arg Glu Phe Asp Thr Ser Pro
1775 1780 1785
Gly Leu Lys Cys Leu Leu Lys Lys Val Ser Gly Ile Gly Gly Ala
1790 1795 1800
Ala Asn Leu Tyr Arg Gln Ser Ala Met Ser Phe Asn Ile Tyr Phe
1805 1810 1815
His Ala Leu Val Cys Ala Val Leu Thr Asn Gln Glu Thr Ile Thr
1820 1825 1830
Ala Glu Gln Val Lys Lys Val Leu Phe Glu Asp Asp Glu Arg Ser
1835 1840 1845
Thr Asp Ser Ser Gln Gln Cys Ser Ser Glu Asp Glu Asp Ile Phe
1850 1855 1860
Glu Glu Thr Ala Gln Val Ser Pro Pro Arg Gly Lys Glu Lys Arg
1865 1870 1875
Gln Trp Arg Ala Arg Met Pro Leu Leu Ser Val Gln Pro Val Ser
1880 1885 1890
Asn Ala Asp Trp Val Trp Leu Val Lys Arg Leu His Lys Leu Cys
1895 1900 1905
Met Glu Leu Cys Asn Asn Tyr Ile Gln Met His Leu Asp Leu Glu
1910 1915 1920
Asn Cys Met Glu Glu Pro Pro Ile Phe Lys Gly Asp Pro Phe Phe
1925 1930 1935
Ile Leu Pro Ser Phe Gln Ser Glu Ser Ser Thr Pro Ser Thr Gly
1940 1945 1950
Gly Phe Ser Gly Lys Glu Thr Pro Ser Glu Asp Asp Arg Ser Gln
1955 1960 1965
Ser Arg Glu His Met Gly Glu Ser Leu Ser Leu Lys Ala Gly Gly
1970 1975 1980
Gly Asp Leu Leu Leu Pro Pro Ser Pro Lys Val Glu Lys Lys Asp
1985 1990 1995
Pro Ser Arg Lys Lys Glu Trp Trp Glu Asn Ala Gly Asn Lys Ile
2000 2005 2010
Tyr Thr Met Ala Ala Asp Lys Thr Ile Ser Lys Leu Met Thr Glu
2015 2020 2025
Tyr Lys Lys Arg Lys Gln Gln His Asn Leu Ser Ala Phe Pro Lys
2030 2035 2040
Glu Val Lys Val Glu Lys Lys Gly Glu Pro Leu Gly Pro Arg Gly
2045 2050 2055
Gln Asp Ser Pro Leu Leu Gln Arg Pro Gln His Leu Met Asp Gln
2060 2065 2070
Gly Gln Met Arg His Ser Phe Ser Ala Gly Pro Glu Leu Leu Arg
2075 2080 2085
Gln Asp Lys Arg Pro Arg Ser Gly Ser Thr Gly Ser Ser Leu Ser
2090 2095 2100
Val Ser Val Arg Asp Ala Glu Ala Gln Ile Gln Ala Trp Thr Asn
2105 2110 2115
Met Val Leu Thr Val Leu Asn Gln Ile Gln Ile Leu Pro Asp Gln
2120 2125 2130
Thr Phe Thr Ala Leu Gln Pro Ala Val Phe Pro Cys Ile Ser Gln
2135 2140 2145
Leu Thr Cys His Val Thr Asp Ile Arg Val Arg Gln Ala Val Arg
2150 2155 2160
Glu Trp Leu Gly Arg Val Gly Arg Val Tyr Asp Ile Ile Val
2165 2170 2175
<210> 8
<211> 1457
<212> DNA
<213> 智人
<220>
<221> CDS
<222> (211)..(1110)
<400> 8
tccgtatgcg cgattcctgt gcgcgaagtt cgggtccgta gtgggctaag ggggagggtt 60
tcaaagggag cgcacttccg ctgccctttc tttcgccagc cttacgggcc cgaaccctcg 120
tgtgaagggt gcagtaccta agccggagcg gggtagaggc gggccggcac ccccttctga 180
cctccagtgc cgccggcctc aagatcagac atg gcc cag aac ttg aag gac ttg 234
Met Ala Gln Asn Leu Lys Asp Leu
1 5
gcg gga cgg ctg ccc gcc ggg ccc cgg ggc atg ggc acg gcc ctg aag 282
Ala Gly Arg Leu Pro Ala Gly Pro Arg Gly Met Gly Thr Ala Leu Lys
10 15 20
ctg ttg ctg ggg gcc ggc gcc gtg gcc tac ggt gtg cgc gaa tct gtg 330
Leu Leu Leu Gly Ala Gly Ala Val Ala Tyr Gly Val Arg Glu Ser Val
25 30 35 40
ttc acc gtg gaa ggc ggg cac aga gcc atc ttc ttc aat cgg atc ggt 378
Phe Thr Val Glu Gly Gly His Arg Ala Ile Phe Phe Asn Arg Ile Gly
45 50 55
gga gtg cag cag gac act atc ctg gcc gag ggc ctt cac ttc agg atc 426
Gly Val Gln Gln Asp Thr Ile Leu Ala Glu Gly Leu His Phe Arg Ile
60 65 70
cct tgg ttc cag tac ccc att atc tat gac att cgg gcc aga cct cga 474
Pro Trp Phe Gln Tyr Pro Ile Ile Tyr Asp Ile Arg Ala Arg Pro Arg
75 80 85
aaa atc tcc tcc cct aca ggc tcc aaa gac cta cag atg gtg aat atc 522
Lys Ile Ser Ser Pro Thr Gly Ser Lys Asp Leu Gln Met Val Asn Ile
90 95 100
tcc ctg cga gtg ttg tct cga ccc aat gct cag gag ctt cct agc atg 570
Ser Leu Arg Val Leu Ser Arg Pro Asn Ala Gln Glu Leu Pro Ser Met
105 110 115 120
tac cag cgc cta ggg ctg gac tac gag gaa cga gtg ttg ccg tcc att 618
Tyr Gln Arg Leu Gly Leu Asp Tyr Glu Glu Arg Val Leu Pro Ser Ile
125 130 135
gtc aac gag gtg ctc aag agt gtg gtg gcc aag ttc aat gcc tca cag 666
Val Asn Glu Val Leu Lys Ser Val Val Ala Lys Phe Asn Ala Ser Gln
140 145 150
ctg atc acc cag cgg gcc cag gta tcc ctg ttg atc cgc cgg gag ctg 714
Leu Ile Thr Gln Arg Ala Gln Val Ser Leu Leu Ile Arg Arg Glu Leu
155 160 165
aca gag agg gcc aag gac ttc agc ctc atc ctg gat gat gtg gcc atc 762
Thr Glu Arg Ala Lys Asp Phe Ser Leu Ile Leu Asp Asp Val Ala Ile
170 175 180
aca gag ctg agc ttt agc cga gag tac aca gct gct gta gaa gcc aaa 810
Thr Glu Leu Ser Phe Ser Arg Glu Tyr Thr Ala Ala Val Glu Ala Lys
185 190 195 200
caa gtg gcc cag cag gag gcc cag cgg gcc caa ttc ttg gta gaa aaa 858
Gln Val Ala Gln Gln Glu Ala Gln Arg Ala Gln Phe Leu Val Glu Lys
205 210 215
gca aag cag gaa cag cgg cag aaa att gtg cag gcc gag ggt gag gcc 906
Ala Lys Gln Glu Gln Arg Gln Lys Ile Val Gln Ala Glu Gly Glu Ala
220 225 230
gag gct gcc aag atg ctt gga gaa gca ctg agc aag aac cct ggc tac 954
Glu Ala Ala Lys Met Leu Gly Glu Ala Leu Ser Lys Asn Pro Gly Tyr
235 240 245
atc aaa ctt cgc aag att cga gca gcc cag aat atc tcc aag acg atc 1002
