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72个抗肿瘤靶向药物全景报告!

2016-07-21 Armstrong 生物制药小编

2016年初,Nature曾专文介绍FDA批准的45款抗肿瘤靶向药物,主要介绍激酶抑制剂和抗体药物。本文将从更广泛的范围梳理抗肿瘤靶向药物,包括更完整的靶向抗肿瘤药物范围,补充市场格局、信号通路介绍等方面信息,描绘一幅更完整的全景图。 靶向药物极大改变了肿瘤等适应症的治疗局面:副作用小、疗效显著,改善患者生存质量的同时,也创造了巨大的市场机会。 一、靶向药物统计

2016年初,Nature曾专文介绍FDA批准的45款抗肿瘤靶向药物,主要介绍激酶抑制剂和抗体药物。本文将从更广泛的范围梳理抗肿瘤靶向药物,包括更完整的靶向抗肿瘤药物范围,补充市场格局、信号通路介绍等方面信息,描绘一幅更完整的全景图。

靶向药物极大改变了肿瘤等适应症的治疗局面:副作用小、疗效显著,改善患者生存质量的同时,也创造了巨大的市场机会。


一、靶向药物统计

截止2016年6月,FDA批准了72个靶向抗肿瘤药物。


近年来靶向抗癌药物,无论是单抗药物还是小分子靶向药物,都呈现快速增长的趋势。


靶向抗癌药物中,单抗药物占据60%的市场份额,小分子药物占据40%的市场份额。


靶向抗癌药物的市场集中度很高,前五名的药企:罗氏、诺华、安进、BMS、辉瑞占据超过85%的市场份额。其中罗氏一家就占据了近半壁江山,三驾马车:利妥昔单抗、赫赛汀单抗、贝伐珠单抗合计销售额即超过200亿美元。


新药的形式愈加丰富,如CAR-T、CAR-NK、双特异性抗体、Aptamer等,将为肿瘤靶向疗法带来更多的可能。这里不再详述。


二、信号通路盘点

参考My Cancer Genome,梳理相关信号通路信息如下。

1.细胞凋亡通路:程序性细胞死亡过程。胞外部分由FAS配基/FAS受体介导,胞内部分由线粒体介导。

药物靶点:BCL-2
代表药物:Venclexta


2.β-Catenin/WNT通路:通过激活基因转录达到多种效应包括细胞生长等。WNT1配基结合到FZD1(一种GPCR)激活该通路。

药物靶点:FZD等


3.细胞周期控制通路:细胞周期包括G1、S、G2、M期,周期调控依赖于一系列周期检验点:CDK4/6+Cyclin  D、RB1+E2F、CDK2+Cyclin  E、CDK2+Cyclin  A、CDK1+Cyclin  A、CDK1+Cyclin  B。

药物靶点:CDK4/6
代表药物:Ibrance


4.蜂窝结构及微环境:肿瘤细胞的胞内和细胞间结构非常重要,如化学物质调节分子等可通过这些结构在胞内或细胞间进行传递。

药物靶点:SRC
代表药物:Sprycel(同时也靶向ABL)



5.染色质重塑/DNA甲基化:染色质重塑可以使得原本高度压缩的DNA结构可以进行转录,重塑过程一般通过组蛋白的修饰如DNA甲基化(一种表观遗传调控机制)来调控

药物靶点:HDAC
代表药物:Istodax、Farydak、Beleodaq、Zolinza、西达本胺


6.细胞毒化疗药物:通常指导致细胞死亡的物质,通过抑制微管蛋白、蛋白功能、DNA合成杀死细胞。

药物靶点:烷化剂、代谢拮抗剂、微管蛋白抑制剂、拓扑异构酶II抑制剂等
代表药物:氮芥、甲氨蝶呤、紫杉醇、依托泊苷


7.DNA损伤/修复:内部因素如氧自由基、复制错误、氧化脱氨和外部因素如紫外照射都会引起DNA损伤,如果DNA修复通路被阻断,细胞将进入衰老或程序性死亡。

药物靶点:PARP
代表药物:Lynparza、Niraparib、Talazoparib、Rucaparib、BGB-290等。


8.G-蛋白信号通路:该通路在代谢调控、神经传导、胚胎发育中发挥作用。G蛋白信号通路通过配基结合GPCR激活,蛋白激酶结合GPCR可导致后者的磷酸化,进而抑制该信号通路。



