Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Trends Pharmacol Sci. 2019 Jun;40(6):388-402. doi: 10.1016/j.tips.2019.04.004. Epub 2019 May 8.
Upon binding of transcription factors to cis-regulatory DNA sequences, transcriptional coregulators are required for the activation or suppression of chromatin-dependent transcriptional signaling. These coregulators are frequently implicated in oncogenesis via causal roles in dysregulated, malignant transcriptional control and represent one of the fastest-growing target classes in small-molecule drug discovery. However, challenges in targeting coregulators include identifying evidence of cancer-specific genetic dependency, matching the pharmacologically addressable protein fold to a functional role in disease pathology, and achieving the necessary selectivity to exploit a given genetic dependency. We discuss here how recent trends in cancer pharmacology have confronted these challenges, positioning coregulators as tractable targets in the development of new cancer therapies.
当转录因子与顺式调控 DNA 序列结合时，转录共激活因子对于激活或抑制依赖染色质的转录信号是必需的。这些共激活因子经常通过在失调的恶性转录控制中发挥因果作用而与肿瘤发生有关，并代表小分子药物发现中增长最快的靶标类别之一。然而，靶向共激活因子的挑战包括确定癌症特异性遗传依赖性的证据、将药理学可寻址的蛋白质折叠与疾病病理中的功能作用相匹配，以及实现利用特定遗传依赖性所需的选择性。在这里，我们讨论了癌症药理学的最新趋势如何应对这些挑战，将共激活因子定位为开发新癌症疗法中的可行靶点。