Ile Lys Leu Arg Lys Ile Arg Ala Ala Gln Asn Ile Ser Lys Thr Ile
250 255 260
gcc aca tca cag aat cgt atc tat ctc aca gct gac aac ctt gtg ctg 1050
Ala Thr Ser Gln Asn Arg Ile Tyr Leu Thr Ala Asp Asn Leu Val Leu
265 270 275 280
aac cta cag gat gaa agt ttc acc agg gga agt gac agc ctc atc aag 1098
Asn Leu Gln Asp Glu Ser Phe Thr Arg Gly Ser Asp Ser Leu Ile Lys
285 290 295
ggt aag aaa tga gcctagtcac caagaactcc acccccagag gaagtggatc 1150
Gly Lys Lys
tgcttctcca gtttttgagg agccagccag gggtccagca cagccctacc ccgccccagt 1210
atcatgcgat ggtcccccac accggttccc tgaacccctc ttggattaag gaagactgaa 1270
gactagcccc ttttctgggg aattactttc ctcctccctg tgttaactgg ggctgttggg 1330
gacagtgcgt gatttctcag tgatttccta cagtgttgtt ccctccctca aggctgggag 1390
gagataaaca ccaacccagg aattctcaat aaatttttat tacttaacct gaaaaaaaaa 1450
aaaaaaa 1457
<210> 9
<211> 299
<212> PRT
<213> 智人
<400> 9
Met Ala Gln Asn Leu Lys Asp Leu Ala Gly Arg Leu Pro Ala Gly Pro
1 5 10 15
Arg Gly Met Gly Thr Ala Leu Lys Leu Leu Leu Gly Ala Gly Ala Val
20 25 30
Ala Tyr Gly Val Arg Glu Ser Val Phe Thr Val Glu Gly Gly His Arg
35 40 45
Ala Ile Phe Phe Asn Arg Ile Gly Gly Val Gln Gln Asp Thr Ile Leu
50 55 60
Ala Glu Gly Leu His Phe Arg Ile Pro Trp Phe Gln Tyr Pro Ile Ile
65 70 75 80
Tyr Asp Ile Arg Ala Arg Pro Arg Lys Ile Ser Ser Pro Thr Gly Ser
85 90 95
Lys Asp Leu Gln Met Val Asn Ile Ser Leu Arg Val Leu Ser Arg Pro
100 105 110
Asn Ala Gln Glu Leu Pro Ser Met Tyr Gln Arg Leu Gly Leu Asp Tyr
115 120 125
Glu Glu Arg Val Leu Pro Ser Ile Val Asn Glu Val Leu Lys Ser Val
130 135 140
Val Ala Lys Phe Asn Ala Ser Gln Leu Ile Thr Gln Arg Ala Gln Val
145 150 155 160
Ser Leu Leu Ile Arg Arg Glu Leu Thr Glu Arg Ala Lys Asp Phe Ser
165 170 175
Leu Ile Leu Asp Asp Val Ala Ile Thr Glu Leu Ser Phe Ser Arg Glu
180 185 190
Tyr Thr Ala Ala Val Glu Ala Lys Gln Val Ala Gln Gln Glu Ala Gln
195 200 205
Arg Ala Gln Phe Leu Val Glu Lys Ala Lys Gln Glu Gln Arg Gln Lys
210 215 220
Ile Val Gln Ala Glu Gly Glu Ala Glu Ala Ala Lys Met Leu Gly Glu
225 230 235 240
Ala Leu Ser Lys Asn Pro Gly Tyr Ile Lys Leu Arg Lys Ile Arg Ala
245 250 255
Ala Gln Asn Ile Ser Lys Thr Ile Ala Thr Ser Gln Asn Arg Ile Tyr
260 265 270
Leu Thr Ala Asp Asn Leu Val Leu Asn Leu Gln Asp Glu Ser Phe Thr
275 280 285
Arg Gly Ser Asp Ser Leu Ile Lys Gly Lys Lys
290 295
<210> 10
<211> 1343
<212> DNA
<213> 智人
<220>
<221> CDS
<222> (211)..(996)
<400> 10
tccgtatgcg cgattcctgt gcgcgaagtt cgggtccgta gtgggctaag ggggagggtt 60
tcaaagggag cgcacttccg ctgccctttc tttcgccagc cttacgggcc cgaaccctcg 120
tgtgaagggt gcagtaccta agccggagcg gggtagaggc gggccggcac ccccttctga 180
cctccagtgc cgccggcctc aagatcagac atg gcc cag aac ttg aag gac ttg 234
Met Ala Gln Asn Leu Lys Asp Leu
1 5
gcg gga cgg ctg ccc gcc ggg ccc cgg ggc atg ggc acg gcc ctg aag 282
Ala Gly Arg Leu Pro Ala Gly Pro Arg Gly Met Gly Thr Ala Leu Lys
10 15 20
ctg ttg ctg ggg gcc ggc gcc gtg gcc tac ggt gtg cgc gaa tct gtg 330
Leu Leu Leu Gly Ala Gly Ala Val Ala Tyr Gly Val Arg Glu Ser Val
25 30 35 40
ttc acc gtg gaa ggc ggg cac aga gcc atc ttc ttc aat cgg atc ggt 378
Phe Thr Val Glu Gly Gly His Arg Ala Ile Phe Phe Asn Arg Ile Gly
45 50 55
gga gtg cag cag gac act atc ctg gcc gag ggc ctt cac ttc agg atc 426
Gly Val Gln Gln Asp Thr Ile Leu Ala Glu Gly Leu His Phe Arg Ile
60 65 70
cct tgg ttc cag tac ccc att atc tat gac att cgg gcc aga cct cga 474
Pro Trp Phe Gln Tyr Pro Ile Ile Tyr Asp Ile Arg Ala Arg Pro Arg
75 80 85
aaa atc tcc tcc cct aca ggc tcc aaa gac cta cag atg gtg aat atc 522
Lys Ile Ser Ser Pro Thr Gly Ser Lys Asp Leu Gln Met Val Asn Ile
90 95 100
tcc ctg cga gtg ttg tct cga ccc aat gct cag gag ctt cct agc atg 570
Ser Leu Arg Val Leu Ser Arg Pro Asn Ala Gln Glu Leu Pro Ser Met
105 110 115 120
tac cag cgc cta ggg ctg gac tac gag gaa cga gtg ttg ccg tcc att 618
Tyr Gln Arg Leu Gly Leu Asp Tyr Glu Glu Arg Val Leu Pro Ser Ile
125 130 135
gtc aac gag gtg ctc aag agt gtg gtg gcc aag ttc aat gcc tca cag 666
Val Asn Glu Val Leu Lys Ser Val Val Ala Lys Phe Asn Ala Ser Gln
140 145 150
ctg atc acc cag cgg gcc cag gta tcc ctg ttg atc cgc cgg gag ctg 714
Leu Ile Thr Gln Arg Ala Gln Val Ser Leu Leu Ile Arg Arg Glu Leu
155 160 165
aca gag agg gcc aag gac ttc agc ctc atc ctg gat gat gtg gcc atc 762
Thr Glu Arg Ala Lys Asp Phe Ser Leu Ile Leu Asp Asp Val Ala Ile
170 175 180
aca gag ctg agc ttt agc cga gag tac aca gct gct gta gaa gcc aaa 810
Thr Glu Leu Ser Phe Ser Arg Glu Tyr Thr Ala Ala Val Glu Ala Lys
185 190 195 200
caa gtg gca ctg agc aag aac cct ggc tac atc aaa ctt cgc aag att 858
Gln Val Ala Leu Ser Lys Asn Pro Gly Tyr Ile Lys Leu Arg Lys Ile
205 210 215
cga gca gcc cag aat atc tcc aag acg atc gcc aca tca cag aat cgt 906
