Blood:诱导Bruton酪氨酸激酶降解或许可成为癌症的新治疗策略

2019-01-06 MedSci MedSci原创

中心点:在癌细胞中,小分子诱导的BTK降解比单纯抑制BTK具有更好的抗增殖作用。在PDX淋巴瘤模型中,先导降解剂DD-03-171可降低肿瘤负担并延长模型动物的存活期。摘要:Bruton酪氨酸激酶(BTK)供价抑制剂依鲁替尼对多种B细胞恶性肿瘤都具有很高的抗癌效果。但,依鲁替尼对BTK没有选择性,存在多重耐药机制,如C481S-BTK突变,可使其疗效大打折扣。Dennis Dobrovolsky等

中心点:

在癌细胞中,小分子诱导的BTK降解比单纯抑制BTK具有更好的抗增殖作用。

在PDX淋巴瘤模型中,先导降解剂DD-03-171可降低肿瘤负担并延长模型动物的存活期。

摘要:

Bruton酪氨酸激酶(BTK)供价抑制剂依鲁替尼对多种B细胞恶性肿瘤都具有很高的抗癌效果。但,依鲁替尼对BTK没有选择性,存在多重耐药机制,如C481S-BTK突变,可使其疗效大打折扣。

Dennis Dobrovolsky等人假设用小分子诱导BTK降解或许可以克服传统酶抑制剂的一些局限性。现其证实BTK降解可有效抑制癌细胞的信号转导和增殖,而且BTK降解剂可有效降解C481S-BTK。

此外,研究人员还发现DD-03-171,一种经过优化的先导化合物,在体外时,可通过降解BTK、IKFZ1和IKFZ3来增强对套细胞淋巴瘤(MCL)细胞的抗增殖效应,而在体内时,对患者来源的移植瘤同样有效。

因此,“三重降解”可能是治疗MCL和克服依鲁替尼耐药的新方法,从而满足MCL和其他B细胞淋巴瘤治疗过程中未满足的一些主要需求。


原始出处:

Dennis Dobrovolsky,et al. Bruton's Tyrosine Kinase degradation as a therapeutic strategy for cancer. Blood 2018 :blood-2018-07-862953; doi: https://doi.org/10.1182/blood-2018-07-862953 

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    2019-01-08 redcrab
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    2019-01-08 smartxiuxiu

    0

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    2019-01-07 明月清辉

    谢谢分享,学习了

    0

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    2019-01-07 天地飞扬

    了解一下,谢谢分享!

    0

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