Transcription factors (TFs) act as major oncodrivers in many cancers and are frequently regarded as high-value therapeutic targets. The functionality of TFs relies on direct protein–DNA interactions, which are notoriously difficult to target with small molecules. However, this prior view of the ‘undruggability’ of protein–DNA interfaces has shifted substantially in recent years, in part because of significant advances in computer-aided drug discovery (CADD). In this review, we highlight recent examples of successful CADD campaigns resulting in drug candidates that directly interfere with protein–DNA interactions of several key cancer TFs, including androgen receptor (AR), ETS-related gene (ERG), MYC, thymocyte selection-associated high mobility group box protein (TOX), topoisomerase II (TOP2), and signal transducer and activator of transcription 3 (STAT3). Importantly, these findings open novel and compelling avenues for therapeutic targeting of over 1600 human TFs implicated in many conditions including and beyond cancer.

转录因子 (TF) 在许多癌症中充当主要的肿瘤驱动因子，并且经常被视为高价值的治疗靶点。TFs 的功能依赖于直接的蛋白质-DNA 相互作用，众所周知，这种相互作用很难用小分子靶向。然而，这种先前关于蛋白质-DNA 界面的“不可抗药性”的观点近年来发生了重大变化，部分原因是计算机辅助药物发现 (CADD) 取得了重大进展。在这篇综述中，我们重点介绍了最近成功的 CADD 活动的例子，这些候选药物直接干扰了几种关键癌症 TF 的蛋白质-DNA 相互作用，包括雄激素受体 (AR)、ETS 相关基因 (ERG)、MYC、胸腺细胞选择-相关的高迁移率组盒蛋白 (TOX)、拓扑异构酶 II (TOP2)、和信号转导和转录激活因子 3 (STAT3)。重要的是，这些发现为治疗靶向 1600 多种人类 TF 开辟了新的和引人注目的途径，这些人类 TF 涉及包括癌症在内的许多疾病。