Arg Ala Ala Gln Asn Ile Ser Lys Thr Ile Ala Thr Ser Gln Asn Arg
220 225 230
atc tat ctc aca gct gac aac ctt gtg ctg aac cta cag gat gaa agt 954
Ile Tyr Leu Thr Ala Asp Asn Leu Val Leu Asn Leu Gln Asp Glu Ser
235 240 245
ttc acc agg gga agt gac agc ctc atc aag ggt aag aaa tga 996
Phe Thr Arg Gly Ser Asp Ser Leu Ile Lys Gly Lys Lys
250 255 260
gcctagtcac caagaactcc acccccagag gaagtggatc tgcttctcca gtttttgagg 1056
agccagccag gggtccagca cagccctacc ccgccccagt atcatgcgat ggtcccccac 1116
accggttccc tgaacccctc ttggattaag gaagactgaa gactagcccc ttttctgggg 1176
aattactttc ctcctccctg tgttaactgg ggctgttggg gacagtgcgt gatttctcag 1236
tgatttccta cagtgttgtt ccctccctca aggctgggag gagataaaca ccaacccagg 1296
aattctcaat aaatttttat tacttaacct gaaaaaaaaa aaaaaaa 1343
<210> 11
<211> 261
<212> PRT
<213> 智人
<400> 11
Met Ala Gln Asn Leu Lys Asp Leu Ala Gly Arg Leu Pro Ala Gly Pro
1 5 10 15
Arg Gly Met Gly Thr Ala Leu Lys Leu Leu Leu Gly Ala Gly Ala Val
20 25 30
Ala Tyr Gly Val Arg Glu Ser Val Phe Thr Val Glu Gly Gly His Arg
35 40 45
Ala Ile Phe Phe Asn Arg Ile Gly Gly Val Gln Gln Asp Thr Ile Leu
50 55 60
Ala Glu Gly Leu His Phe Arg Ile Pro Trp Phe Gln Tyr Pro Ile Ile
65 70 75 80
Tyr Asp Ile Arg Ala Arg Pro Arg Lys Ile Ser Ser Pro Thr Gly Ser
85 90 95
Lys Asp Leu Gln Met Val Asn Ile Ser Leu Arg Val Leu Ser Arg Pro
100 105 110
Asn Ala Gln Glu Leu Pro Ser Met Tyr Gln Arg Leu Gly Leu Asp Tyr
115 120 125
Glu Glu Arg Val Leu Pro Ser Ile Val Asn Glu Val Leu Lys Ser Val
130 135 140
Val Ala Lys Phe Asn Ala Ser Gln Leu Ile Thr Gln Arg Ala Gln Val
145 150 155 160
Ser Leu Leu Ile Arg Arg Glu Leu Thr Glu Arg Ala Lys Asp Phe Ser
165 170 175
Leu Ile Leu Asp Asp Val Ala Ile Thr Glu Leu Ser Phe Ser Arg Glu
180 185 190
Tyr Thr Ala Ala Val Glu Ala Lys Gln Val Ala Leu Ser Lys Asn Pro
195 200 205
Gly Tyr Ile Lys Leu Arg Lys Ile Arg Ala Ala Gln Asn Ile Ser Lys
210 215 220
Thr Ile Ala Thr Ser Gln Asn Arg Ile Tyr Leu Thr Ala Asp Asn Leu
225 230 235 240
Val Leu Asn Leu Gln Asp Glu Ser Phe Thr Arg Gly Ser Asp Ser Leu
245 250 255
Ile Lys Gly Lys Lys
260
<210> 12
<211> 6330
<212> DNA
<213> 智人
<220>
<221> CDS
<222> (235)..(2022)
<400> 12
aggagctggc ggagggcgtt cgtcctggga ctgcacttgc tcccgtcggg tcgcccggct 60
tcaccggacc cgcaggctcc cggggcaggg ccggggccag agctcgcgtg tcggcgggac 120
atgcgctgcg tcgcctctaa cctcgggctg tgctcttttt ccaggtggcc cgccggtttc 180
tgagccttct gccctgcggg gacacggtct gcaccctgcc cgcggccacg gacc atg 237
Met
1
acc atg acc ctc cac acc aaa gca tct ggg atg gcc cta ctg cat cag 285
Thr Met Thr Leu His Thr Lys Ala Ser Gly Met Ala Leu Leu His Gln
5 10 15
atc caa ggg aac gag ctg gag ccc ctg aac cgt ccg cag ctc aag atc 333
Ile Gln Gly Asn Glu Leu Glu Pro Leu Asn Arg Pro Gln Leu Lys Ile
20 25 30
ccc ctg gag cgg ccc ctg ggc gag gtg tac ctg gac agc agc aag ccc 381
Pro Leu Glu Arg Pro Leu Gly Glu Val Tyr Leu Asp Ser Ser Lys Pro
35 40 45
gcc gtg tac aac tac ccc gag ggc gcc gcc tac gag ttc aac gcc gcg 429
Ala Val Tyr Asn Tyr Pro Glu Gly Ala Ala Tyr Glu Phe Asn Ala Ala
50 55 60 65
gcc gcc gcc aac gcg cag gtc tac ggt cag acc ggc ctc ccc tac ggc 477
Ala Ala Ala Asn Ala Gln Val Tyr Gly Gln Thr Gly Leu Pro Tyr Gly
70 75 80
ccc ggg tct gag gct gcg gcg ttc ggc tcc aac ggc ctg ggg ggt ttc 525
Pro Gly Ser Glu Ala Ala Ala Phe Gly Ser Asn Gly Leu Gly Gly Phe
85 90 95
ccc cca ctc aac agc gtg tct ccg agc ccg ctg atg cta ctg cac ccg 573
Pro Pro Leu Asn Ser Val Ser Pro Ser Pro Leu Met Leu Leu His Pro
100 105 110
ccg ccg cag ctg tcg cct ttc ctg cag ccc cac ggc cag cag gtg ccc 621
Pro Pro Gln Leu Ser Pro Phe Leu Gln Pro His Gly Gln Gln Val Pro
115 120 125
tac tac ctg gag aac gag ccc agc ggc tac acg gtg cgc gag gcc ggc 669
Tyr Tyr Leu Glu Asn Glu Pro Ser Gly Tyr Thr Val Arg Glu Ala Gly
130 135 140 145
ccg ccg gca ttc tac agg cca aat tca gat aat cga cgc cag ggt ggc 717
Pro Pro Ala Phe Tyr Arg Pro Asn Ser Asp Asn Arg Arg Gln Gly Gly
150 155 160
aga gaa aga ttg gcc agt acc aat gac aag gga agt atg gct atg gaa 765
Arg Glu Arg Leu Ala Ser Thr Asn Asp Lys Gly Ser Met Ala Met Glu
165 170 175
tct gcc aag gag act cgc tac tgt gca gtg tgc aat gac tat gct tca 813
Ser Ala Lys Glu Thr Arg Tyr Cys Ala Val Cys Asn Asp Tyr Ala Ser
180 185 190
ggc tac cat tat gga gtc tgg tcc tgt gag ggc tgc aag gcc ttc ttc 861
Gly Tyr His Tyr Gly Val Trp Ser Cys Glu Gly Cys Lys Ala Phe Phe
195 200 205
aag aga agt att caa gga cat aac gac tat atg tgt cca gcc acc aac 909
Lys Arg Ser Ile Gln Gly His Asn Asp Tyr Met Cys Pro Ala Thr Asn
210 215 220 225
cag tgc acc att gat aaa aac agg agg aag agc tgc cag gcc tgc cgg 957
Gln Cys Thr Ile Asp Lys Asn Arg Arg Lys Ser Cys Gln Ala Cys Arg
230 235 240
ctc cgc aaa tgc tac gaa gtg gga atg atg aaa ggt ggg ata cga aaa 1005
