David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, MA 02139, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, MA 02142, USA.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, MA 02139, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, MA 02142, USA.
Trends Mol Med. 2020 May;26(5):508-518. doi: 10.1016/j.molmed.2020.01.004. Epub 2020 Feb 15.
Transcription factors have roles at focal points in signaling pathways, controlling many normal cellular processes, such as cell growth and proliferation, metabolism, apoptosis, immune responses, and differentiation. Their activity is frequently deregulated in disease and targeting this class of proteins is a major focus of interest. However, the structural disorder and lack of binding pockets have made design of small molecules for transcription factors challenging. Here, we review some of the most recent developments for small molecule inhibitors of transcription factors emphasized in James Darnell's vision 17 years ago. We also discuss the progress so far on transcription factors recently nominated by genome-scale loss-of-function screens from the cancer dependency map project.
转录因子在信号通路的关键点发挥作用，控制许多正常的细胞过程，如细胞生长和增殖、代谢、凋亡、免疫反应和分化。它们的活性在疾病中经常失调，针对这类蛋白质是主要的研究重点。然而，由于结构的无序性和缺乏结合口袋，使得设计转录因子的小分子药物具有挑战性。在这里，我们回顾了 17 年前 James Darnell 提出的重点研究的转录因子小分子抑制剂的一些最新进展。我们还讨论了迄今为止在癌症依赖图谱项目的全基因组功能丧失筛选中提名的转录因子的进展。
