Many diseases, including cancer, stem from aberrant activation and overexpression of oncoproteins that are associated with multiple signaling pathways. Although proteins with catalytic activity are able to be successfully drugged, the majority of other protein families, such as transcription factors, remain intractable due to their lack of ligandable sites. In this study, we report the development of TRAnscription Factor TArgeting Chimeras (TRAFTACs) as a generalizable strategy for targeted transcription-factor degradation. Herein, we show that TRAFTACs, which consist of a chimeric oligonucleotide that simultaneously binds to the transcription-factor of interest (TOI) and to HaloTag fused dCas9 protein, can induce degradation of the former via the proteasomal pathway. Application of TRAFTACs to two oncogenic TOIs, NF-κB and brachyury, suggests that TRAFTACs can be successfully employed for the targeted degradation of other DNA-binding proteins with minor changes to the chimeric oligonucleotide.

中文翻译：

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TRAFTACs靶向降解转录因子：靶向嵌合体的转录因子。

许多疾病，包括癌症，都源于与多种信号通路相关的癌蛋白的异常激活和过表达。尽管具有催化活性的蛋白质能够被成功地药物化，但是由于缺乏配体位点，大多数其他蛋白质家族（如转录因子）仍然难以治疗。在这项研究中，我们报告了TRAnscription因子特异嵌合体（TRAFTACs）的发展，作为靶向转录因子降解的通用策略。本文中，我们显示TRAFTACs由同时与目标转录因子（TOI）和HaloTag融合的dCas9蛋白结合的嵌合寡核苷酸组成，可以通过蛋白酶体途径诱导前者降解。TRAFTAC在两种致癌TOIsNF-κB和brachyury中的应用，