Leu Arg Lys Cys Tyr Glu Val Gly Met Met Lys Gly Gly Ile Arg Lys
245 250 255
gac cga aga gga ggg aga atg ttg aaa cac aag cgc cag aga gat gat 1053
Asp Arg Arg Gly Gly Arg Met Leu Lys His Lys Arg Gln Arg Asp Asp
260 265 270
ggg gag ggc agg ggt gaa gtg ggg tct gct gga gac atg aga gct gcc 1101
Gly Glu Gly Arg Gly Glu Val Gly Ser Ala Gly Asp Met Arg Ala Ala
275 280 285
aac ctt tgg cca agc ccg ctc atg atc aaa cgc tct aag aag aac agc 1149
Asn Leu Trp Pro Ser Pro Leu Met Ile Lys Arg Ser Lys Lys Asn Ser
290 295 300 305
ctg gcc ttg tcc ctg acg gcc gac cag atg gtc agt gcc ttg ttg gat 1197
Leu Ala Leu Ser Leu Thr Ala Asp Gln Met Val Ser Ala Leu Leu Asp
310 315 320
gct gag ccc ccc ata ctc tat tcc gag tat gat cct acc aga ccc ttc 1245
Ala Glu Pro Pro Ile Leu Tyr Ser Glu Tyr Asp Pro Thr Arg Pro Phe
325 330 335
agt gaa gct tcg atg atg ggc tta ctg acc aac ctg gca gac agg gag 1293
Ser Glu Ala Ser Met Met Gly Leu Leu Thr Asn Leu Ala Asp Arg Glu
340 345 350
ctg gtt cac atg atc aac tgg gcg aag agg gtg cca ggc ttt gtg gat 1341
Leu Val His Met Ile Asn Trp Ala Lys Arg Val Pro Gly Phe Val Asp
355 360 365
ttg acc ctc cat gat cag gtc cac ctt cta gaa tgt gcc tgg cta gag 1389
Leu Thr Leu His Asp Gln Val His Leu Leu Glu Cys Ala Trp Leu Glu
370 375 380 385
atc ctg atg att ggt ctc gtc tgg cgc tcc atg gag cac cca ggg aag 1437
Ile Leu Met Ile Gly Leu Val Trp Arg Ser Met Glu His Pro Gly Lys
390 395 400
cta ctg ttt gct cct aac ttg ctc ttg gac agg aac cag gga aaa tgt 1485
Leu Leu Phe Ala Pro Asn Leu Leu Leu Asp Arg Asn Gln Gly Lys Cys
405 410 415
gta gag ggc atg gtg gag atc ttc gac atg ctg ctg gct aca tca tct 1533
Val Glu Gly Met Val Glu Ile Phe Asp Met Leu Leu Ala Thr Ser Ser
420 425 430
cgg ttc cgc atg atg aat ctg cag gga gag gag ttt gtg tgc ctc aaa 1581
Arg Phe Arg Met Met Asn Leu Gln Gly Glu Glu Phe Val Cys Leu Lys
435 440 445
tct att att ttg ctt aat tct gga gtg tac aca ttt ctg tcc agc acc 1629
Ser Ile Ile Leu Leu Asn Ser Gly Val Tyr Thr Phe Leu Ser Ser Thr
450 455 460 465
ctg aag tct ctg gaa gag aag gac cat atc cac cga gtc ctg gac aag 1677
Leu Lys Ser Leu Glu Glu Lys Asp His Ile His Arg Val Leu Asp Lys
470 475 480
atc aca gac act ttg atc cac ctg atg gcc aag gca ggc ctg acc ctg 1725
Ile Thr Asp Thr Leu Ile His Leu Met Ala Lys Ala Gly Leu Thr Leu
485 490 495
cag cag cag cac cag cgg ctg gcc cag ctc ctc ctc atc ctc tcc cac 1773
Gln Gln Gln His Gln Arg Leu Ala Gln Leu Leu Leu Ile Leu Ser His
500 505 510
atc agg cac atg agt aac aaa ggc atg gag cat ctg tac agc atg aag 1821
Ile Arg His Met Ser Asn Lys Gly Met Glu His Leu Tyr Ser Met Lys
515 520 525
tgc aag aac gtg gtg ccc ctc tat gac ctg ctg ctg gag atg ctg gac 1869
Cys Lys Asn Val Val Pro Leu Tyr Asp Leu Leu Leu Glu Met Leu Asp
530 535 540 545
gcc cac cgc cta cat gcg ccc act agc cgt gga ggg gca tcc gtg gag 1917
Ala His Arg Leu His Ala Pro Thr Ser Arg Gly Gly Ala Ser Val Glu
550 555 560
gag acg gac caa agc cac ttg gcc act gcg ggc tct act tca tcg cat 1965
Glu Thr Asp Gln Ser His Leu Ala Thr Ala Gly Ser Thr Ser Ser His
565 570 575
tcc ttg caa aag tat tac atc acg ggg gag gca gag ggt ttc cct gcc 2013
Ser Leu Gln Lys Tyr Tyr Ile Thr Gly Glu Ala Glu Gly Phe Pro Ala
580 585 590
acg gtc tga gagctccctg gctcccacac ggttcagata atccctgctg 2062
Thr Val
595
cattttaccc tcatcatgca ccactttagc caaattctgt ctcctgcata cactccggca 2122
tgcatccaac accaatggct ttctagatga gtggccattc atttgcttgc tcagttctta 2182
gtggcacatc ttctgtcttc tgttgggaac agccaaaggg attccaaggc taaatctttg 2242
taacagctct ctttccccct tgctatgtta ctaagcgtga ggattcccgt agctcttcac 2302
agctgaactc agtctatggg ttggggctca gataactctg tgcatttaag ctacttgtag 2362
agacccaggc ctggagagta gacattttgc ctctgataag cactttttaa atggctctaa 2422
gaataagcca cagcaaagaa tttaaagtgg ctcctttaat tggtgacttg gagaaagcta 2482
ggtcaagggt ttattatagc accctcttgt attcctatgg caatgcatcc ttttatgaaa 2542
gtggtacacc ttaaagcttt tatatgactg tagcagagta tctggtgatt gtcaattcat 2602
tccccctata ggaatacaag gggcacacag ggaaggcaga tcccctagtt ggcaagacta 2662
ttttaacttg atacactgca gattcagatg tgctgaaagc tctgcctctg gctttccggt 2722
catgggttcc agttaattca tgcctcccat ggacctatgg agagcagcaa gttgatctta 2782
gttaagtctc cctatatgag ggataagttc ctgatttttg tttttatttt tgtgttacaa 2842
aagaaagccc tccctccctg aacttgcagt aaggtcagct tcaggacctg ttccagtggg 2902
cactgtactt ggatcttccc ggcgtgtgtg tgccttacac aggggtgaac tgttcactgt 2962
ggtgatgcat gatgagggta aatggtagtt gaaaggagca ggggccctgg tgttgcattt 3022
agccctgggg catggagctg aacagtactt gtgcaggatt gttgtggcta ctagagaaca 3082
agagggaaag tagggcagaa actggataca gttctgaggc acagccagac ttgctcaggg 3142
tggccctgcc acaggctgca gctacctagg aacattcctt gcagaccccg cattgccctt 3202
tgggggtgcc ctgggatccc tggggtagtc cagctcttct tcatttccca gcgtggccct 3262