9.Hedgehog信号通路:该通路促进胚胎发育过程中的细胞生长和分化,在癌细胞中通常会异常活化。Heggehog配基结合细胞表面的PTCH1,激活该通路。在配基缺失的情况下,通路被PTCH1抑制,通过把SMO锁定在小泡结构中抑制SMO的活化。

药物靶点:SMO
代表药物:Erivedge


10.激素信号通路:类固醇激素信号通路在激活转录和基因表达过程中起作用,通路可被类固醇激素如雌激素、孕激素激活。

药物靶点:芳香酶抑制剂、HSP90抑制剂、类固醇受体(雄激素、雌激素、孕激素)
代表药物:Femara、Luminespib、Casodex、Faslodax、他莫昔芬


11.免疫检验点:如CTLA4在CD4+和CD8+的T细胞表达,PD-1在T细胞和B细胞表达,两者都可以组织T细胞的活化。通过阻断该通路可以激活T细胞,杀死肿瘤细胞。后来又出现一些需激活的免疫检验点。

药物靶点:CTLA4-Fc、PD-1、PD-L1、OX-40等
代表药物:Yervoy、Keytruda、Opdivo、Tecentriq


12.JAK-STAT信号通路:JAK-STAT信号通路在基因转录和免疫调节中发挥作用。JAK1/2/3是胞内的酪氨酸激酶,STAT则是激活基因表达的转录因子。该通路通过结合配基如白介素、干扰素、生长因子等激活。

药物靶点:JAK
代表药物:Xeljanz、Jakaf


13.激酶融合通路:激酶融合是肿瘤细胞中发生的2个基因重排的现象,其中1个是激酶基因。激酶融合促进基因转录、细胞生长、分化和存活。

药物靶点:JAK、ABL、ALK、FGFE1/2/3、NTRK1/2/3、RET、ROS1等
代表药物:Jakafi、Sprycel、Alecensa、Iclusig、ENtrectinib、Nexavar等


14.MAPK通路:分裂素活化蛋白激酶信号通路促进细胞生长、分化和存活。

药物靶点:BRAF、ERK、MEK、SRC
代表药物:Zelboraf、Ralimetinib、Mekinist、Saracatinib


15.代谢通路:代谢通路是指通过糖有氧呼吸和无氧呼吸的分解产生能量,促进细胞生长、分化和存活。

药物靶点:IDH1
代表药物:AG-120


16.PI3K/AKT1/mTOR通路:该通路在细胞生长、蛋白翻译、凋亡的调控中发挥作用。该通路通过保外生长因子如IGF1结合相应的RTK来激活,同时可被PTEN抑制。

药物靶点:mTOR
代表药物:Affinitor、Torisel


17.蛋白降解/泛素化:泛素化修饰底物蛋白,介导该蛋白被蛋白酶体降解。泛素化也可以影响蛋白质的活性和相互作用。


18.RTK/GF信号通路:受体酪氨酸激酶/生长因子信号通路在细胞生长、分化、存活、基因转录、代谢调节等发挥作用。该通路通过配基如生长因子的结合激活。

药物靶点:酪氨酸激酶TKI
代表药物:Sprycel、Gleevec等19.RNA剪接:RNA剪接指内含子剪切和外显子连接的过程,该过程通过RNA分子与剪接体结合而激活。


20.TGFβ通路:TGFβ通路在癌症发生、进展和转移过程中发挥重要作用。SMAD发挥重要的信号转导作用。

药物靶点:TGFBR1
代表药物:Galunisertib


三、抗肿瘤药物靶点统计

附表二 抗肿瘤药物靶点统计


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    2017-07-05 bioon16
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    2016-10-24 马里奥8433

