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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Discovery of IAP-recruiting BCL-X-L PROTACs as potent degraders across multiple cancer cell lines
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Discovery of IAP-recruiting BCL-X-L PROTACs as potent degraders across multiple cancer cell lines

机译：在多种癌细胞系中发现IAP募集的BCL-X-L Protacs作为有效的降解剂

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摘要

Targeting BCL-X-L via PROTACs is a promising strategy in reducing BCL-X-L inhibition associated platelet toxicity. Recently, we reported potent BCL-X-L PROTAC degraders that recruit VHL or CRBN E3 ligase. However, low protein expression or mutation of the responsible E3 ligase has been known to result in decreased protein degradation efficiency of the corresponding PROTACs. To overcome these mechanisms of resistance, PROTACs based on recruiting alternative E3 ligases could be generated. Thus, we designed and synthesized a series of PROTACs that recruit IAP E3 ligases for BCL-X-L degradation. Among those PROTACs, compound 8a efficiently degrades BCL-X-L in malignant T-cell lymphoma cell line MyLa 1929 while CRBN-based PROTACs that have high potency in other cancer cell lines show compromised potency, likely due to the low CRBN expression. Moreover, compared with the parent compound ABT-263, PROTAC 8a shows comparable cell killing effects in MyLa 1929 cells whereas the on-target platelet toxicity is significantly reduced. Our findings expand the anti-tumor spectra of BCL-X-L degraders and further highlight the importance of selecting suitable E3 members to achieve effective cellular activity. (C) 2020 Elsevier Masson SAS. All rights reserved.
机译：靶向BCL-X-L通过Protacs是降低Bcl-X-L抑制相关的血小板毒性的有希望的策略。最近，我们报道了有效的Bcl-X-L Protac降解剂，其募集VHL或CRBN E3连接酶。然而，已知负责的E3连接酶的低蛋白质表达或突变导致相应的蛋白质的蛋白质降解效率降低。为了克服这些抗性机制，可以产生基于募集替代E3连接酶的Protacs。因此，我们设计并合成了一系列诱发IAP E3连接的Protac，用于Bcl-X-L降解。在这些斑块中，化合物8a有效地降解了恶性T细胞淋巴瘤细胞系Myla 1929中的Bcl-X-L，而其他癌细胞系中具有高效力的基于CRBN的斑块显示出受损的效力，可能是由于低CRBN表达。此外，与母体化合物ABT-263相比，Protac 8a显​​示了MyLa 1929细胞中的可比细胞杀伤作用，而目标血小板毒性显着降低。我们的发现扩展了Bcl-X-L降解剂的抗肿瘤光谱，进一步突出了选择合适的E3成员以实现有效细胞活性的重要性。 （c）2020 Elsevier Masson SAS。版权所有。

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  • 来源
  • 作者

    Zhang Xuan; He Yonghan; Zhang Peiyi; Budamagunta Vivekananda; Lv Dongwen; Thummuri Dinesh; Yang Yang; Pei Jing; Yuan Yaxia; Zhou Daohong; Zheng Guangrong;

  • 作者单位

    Univ Florida Coll Pharm Dept Med Chem 1333 Ctr Dr Gainesville FL 32610 USA;

    Univ Florida Coll Pharm Dept Pharmacodynam 1333 Ctr Dr Gainesville FL 32610 USA;

    Univ Florida Coll Pharm Dept Med Chem 1333 Ctr Dr Gainesville FL 32610 USA;

    Univ Florida Coll Pharm Dept Pharmacodynam 1333 Ctr Dr Gainesville FL 32610 USA;

    Univ Florida Coll Pharm Dept Pharmacodynam 1333 Ctr Dr Gainesville FL 32610 USA;

    Univ Florida Coll Pharm Dept Pharmacodynam 1333 Ctr Dr Gainesville FL 32610 USA;

    Univ Florida Coll Pharm Dept Pharmacodynam 1333 Ctr Dr Gainesville FL 32610 USA;

    Univ Florida Coll Pharm Dept Pharmacodynam 1333 Ctr Dr Gainesville FL 32610 USA;

    Univ Florida Coll Pharm Dept Pharmacodynam 1333 Ctr Dr Gainesville FL 32610 USA;

    Univ Florida Coll Pharm Dept Pharmacodynam 1333 Ctr Dr Gainesville FL 32610 USA;

    Univ Florida Coll Pharm Dept Med Chem 1333 Ctr Dr Gainesville FL 32610 USA;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
  • 关键词

    BCL-X-L; PROTAC; SNIPER; IAPs; Degradation;

    机译：bcl-x-l;protac;狙击手;iaps;退化;

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