ggttggaaga agcagctgtc acagctgctg tagacagctg tgttcctaca attggcccag 3322
caccctgggg cacgggagaa gggtggggac cgttgctgtc actactcagg ctgactgggg 3382
cctggtcaga ttacgtatgc ccttggtggt ttagagataa tccaaaatca gggtttggtt 3442
tggggaagaa aatcctcccc cttcctcccc cgccccgttc cctaccgcct ccactcctgc 3502
cagctcattt ccttcaattt cctttgacct ataggctaaa aaagaaaggc tcattccagc 3562
cacagggcag ccttccctgg gcctttgctt ctctagcaca attatgggtt acttcctttt 3622
tcttaacaaa aaagaatgtt tgatttcctc tgggtgacct tattgtctgt aattgaaacc 3682
ctattgagag gtgatgtctg tgttagccaa tgacccaggt gagctgctcg ggcttctctt 3742
ggtatgtctt gtttggaaaa gtggatttca ttcatttctg attgtccagt taagtgatca 3802
ccaaaggact gagaatctgg gagggcaaaa aaaaaaaaaa agtttttatg tgcacttaaa 3862
tttggggaca attttatgta tctgtgttaa ggatatgttt aagaacataa ttcttttgtt 3922
gctgtttgtt taagaagcac cttagtttgt ttaagaagca ccttatatag tataatatat 3982
atttttttga aattacattg cttgtttatc agacaattga atgtagtaat tctgttctgg 4042
atttaatttg actgggttaa catgcaaaaa ccaaggaaaa atatttagtt tttttttttt 4102
tttttgtata cttttcaagc taccttgtca tgtatacagt catttatgcc taaagcctgg 4162
tgattattca tttaaatgaa gatcacattt catatcaact tttgtatcca cagtagacaa 4222
aatagcacta atccagatgc ctattgttgg atactgaatg acagacaatc ttatgtagca 4282
aagattatgc ctgaaaagga aaattattca gggcagctaa ttttgctttt accaaaatat 4342
cagtagtaat atttttggac agtagctaat gggtcagtgg gttcttttta atgtttatac 4402
ttagattttc ttttaaaaaa attaaaataa aacaaaaaaa aatttctagg actagacgat 4462
gtaataccag ctaaagccaa acaattatac agtggaaggt tttacattat tcatccaatg 4522
tgtttctatt catgttaaga tactactaca tttgaagtgg gcagagaaca tcagatgatt 4582
gaaatgttcg cccaggggtc tccagcaact ttggaaatct ctttgtattt ttacttgaag 4642
tgccactaat ggacagcaga tattttctgg ctgatgttgg tattgggtgt aggaacatga 4702
tttaaaaaaa aactcttgcc tctgctttcc cccactctga ggcaagttaa aatgtaaaag 4762
atgtgattta tctggggggc tcaggtatgg tggggaagtg gattcaggaa tctggggaat 4822
ggcaaatata ttaagaagag tattgaaagt atttggagga aaatggttaa ttctgggtgt 4882
gcaccagggt tcagtagagt ccacttctgc cctggagacc acaaatcaac tagctccatt 4942
tacagccatt tctaaaatgg cagcttcagt tctagagaag aaagaacaac atcagcagta 5002
aagtccatgg aatagctagt ggtctgtgtt tcttttcgcc attgcctagc ttgccgtaat 5062
gattctataa tgccatcatg cagcaattat gagaggctag gtcatccaaa gagaagaccc 5122
tatcaatgta ggttgcaaaa tctaacccct aaggaagtgc agtctttgat ttgatttccc 5182
tagtaacctt gcagatatgt ttaaccaagc catagcccat gccttttgag ggctgaacaa 5242
ataagggact tactgataat ttacttttga tcacattaag gtgttctcac cttgaaatct 5302
tatacactga aatggccatt gatttaggcc actggcttag agtactcctt cccctgcatg 5362
acactgatta caaatacttt cctattcata ctttccaatt atgagatgga ctgtgggtac 5422
tgggagtgat cactaacacc atagtaatgt ctaatattca caggcagatc tgcttgggga 5482
agctagttat gtgaaaggca aatagagtca tacagtagct caaaaggcaa ccataattct 5542
ctttggtgca ggtcttggga gcgtgatcta gattacactg caccattccc aagttaatcc 5602
cctgaaaact tactctcaac tggagcaaat gaactttggt cccaaatatc catcttttca 5662
gtagcgttaa ttatgctctg tttccaactg catttccttt ccaattgaat taaagtgtgg 5722
cctcgttttt agtcatttaa aattgttttc taagtaattg ctgcctctat tatggcactt 5782
caattttgca ctgtcttttg agattcaaga aaaatttcta ttcttttttt tgcatccaat 5842
tgtgcctgaa cttttaaaat atgtaaatgc tgccatgttc caaacccatc gtcagtgtgt 5902
gtgtttagag ctgtgcaccc tagaaacaac atattgtccc atgagcaggt gcctgagaca 5962
cagacccctt tgcattcaca gagaggtcat tggttataga gacttgaatt aataagtgac 6022
attatgccag tttctgttct ctcacaggtg ataaacaatg ctttttgtgc actacatact 6082
cttcagtgta gagctcttgt tttatgggaa aaggctcaaa tgccaaattg tgtttgatgg 6142
attaatatgc ccttttgccg atgcatacta ttactgatgt gactcggttt tgtcgcagct 6202
ttgctttgtt taatgaaaca cacttgtaaa cctcttttgc actttgaaaa agaatccagc 6262
gggatgctcg agcacctgta aacaattttc tcaacctatt tgatgttcaa ataaagaatt 6322
aaactaaa 6330
<210> 13
<211> 595
<212> PRT
<213> 智人
<400> 13
Met Thr Met Thr Leu His Thr Lys Ala Ser Gly Met Ala Leu Leu His
1 5 10 15
Gln Ile Gln Gly Asn Glu Leu Glu Pro Leu Asn Arg Pro Gln Leu Lys
20 25 30
Ile Pro Leu Glu Arg Pro Leu Gly Glu Val Tyr Leu Asp Ser Ser Lys
35 40 45
Pro Ala Val Tyr Asn Tyr Pro Glu Gly Ala Ala Tyr Glu Phe Asn Ala
50 55 60
Ala Ala Ala Ala Asn Ala Gln Val Tyr Gly Gln Thr Gly Leu Pro Tyr
65 70 75 80
Gly Pro Gly Ser Glu Ala Ala Ala Phe Gly Ser Asn Gly Leu Gly Gly
85 90 95
Phe Pro Pro Leu Asn Ser Val Ser Pro Ser Pro Leu Met Leu Leu His
100 105 110
Pro Pro Pro Gln Leu Ser Pro Phe Leu Gln Pro His Gly Gln Gln Val
115 120 125
Pro Tyr Tyr Leu Glu Asn Glu Pro Ser Gly Tyr Thr Val Arg Glu Ala
130 135 140
Gly Pro Pro Ala Phe Tyr Arg Pro Asn Ser Asp Asn Arg Arg Gln Gly
145 150 155 160
Gly Arg Glu Arg Leu Ala Ser Thr Asn Asp Lys Gly Ser Met Ala Met
165 170 175
Glu Ser Ala Lys Glu Thr Arg Tyr Cys Ala Val Cys Asn Asp Tyr Ala
180 185 190
