Oncotarget:PD-1 / PD-L1免疫检查点的小分子抑制剂能够减轻PD-L1诱导的T细胞耗竭

2017-12-21 MedSci MedSci原创

尽管针对PD-1 / PD-L1免疫检查点的抗体近年来在抗癌治疗方面取得了令人瞩目的成就。 相比之下,目前仍没有针对PD-1 / PD-L1免疫检查点的小分子化合物的报道,相比于经静脉注射给药或皮下注射给药方式,小分子独有的口服给药方式会极大提高患者的依从性。近日波兰学者在Oncotarget杂志中报道了几种小分子能够减轻PD-1 / PD-L1免疫检查点介导的Jurkat T淋巴细胞衰竭,这两种

尽管针对PD-1 / PD-L1免疫检查点的抗体近年来在抗癌治疗方面取得了令人瞩目的成就。 相比之下,目前仍没有针对PD-1 / PD-L1免疫检查点的小分子化合物的报道,相比于经静脉注射给药或皮下注射给药方式,小分子独有的口服给药方式会极大提高患者的依从性。近日波兰学者在Oncotarget杂志中报道了几种小分子能够减轻PD-1 / PD-L1免疫检查点介导的Jurkat T淋巴细胞衰竭,这两种优化后的PD-1 / PD-L1相互作用的小分子抑制剂分别为Bristol-Myers Squibb研发的BMS-1001 BMS-1166BMS-1001 BMS-1166均能与PD-L1结合,进而阻止PD-L1PD-1的结合。

体外实验表明,BMS-1001 BMS-1166毒性较低,且能够阻止游离的PD-L1与细胞表面的PD-1结合。结果显示,BMS-1001 BMS-1166均能减轻游离的PD-L1T细胞受体介导的T-淋巴细胞的活化的抑制作用,除了作用于游离型PD-L1,这两种化合物对细胞表面的PD-L1作用更强。X光衍射数据进一步揭示了BMS-1001 BMS-1166化学基团与PD-L1的作用机制。因此这些实验数据对于口服型免疫检查点的设计具有重要指导意义。

原始出处:

Skalniak, Lukasz, et al. "Small-molecule inhibitors of PD-1/PD-L1 immune checkpoint alleviate the PD-L1-induced exhaustion of T-cells.Oncotarget 2017 8.42: 72167. doi: 10.18632/oncotarget.20050

