Transcription is epigenetically regulated by the orchestrated function of chromatin-binding proteins that tightly control the expression of master transcription factors, effectors, and supportive housekeeping genes required for establishing and propagating the normal and malignant cell state. Rapid advances in chemical biology and functional genomics have facilitated exploration of targeting epigenetic proteins, yielding effective strategies to target transcription while reducing toxicities to untransformed cells. Here, we review recent developments in conventional active site and allosteric inhibitors, peptidomimetics, and novel proteolysis-targeted chimera (PROTAC) technology that have deepened our understanding of transcriptional processes and led to promising preclinical compounds for therapeutic translation, particularly in cancer.

转录受到染色质结合蛋白精心设计的功能的表观遗传调节，这些蛋白严格控制建立和传播正常和恶性细胞状态所需的主转录因子、效应子和支持性管家基因的表达。化学生物学和功能基因组学的快速发展促进了针对表观遗传蛋白的探索，产生了靶向转录的有效策略，同时减少了对未转化细胞的毒性。在这里，我们回顾了传统活性位点和变构抑制剂、肽模拟物和新型蛋白水解靶向嵌合体 (PROTAC) 技术的最新进展，这些技术加深了我们对转录过程的理解，并产生了用于治疗转化的有前途的临床前化合物，特别是在癌症方面。