Ser Gly Tyr His Tyr Gly Val Trp Ser Cys Glu Gly Cys Lys Ala Phe
195 200 205
Phe Lys Arg Ser Ile Gln Gly His Asn Asp Tyr Met Cys Pro Ala Thr
210 215 220
Asn Gln Cys Thr Ile Asp Lys Asn Arg Arg Lys Ser Cys Gln Ala Cys
225 230 235 240
Arg Leu Arg Lys Cys Tyr Glu Val Gly Met Met Lys Gly Gly Ile Arg
245 250 255
Lys Asp Arg Arg Gly Gly Arg Met Leu Lys His Lys Arg Gln Arg Asp
260 265 270
Asp Gly Glu Gly Arg Gly Glu Val Gly Ser Ala Gly Asp Met Arg Ala
275 280 285
Ala Asn Leu Trp Pro Ser Pro Leu Met Ile Lys Arg Ser Lys Lys Asn
290 295 300
Ser Leu Ala Leu Ser Leu Thr Ala Asp Gln Met Val Ser Ala Leu Leu
305 310 315 320
Asp Ala Glu Pro Pro Ile Leu Tyr Ser Glu Tyr Asp Pro Thr Arg Pro
325 330 335
Phe Ser Glu Ala Ser Met Met Gly Leu Leu Thr Asn Leu Ala Asp Arg
340 345 350
Glu Leu Val His Met Ile Asn Trp Ala Lys Arg Val Pro Gly Phe Val
355 360 365
Asp Leu Thr Leu His Asp Gln Val His Leu Leu Glu Cys Ala Trp Leu
370 375 380
Glu Ile Leu Met Ile Gly Leu Val Trp Arg Ser Met Glu His Pro Gly
385 390 395 400
Lys Leu Leu Phe Ala Pro Asn Leu Leu Leu Asp Arg Asn Gln Gly Lys
405 410 415
Cys Val Glu Gly Met Val Glu Ile Phe Asp Met Leu Leu Ala Thr Ser
420 425 430
Ser Arg Phe Arg Met Met Asn Leu Gln Gly Glu Glu Phe Val Cys Leu
435 440 445
Lys Ser Ile Ile Leu Leu Asn Ser Gly Val Tyr Thr Phe Leu Ser Ser
450 455 460
Thr Leu Lys Ser Leu Glu Glu Lys Asp His Ile His Arg Val Leu Asp
465 470 475 480
Lys Ile Thr Asp Thr Leu Ile His Leu Met Ala Lys Ala Gly Leu Thr
485 490 495
Leu Gln Gln Gln His Gln Arg Leu Ala Gln Leu Leu Leu Ile Leu Ser
500 505 510
His Ile Arg His Met Ser Asn Lys Gly Met Glu His Leu Tyr Ser Met
515 520 525
Lys Cys Lys Asn Val Val Pro Leu Tyr Asp Leu Leu Leu Glu Met Leu
530 535 540
Asp Ala His Arg Leu His Ala Pro Thr Ser Arg Gly Gly Ala Ser Val
545 550 555 560
Glu Glu Thr Asp Gln Ser His Leu Ala Thr Ala Gly Ser Thr Ser Ser
565 570 575
His Ser Leu Gln Lys Tyr Tyr Ile Thr Gly Glu Ala Glu Gly Phe Pro
580 585 590
Ala Thr Val
595
<210> 14
<211> 2169
<212> DNA
<213> 智人
<220>
<221> CDS
<222> (469)..(2061)
<400> 14
ctcggtcttt aaaaggaaga aggggcttat cgttaagtcg cttgtgatct tttcagtttc 60
tccagctgct ggctttttgg acacccactc ccccgccagg aggcagttgc aagcgcggag 120
gctgcgagaa ataactgcct cttgaaactt gcagggcgaa gagcaggcgg cgagcgctgg 180
gccggggagg gaccacccga gctgcgacgg gctctggggc tgcggggcag ggctggcgcc 240
cggagcctga gctgcaggag gtgcgctcgc tttcctcaac aggtggcggc ggggcgcgcg 300
ccgggagacc ccccctaatg cgggaaaagc acgtgtccgc attttagaga aggcaaggcc 360
ggtgtgttta tctgcaagcc attatacttg cccacgaatc tttgagaaca ttataatgac 420
ctttgtgcct cttcttgcaa ggtgttttct cagctgttat ctcaagac atg gat ata 477
Met Asp Ile
1
aaa aac tca cca tct agc ctt aat tct cct tcc tcc tac aac tgc agt 525
Lys Asn Ser Pro Ser Ser Leu Asn Ser Pro Ser Ser Tyr Asn Cys Ser
5 10 15
caa tcc atc tta ccc ctg gag cac ggc tcc ata tac ata cct tcc tcc 573
Gln Ser Ile Leu Pro Leu Glu His Gly Ser Ile Tyr Ile Pro Ser Ser
20 25 30 35
tat gta gac agc cac cat gaa tat cca gcc atg aca ttc tat agc cct 621
Tyr Val Asp Ser His His Glu Tyr Pro Ala Met Thr Phe Tyr Ser Pro
40 45 50
gct gtg atg aat tac agc att ccc agc aat gtc act aac ttg gaa ggt 669
Ala Val Met Asn Tyr Ser Ile Pro Ser Asn Val Thr Asn Leu Glu Gly
55 60 65
ggg cct ggt cgg cag acc aca agc cca aat gtg ttg tgg cca aca cct 717
Gly Pro Gly Arg Gln Thr Thr Ser Pro Asn Val Leu Trp Pro Thr Pro
70 75 80
ggg cac ctt tct cct tta gtg gtc cat cgc cag tta tca cat ctg tat 765
Gly His Leu Ser Pro Leu Val Val His Arg Gln Leu Ser His Leu Tyr
85 90 95
gcg gaa cct caa aag agt ccc tgg tgt gaa gca aga tcg cta gaa cac 813
Ala Glu Pro Gln Lys Ser Pro Trp Cys Glu Ala Arg Ser Leu Glu His
100 105 110 115
acc tta cct gta aac aga gag aca ctg aaa agg aag gtt agt ggg aac 861
Thr Leu Pro Val Asn Arg Glu Thr Leu Lys Arg Lys Val Ser Gly Asn
120 125 130
cgt tgc gcc agc cct gtt act ggt cca ggt tca aag agg gat gct cac 909
Arg Cys Ala Ser Pro Val Thr Gly Pro Gly Ser Lys Arg Asp Ala His
135 140 145
ttc tgc gct gtc tgc agc gat tac gca tcg gga tat cac tat gga gtc 957
Phe Cys Ala Val Cys Ser Asp Tyr Ala Ser Gly Tyr His Tyr Gly Val
150 155 160
tgg tcg tgt gaa gga tgt aag gcc ttt ttt aaa aga agc att caa gga 1005
Trp Ser Cys Glu Gly Cys Lys Ala Phe Phe Lys Arg Ser Ile Gln Gly
165 170 175
cat aat gat tat att tgt cca gct aca aat cag tgt aca atc gat aaa 1053
His Asn Asp Tyr Ile Cys Pro Ala Thr Asn Gln Cys Thr Ile Asp Lys
180 185 190 195
aac cgg cgc aag agc tgc cag gcc tgc cga ctt cgg aag tgt tac gaa 1101
Asn Arg Arg Lys Ser Cys Gln Ala Cys Arg Leu Arg Lys Cys Tyr Glu
200 205 210
gtg gga atg gtg aag tgt ggc tcc cgg aga gag aga tgt ggg tac cgc 1149
Val Gly Met Val Lys Cys Gly Ser Arg Arg Glu Arg Cys Gly Tyr Arg
215 220 225
