文章：

靶向癌症转录因子-从无药到现实

Targeting transcription factors in cancer — from undruggable to reality

原文发布日期：2019-09-11

DOI: 10.1038/s41568-019-0196-7

类型: Review Article

开放获取: 否

英文摘要：

Mutated or dysregulated transcription factors represent a unique class of drug targets that mediate aberrant gene expression, including blockade of differentiation and cell death gene expression programmes, hallmark properties of cancers. Transcription factor activity is altered in numerous cancer types via various direct mechanisms including chromosomal translocations, gene amplification or deletion, point mutations and alteration of expression, as well as indirectly through non-coding DNA mutations that affect transcription factor binding. Multiple approaches to target transcription factor activity have been demonstrated, preclinically and, in some cases, clinically, including inhibition of transcription factor–cofactor protein–protein interactions, inhibition of transcription factor–DNA binding and modulation of levels of transcription factor activity by altering levels of ubiquitylation and subsequent proteasome degradation or by inhibition of regulators of transcription factor expression. In addition, several new approaches to targeting transcription factors have recently emerged including modulation of auto-inhibition, proteolysis targeting chimaeras (PROTACs), use of cysteine reactive inhibitors, targeting intrinsically disordered regions of transcription factors and combinations of transcription factor inhibitors with kinase inhibitors to block the development of resistance. These innovations in drug development hold great promise to yield agents with unique properties that are likely to impact future cancer treatment.

摘要翻译： 

突变或失调的转录因子代表了一类独特的药物靶点，它们介导异常基因表达，包括阻断分化和细胞死亡基因表达程序——这些是癌症的标志性特征。在多种癌症类型中，转录因子活性通过多种直接机制发生改变，包括染色体易位、基因扩增或缺失、点突变和表达水平变化，以及通过影响转录因子结合的非编码DNA突变的间接机制。靶向转录因子活性的多种方法已在临床前及部分临床案例中得到验证，包括抑制转录因子-辅因子蛋白相互作用、阻断转录因子-DNA结合，以及通过调节泛素化水平和后续的蛋白酶体降解或抑制转录因子表达调控因子来调控转录因子活性水平。此外，近期涌现出若干靶向转录因子的新策略，包括调控自抑制机制、蛋白降解靶向嵌合体技术、半胱氨酸反应抑制剂的应用、靶向转录因子的内在无序区域，以及将转录因子抑制剂与激酶抑制剂联用以阻断耐药性产生。这些药物研发领域的创新有望产生具有独特特性的治疗药物，为未来癌症治疗带来重要影响。

原文链接：

Targeting transcription factors in cancer — from undruggable to reality