Human cancers undergo an extremely diverse range of DNA mutations and rearrangements to generate oncogenes and to inactivate tumor suppressors in the process of their malignant transformation. As a consequence, decades of research have focused on the genes and the molecular pathways as well as the mechanisms that promote the growth of specific tumor cell types. This in turn has motivated the discovery and development of precision drugs that can target tumor-specific mechanisms. Although notable successes have been achieved, particularly with the targeting of oncogenes that encode protein kinases, many known drivers of human cancers have remained hitherto “undruggable” (1). These include unmutated transcription factors (TFs) such as Myc, Myb, E2F, and nuclear factor κB or chimeric transcriptional regulators generated by chromosomal translocations and novel gene fusions such as those encoding E2A-PBX1 and E2A-HLF. The DNA-binding domains of such oncogenic TFs, which confer specificity to their genomic actions, have proven to be intractable surfaces for selective and potent small molecules that can be developed into drugs.

中文翻译：

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在癌症治疗中靶向RNA聚合酶II介体亚基[细胞生物学]

人类癌症会经历极为多样的DNA突变和重排，以生成癌基因并在其恶性转化过程中使肿瘤抑制因子失活。结果，数十年来的研究集中在基因和分子途径以及促进特定肿瘤细胞类型生长的机制上。反过来，这激发了可以靶向肿瘤特异性机制的精密药物的发现和开发。尽管已经取得了显著成就，尤其是针对编码蛋白激酶的致癌基因，但迄今为止，许多已知的人类癌症驱动因素仍然“难以忍受”（1）。这些包括未突变的转录因子（TFs）（例如Myc，Myb，E2F和核因子κB）或由染色体易位和新型基因融合（例如编码E2A-PBX1和E2A-HLF的基因融合物）产生的嵌合转录调节因子。这种致癌性TF的DNA结合结构域赋予其基因组作用特异性，已被证明是可开发为药物的选择性强效小分子的难处理表面。