ctt gtg cgg aga cag aga agt gcc gac gag cag ctg cac tgt gcc ggc 1197
Leu Val Arg Arg Gln Arg Ser Ala Asp Glu Gln Leu His Cys Ala Gly
230 235 240
aag gcc aag aga agt ggc ggc cac gcg ccc cga gtg cgg gag ctg ctg 1245
Lys Ala Lys Arg Ser Gly Gly His Ala Pro Arg Val Arg Glu Leu Leu
245 250 255
ctg gac gcc ctg agc ccc gag cag cta gtg ctc acc ctc ctg gag gct 1293
Leu Asp Ala Leu Ser Pro Glu Gln Leu Val Leu Thr Leu Leu Glu Ala
260 265 270 275
gag ccg ccc cat gtg ctg atc agc cgc ccc agt gcg ccc ttc acc gag 1341
Glu Pro Pro His Val Leu Ile Ser Arg Pro Ser Ala Pro Phe Thr Glu
280 285 290
gcc tcc atg atg atg tcc ctg acc aag ttg gcc gac aag gag ttg gta 1389
Ala Ser Met Met Met Ser Leu Thr Lys Leu Ala Asp Lys Glu Leu Val
295 300 305
cac atg atc agc tgg gcc aag aag att ccc ggc ttt gtg gag ctc agc 1437
His Met Ile Ser Trp Ala Lys Lys Ile Pro Gly Phe Val Glu Leu Ser
310 315 320
ctg ttc gac caa gtg cgg ctc ttg gag agc tgt tgg atg gag gtg tta 1485
Leu Phe Asp Gln Val Arg Leu Leu Glu Ser Cys Trp Met Glu Val Leu
325 330 335
atg atg ggg ctg atg tgg cgc tca att gac cac ccc ggc aag ctc atc 1533
Met Met Gly Leu Met Trp Arg Ser Ile Asp His Pro Gly Lys Leu Ile
340 345 350 355
ttt gct cca gat ctt gtt ctg gac agg gat gag ggg aaa tgc gta gaa 1581
Phe Ala Pro Asp Leu Val Leu Asp Arg Asp Glu Gly Lys Cys Val Glu
360 365 370
gga att ctg gaa atc ttt gac atg ctc ctg gca act act tca agg ttt 1629
Gly Ile Leu Glu Ile Phe Asp Met Leu Leu Ala Thr Thr Ser Arg Phe
375 380 385
cga gag tta aaa ctc caa cac aaa gaa tat ctc tgt gtc aag gcc atg 1677
Arg Glu Leu Lys Leu Gln His Lys Glu Tyr Leu Cys Val Lys Ala Met
390 395 400
atc ctg ctc aat tcc agt atg tac cct ctg gtc aca gcg acc cag gat 1725
Ile Leu Leu Asn Ser Ser Met Tyr Pro Leu Val Thr Ala Thr Gln Asp
405 410 415
gct gac agc agc cgg aag ctg gct cac ttg ctg aac gcc gtg acc gat 1773
Ala Asp Ser Ser Arg Lys Leu Ala His Leu Leu Asn Ala Val Thr Asp
420 425 430 435
gct ttg gtt tgg gtg att gcc aag agc ggc atc tcc tcc cag cag caa 1821
Ala Leu Val Trp Val Ile Ala Lys Ser Gly Ile Ser Ser Gln Gln Gln
440 445 450
tcc atg cgc ctg gct aac ctc ctg atg ctc ctg tcc cac gtc agg cat 1869
Ser Met Arg Leu Ala Asn Leu Leu Met Leu Leu Ser His Val Arg His
455 460 465
gcg agt aac aag ggc atg gaa cat ctg ctc aac atg aag tgc aaa aat 1917
Ala Ser Asn Lys Gly Met Glu His Leu Leu Asn Met Lys Cys Lys Asn
470 475 480
gtg gtc cca gtg tat gac ctg ctg ctg gag atg ctg aat gcc cac gtg 1965
Val Val Pro Val Tyr Asp Leu Leu Leu Glu Met Leu Asn Ala His Val
485 490 495
ctt cgc ggg tgc aag tcc tcc atc acg ggg tcc gag tgc agc ccg gca 2013
Leu Arg Gly Cys Lys Ser Ser Ile Thr Gly Ser Glu Cys Ser Pro Ala
500 505 510 515
gag gac agt aaa agc aaa gag ggc tcc cag aac cca cag tct cag tga 2061
Glu Asp Ser Lys Ser Lys Glu Gly Ser Gln Asn Pro Gln Ser Gln
520 525 530
cgcctggccc tgaggtgaac tggcccacag aggtcacagg ctgaagcgtg aactccagtg 2121
tgtcaggagc ctgggcttca tctttctgct gtgtggtccc tcatttgg 2169
<210> 15
<211> 530
<212> PRT
<213> 智人
<400> 15
Met Asp Ile Lys Asn Ser Pro Ser Ser Leu Asn Ser Pro Ser Ser Tyr
1 5 10 15
Asn Cys Ser Gln Ser Ile Leu Pro Leu Glu His Gly Ser Ile Tyr Ile
20 25 30
Pro Ser Ser Tyr Val Asp Ser His His Glu Tyr Pro Ala Met Thr Phe
35 40 45
Tyr Ser Pro Ala Val Met Asn Tyr Ser Ile Pro Ser Asn Val Thr Asn
50 55 60
Leu Glu Gly Gly Pro Gly Arg Gln Thr Thr Ser Pro Asn Val Leu Trp
65 70 75 80
Pro Thr Pro Gly His Leu Ser Pro Leu Val Val His Arg Gln Leu Ser
85 90 95
His Leu Tyr Ala Glu Pro Gln Lys Ser Pro Trp Cys Glu Ala Arg Ser
100 105 110
Leu Glu His Thr Leu Pro Val Asn Arg Glu Thr Leu Lys Arg Lys Val
115 120 125
Ser Gly Asn Arg Cys Ala Ser Pro Val Thr Gly Pro Gly Ser Lys Arg
130 135 140
Asp Ala His Phe Cys Ala Val Cys Ser Asp Tyr Ala Ser Gly Tyr His
145 150 155 160
Tyr Gly Val Trp Ser Cys Glu Gly Cys Lys Ala Phe Phe Lys Arg Ser
165 170 175
Ile Gln Gly His Asn Asp Tyr Ile Cys Pro Ala Thr Asn Gln Cys Thr
180 185 190
Ile Asp Lys Asn Arg Arg Lys Ser Cys Gln Ala Cys Arg Leu Arg Lys
195 200 205
Cys Tyr Glu Val Gly Met Val Lys Cys Gly Ser Arg Arg Glu Arg Cys
210 215 220
Gly Tyr Arg Leu Val Arg Arg Gln Arg Ser Ala Asp Glu Gln Leu His
225 230 235 240
Cys Ala Gly Lys Ala Lys Arg Ser Gly Gly His Ala Pro Arg Val Arg
245 250 255
Glu Leu Leu Leu Asp Ala Leu Ser Pro Glu Gln Leu Val Leu Thr Leu
260 265 270
Leu Glu Ala Glu Pro Pro His Val Leu Ile Ser Arg Pro Ser Ala Pro
275 280 285
Phe Thr Glu Ala Ser Met Met Met Ser Leu Thr Lys Leu Ala Asp Lys
290 295 300
Glu Leu Val His Met Ile Ser Trp Ala Lys Lys Ile Pro Gly Phe Val
305 310 315 320
Glu Leu Ser Leu Phe Asp Gln Val Arg Leu Leu Glu Ser Cys Trp Met
325 330 335
Glu Val Leu Met Met Gly Leu Met Trp Arg Ser Ile Asp His Pro Gly
340 345 350
