Su Bonnie G, Henley Matthew J
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States.
The Broad Institute of MIT and Harvard, Cambridge, MA, United States.
Front Mol Biosci. 2021 Dec 21;8:795743. doi: 10.3389/fmolb.2021.795743. eCollection 2021.
Transcription factors (TFs) are one of the most promising but underutilized classes of drug targets. The high degree of intrinsic disorder in both the structure and the interactions (i.e., "fuzziness") of TFs is one of the most important challenges to be addressed in this context. Here, we discuss the impacts of fuzziness on transcription factor drug discovery, describing how disorder poses fundamental problems to the typical drug design, and screening approaches used for other classes of proteins such as receptors or enzymes. We then speculate on ways modern biophysical and chemical biology approaches could synergize to overcome many of these challenges by directly addressing the challenges imposed by TF disorder and fuzziness.
转录因子（TFs）是最具潜力但尚未得到充分利用的药物靶点类别之一。转录因子在结构和相互作用方面高度的内在无序性（即“模糊性”）是在这一背景下需要解决的最重要挑战之一。在此，我们讨论模糊性对转录因子药物发现的影响，描述无序性如何给典型的药物设计带来根本性问题，以及用于其他类蛋白质（如受体或酶）的筛选方法。然后，我们推测现代生物物理和化学生物学方法如何能够协同作用，通过直接应对转录因子无序性和模糊性带来的挑战来克服其中许多挑战。