    不错 值得收藏

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1948470, encodeId=afca19484e042, content=<a href='/topic/show?id=8d388313290' target=_blank style='color:#2F92EE;'>#肿瘤靶向#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83132, encryptionId=8d388313290, topicName=肿瘤靶向)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=66962500501, createdName=yige2004, createdTime=Wed Apr 12 02:44:00 CST 2017, time=2017-04-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1770806, encodeId=6d221e708060d, content=<a href='/topic/show?id=061c29449fe' target=_blank style='color:#2F92EE;'>#全景#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=29449, encryptionId=061c29449fe, topicName=全景)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=159438183015, createdName=bioon16, createdTime=Wed Jul 05 20:44:00 CST 2017, time=2017-07-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=150772, encodeId=909c150e7207, content=不错 值得收藏, beContent=null, objectType=article, channel=null, level=null, likeNumber=93, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/DYAIOgq83eocJY6moGTnYzC8V8lUl3k679Uxh0PVMjIamhoDYuSYr6D4KDKlbpuNuCKFlJaiaVrmFIrbseIWqUA/132, createdBy=ad571630249, createdName=马里奥8433, createdTime=Mon Oct 24 08:49:41 CST 2016, time=2016-10-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=131065, encodeId=fe9d13106566, content=赞了!深度好文,深入学习。, beContent=null, objectType=article, channel=null, level=null, likeNumber=89, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7s7ZCKOmmbBTD6nE7gcd5OZpvyGEzkxBP3S275k5ZJVrsPkotZhBglRHM9rKvcj1OgkssqhcnoPw8zIaMZTF8c/0, createdBy=4c441942088, createdName=ylzr123, createdTime=Mon Sep 19 22:57:00 CST 2016, time=2016-09-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=110677, encodeId=18a31106e7e5, content=学习了,有意思, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/11/23/ac01daf0962458a9eb8c0b1e2f6ce5bc.jpg, createdBy=04b81710322, createdName=1771ae4158m, createdTime=Sun Sep 04 08:56:00 CST 2016, time=2016-09-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=98375, encodeId=5888983e573, content=继续努力, beContent=null, objectType=article, channel=null, level=null, likeNumber=102, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=45101626056, createdName=忠诚向上, createdTime=Sun Aug 14 12:32:00 CST 2016, time=2016-08-14, status=1, ipAttribution=)]
    2016-09-19 ylzr123

    赞了!深度好文,深入学习。

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=1948470, encodeId=afca19484e042, content=<a href='/topic/show?id=8d388313290' target=_blank style='color:#2F92EE;'>#肿瘤靶向#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83132, encryptionId=8d388313290, topicName=肿瘤靶向)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=66962500501, createdName=yige2004, createdTime=Wed Apr 12 02:44:00 CST 2017, time=2017-04-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1770806, encodeId=6d221e708060d, content=<a href='/topic/show?id=061c29449fe' target=_blank style='color:#2F92EE;'>#全景#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=29449, encryptionId=061c29449fe, topicName=全景)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=159438183015, createdName=bioon16, createdTime=Wed Jul 05 20:44:00 CST 2017, time=2017-07-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=150772, encodeId=909c150e7207, content=不错 值得收藏, beContent=null, objectType=article, channel=null, level=null, likeNumber=93, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/DYAIOgq83eocJY6moGTnYzC8V8lUl3k679Uxh0PVMjIamhoDYuSYr6D4KDKlbpuNuCKFlJaiaVrmFIrbseIWqUA/132, createdBy=ad571630249, createdName=马里奥8433, createdTime=Mon Oct 24 08:49:41 CST 2016, time=2016-10-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=131065, encodeId=fe9d13106566, content=赞了!深度好文,深入学习。, beContent=null, objectType=article, channel=null, level=null, likeNumber=89, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7s7ZCKOmmbBTD6nE7gcd5OZpvyGEzkxBP3S275k5ZJVrsPkotZhBglRHM9rKvcj1OgkssqhcnoPw8zIaMZTF8c/0, createdBy=4c441942088, createdName=ylzr123, createdTime=Mon Sep 19 22:57:00 CST 2016, time=2016-09-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=110677, encodeId=18a31106e7e5, content=学习了,有意思, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/11/23/ac01daf0962458a9eb8c0b1e2f6ce5bc.jpg, createdBy=04b81710322, createdName=1771ae4158m, createdTime=Sun Sep 04 08:56:00 CST 2016, time=2016-09-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=98375, encodeId=5888983e573, content=继续努力, beContent=null, objectType=article, channel=null, level=null, likeNumber=102, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=45101626056, createdName=忠诚向上, createdTime=Sun Aug 14 12:32:00 CST 2016, time=2016-08-14, status=1, ipAttribution=)]
    2016-09-04 1771ae4158m

    学习了,有意思

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    2016-08-14 忠诚向上

    继续努力

    0

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