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12:10:00 CST 2017, time=2017-12-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=271572, encodeId=e8e62e157238, content=henhao, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NcXNhUvfhzd2VdicMnaLeK2Im5gKx4Ucxd8Bwu6S7RG0uILBFQx5HTW2bU4VricDYlQqN20ibASSMYAeGrZrrTpy2Q/0, createdBy=b10c1938054, createdName=1e0e5697m83(暂无匿称), createdTime=Fri Dec 22 16:46:33 CST 2017, time=2017-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=271515, encodeId=53212e15159e, content=henhao, beContent=null, objectType=article, channel=null, level=null, likeNumber=94, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NcXNhUvfhzd2VdicMnaLeK2Im5gKx4Ucxd8Bwu6S7RG0uILBFQx5HTW2bU4VricDYlQqN20ibASSMYAeGrZrrTpy2Q/0, createdBy=353a2047758, createdName=137****9095, createdTime=Fri Dec 22 11:42:17 CST 2017, time=2017-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=271430, encodeId=b3842e1430bf, content=一起学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/TDiaAWyicHgedzX3wKo3qcxudVJib7AfibfvNeufHRF2jG3Bw8MmZyWjIhtBV1mpJI7Sy9n7RcBKK5t3CuOKuOFxkg/0, createdBy=dd702206933, createdName=wzb521zf, createdTime=Fri Dec 22 07:19:21 CST 2017, time=2017-12-22, status=1, ipAttribution=)]
    2018-12-03 宋威
  5. [GetPortalCommentsPageByObjectIdResponse(id=1851600, encodeId=cd9d185160057, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Sun Dec 02 05:10:00 CST 2018, time=2018-12-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1678213, encodeId=803b16e821305, content=<a href='/topic/show?id=f34c46963cc' target=_blank style='color:#2F92EE;'>#小分子抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=46963, encryptionId=f34c46963cc, topicName=小分子抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=null, 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objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13921, encryptionId=be71139214f, topicName=PD-L1)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e76f39, createdName=smartjoy, createdTime=Sat Dec 23 12:10:00 CST 2017, time=2017-12-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1340482, encodeId=d5ac134048279, content=<a href='/topic/show?id=dd1a29055c8' target=_blank style='color:#2F92EE;'>#免疫检查点#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=29055, encryptionId=dd1a29055c8, topicName=免疫检查点)], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKUdkK5dVTue7YQDvwqM1ugOuEpDZEzvXhoGClFiavehcrNAYDuPbks3MkKLPpyAEicgic80KguxwicYQ/132, createdBy=ec952500165, createdName=ms5187542471278033, createdTime=Sat Dec 23 12:10:00 CST 2017, time=2017-12-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=271572, encodeId=e8e62e157238, content=henhao, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NcXNhUvfhzd2VdicMnaLeK2Im5gKx4Ucxd8Bwu6S7RG0uILBFQx5HTW2bU4VricDYlQqN20ibASSMYAeGrZrrTpy2Q/0, createdBy=b10c1938054, createdName=1e0e5697m83(暂无匿称), createdTime=Fri Dec 22 16:46:33 CST 2017, time=2017-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=271515, encodeId=53212e15159e, content=henhao, beContent=null, objectType=article, channel=null, level=null, likeNumber=94, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NcXNhUvfhzd2VdicMnaLeK2Im5gKx4Ucxd8Bwu6S7RG0uILBFQx5HTW2bU4VricDYlQqN20ibASSMYAeGrZrrTpy2Q/0, createdBy=353a2047758, createdName=137****9095, createdTime=Fri Dec 22 11:42:17 CST 2017, time=2017-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=271430, encodeId=b3842e1430bf, content=一起学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/TDiaAWyicHgedzX3wKo3qcxudVJib7AfibfvNeufHRF2jG3Bw8MmZyWjIhtBV1mpJI7Sy9n7RcBKK5t3CuOKuOFxkg/0, createdBy=dd702206933, createdName=wzb521zf, createdTime=Fri Dec 22 07:19:21 CST 2017, time=2017-12-22, status=1, ipAttribution=)]
    2018-06-12 仁医06
  6. 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12:10:00 CST 2017, time=2017-12-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=271572, encodeId=e8e62e157238, content=henhao, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NcXNhUvfhzd2VdicMnaLeK2Im5gKx4Ucxd8Bwu6S7RG0uILBFQx5HTW2bU4VricDYlQqN20ibASSMYAeGrZrrTpy2Q/0, createdBy=b10c1938054, createdName=1e0e5697m83(暂无匿称), createdTime=Fri Dec 22 16:46:33 CST 2017, time=2017-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=271515, encodeId=53212e15159e, content=henhao, beContent=null, objectType=article, channel=null, level=null, likeNumber=94, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NcXNhUvfhzd2VdicMnaLeK2Im5gKx4Ucxd8Bwu6S7RG0uILBFQx5HTW2bU4VricDYlQqN20ibASSMYAeGrZrrTpy2Q/0, createdBy=353a2047758, createdName=137****9095, createdTime=Fri Dec 22 11:42:17 CST 2017, time=2017-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=271430, encodeId=b3842e1430bf, content=一起学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/TDiaAWyicHgedzX3wKo3qcxudVJib7AfibfvNeufHRF2jG3Bw8MmZyWjIhtBV1mpJI7Sy9n7RcBKK5t3CuOKuOFxkg/0, createdBy=dd702206933, createdName=wzb521zf, createdTime=Fri Dec 22 07:19:21 CST 2017, time=2017-12-22, status=1, ipAttribution=)]
    2017-12-23 smartjoy
  7. 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  8. 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createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NcXNhUvfhzd2VdicMnaLeK2Im5gKx4Ucxd8Bwu6S7RG0uILBFQx5HTW2bU4VricDYlQqN20ibASSMYAeGrZrrTpy2Q/0, createdBy=353a2047758, createdName=137****9095, createdTime=Fri Dec 22 11:42:17 CST 2017, time=2017-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=271430, encodeId=b3842e1430bf, content=一起学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/TDiaAWyicHgedzX3wKo3qcxudVJib7AfibfvNeufHRF2jG3Bw8MmZyWjIhtBV1mpJI7Sy9n7RcBKK5t3CuOKuOFxkg/0, createdBy=dd702206933, createdName=wzb521zf, createdTime=Fri Dec 22 07:19:21 CST 2017, time=2017-12-22, status=1, ipAttribution=)]
    2017-12-22 1e0e5697m83(暂无匿称)

    henhao

    0

  9. 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createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NcXNhUvfhzd2VdicMnaLeK2Im5gKx4Ucxd8Bwu6S7RG0uILBFQx5HTW2bU4VricDYlQqN20ibASSMYAeGrZrrTpy2Q/0, createdBy=353a2047758, createdName=137****9095, createdTime=Fri Dec 22 11:42:17 CST 2017, time=2017-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=271430, encodeId=b3842e1430bf, content=一起学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/TDiaAWyicHgedzX3wKo3qcxudVJib7AfibfvNeufHRF2jG3Bw8MmZyWjIhtBV1mpJI7Sy9n7RcBKK5t3CuOKuOFxkg/0, createdBy=dd702206933, createdName=wzb521zf, createdTime=Fri Dec 22 07:19:21 CST 2017, time=2017-12-22, status=1, ipAttribution=)]
    2017-12-22 137****9095

    henhao

    0

  10. 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