Lys Leu Ile Phe Ala Pro Asp Leu Val Leu Asp Arg Asp Glu Gly Lys
355 360 365
Cys Val Glu Gly Ile Leu Glu Ile Phe Asp Met Leu Leu Ala Thr Thr
370 375 380
Ser Arg Phe Arg Glu Leu Lys Leu Gln His Lys Glu Tyr Leu Cys Val
385 390 395 400
Lys Ala Met Ile Leu Leu Asn Ser Ser Met Tyr Pro Leu Val Thr Ala
405 410 415
Thr Gln Asp Ala Asp Ser Ser Arg Lys Leu Ala His Leu Leu Asn Ala
420 425 430
Val Thr Asp Ala Leu Val Trp Val Ile Ala Lys Ser Gly Ile Ser Ser
435 440 445
Gln Gln Gln Ser Met Arg Leu Ala Asn Leu Leu Met Leu Leu Ser His
450 455 460
Val Arg His Ala Ser Asn Lys Gly Met Glu His Leu Leu Asn Met Lys
465 470 475 480
Cys Lys Asn Val Val Pro Val Tyr Asp Leu Leu Leu Glu Met Leu Asn
485 490 495
Ala His Val Leu Arg Gly Cys Lys Ser Ser Ile Thr Gly Ser Glu Cys
500 505 510
Ser Pro Ala Glu Asp Ser Lys Ser Lys Glu Gly Ser Gln Asn Pro Gln
515 520 525
Ser Gln
530
<210> 16
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> an HA-tag peptide
<400> 16
Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
1 5
<210> 17
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 含Ser39的PHB2肽
<400> 17
Tyr Gly Val Arg Glu Ser Val Phe Thr Val Glu
1 5 10
<210> 18
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> BIG3的人工合成引物序列
<400> 18
cttgacaagg cctttggagt 20
<210> 19
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> BIG3的人工合成引物序列
<400> 19
caatatgctt ttcccgcttt 20
<210> 20
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> β2-MG的人工合成引物序列
<400> 20
aacttagagg tggggagcag 20
<210> 21
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> β2-MG的人工合成引物序列
<400> 21
cacaaccatg ccttacttta tc 22
Claims (15)
1.一种肽或其盐,其包含:在SEQ ID NO.4或SEQ ID NO.5所记载的氨基酸序列中,至少2对氨基酸残基被相同数量的钉合结构取代而成的氨基酸序列。
2.根据权利要求1所述的肽或其盐,其中,
2对氨基酸残基被2个钉合结构取代。
3.根据权利要求1或2所述的肽或其盐,其中,
2对氨基酸残基为以下的(a)和(b):
(a)从SEQ ID NO.4所记载的氨基酸序列的N末端起第3个和第7个氨基酸残基;
(b)从SEQ ID NO.4所记载的氨基酸序列的N末端起第8个和第12个氨基酸残基。
4.根据权利要求1或2所述的肽或其盐,其中,
2对氨基酸残基为以下的(c)和(d):
(c)从SEQ ID NO.5所记载的氨基酸序列的N末端起第3个和第7个氨基酸残基;
(d)从SEQ ID NO.5所记载的氨基酸序列的N末端起第10个和第14个氨基酸残基。
7.根据权利要求1~6中任一项所述的肽或其盐,其中,
N末端和C末端的氨基酸残基的任一者或两者经过了修饰。
8.根据权利要求7所述的肽或其盐,其中,
N末端和C末端的氨基酸残基的任一者或两者通过乙酰化、酰胺化和HA标签添加中的任一项或这些的组合而经过了修饰。
9.根据权利要求8所述的肽或其盐,其中,
N末端的氨基酸残基被乙酰化,并且,C末端的氨基酸残基被酰胺化。
10.根据权利要求1~9中任一项所述的肽或其盐,其中,
所有的氨基酸残基被D型的氨基酸残基所取代。
11.一种肽或其盐,其是权利要求1~9中任一项所述的肽的逆反体。
12.一种药物组合物,其包含:权利要求1~11中任一项所述的肽或其盐、和药学上允许的载体。
13.根据权利要求12所述的药物组合物,其用于癌症治疗。
14.根据权利要求13所述的药物组合物,其中,
癌症为乳腺癌或前列腺癌。
15.根据权利要求13或14所述的药物组合物,其中,
癌症为雌激素受体阳性的癌症。
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PCT/JP2018/026904 WO2019017384A1 (ja) | 2017-07-19 | 2018-07-18 | ペプチド誘導体及びそれを含む医薬組成物 |
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EP (1) | EP3656783A4 (zh) |
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CN (1) | CN111148752B (zh) |
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Citations (2)
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WO2013018690A1 (ja) * | 2011-07-29 | 2013-02-07 | 国立大学法人徳島大学 | Erap1由来ペプチド及びその使用 |
CN105492460A (zh) * | 2013-06-14 | 2016-04-13 | 哈佛大学的校长及成员们 | 稳定化多肽胰岛素受体调控剂 |
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JP5109131B2 (ja) | 2005-02-10 | 2012-12-26 | オンコセラピー・サイエンス株式会社 | 膀胱癌を診断する方法 |
JP4647456B2 (ja) | 2005-10-11 | 2011-03-09 | オンコセラピー・サイエンス株式会社 | 新規基質を用いたttk活性抑制剤のスクリーニング方法 |
BRPI0716498A2 (pt) | 2006-08-10 | 2015-01-27 | Oncotherapy Science Inc | Genes e polipeptídeos relacionados a cânceres de mama |
WO2017012646A1 (en) | 2015-07-20 | 2017-01-26 | Volvo Construction Equipment Ab | Movable armrest assembly |
EP3406626A4 (en) | 2016-01-19 | 2020-02-19 | Tokushima University | PEPTIDE FOR CANCER TREATMENT, AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME |
JP6159432B1 (ja) | 2016-02-08 | 2017-07-05 | 株式会社コロプラ | プログラム及びコンピュータ |
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WO2013018690A1 (ja) * | 2011-07-29 | 2013-02-07 | 国立大学法人徳島大学 | Erap1由来ペプチド及びその使用 |
CN105492460A (zh) * | 2013-06-14 | 2016-04-13 | 哈佛大学的校长及成员们 | 稳定化多肽胰岛素受体调控剂 |
JP2016523241A (ja) * | 2013-06-14 | 2016-08-08 | プレジデント アンド フェローズ オブ ハーバード カレッジ | 安定化されたポリペプチドインスリン受容体調節剤 |
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AU2018302855A1 (en) | 2020-02-06 |
JP7291327B2 (ja) | 2023-06-15 |
KR20200029567A (ko) | 2020-03-18 |
SG11202000424VA (en) | 2020-02-27 |
CN111148752B (zh) | 2024-01-16 |
US11091517B2 (en) | 2021-08-17 |
IL272080A (en) | 2020-03-31 |
AU2018302855B2 (en) | 2022-08-18 |
KR102658844B1 (ko) | 2024-04-17 |
CA3070210A1 (en) | 2019-01-24 |
EP3656783A4 (en) | 2021-04-07 |
EP3656783A1 (en) | 2020-05-27 |
JPWO2019017384A1 (ja) | 2020-05-28 |
WO2019017384A1 (ja) | 2019-01-24 |
US20200255474A1 (en) | 2020-08-13 |
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