MYC is a major oncogenic transcriptional driver of most human cancers that has remained intractable to direct targeting because much of MYC is intrinsically disordered. Here, we have performed a cysteine-reactive covalent ligand screen to identify compounds that could disrupt the binding of MYC to its DNA consensus sequence in vitro and also impair MYC transcriptional activity in situ in cells. We have identified a covalent ligand, EN4, that targets cysteine 171 of MYC within a predicted intrinsically disordered region of the protein. We show that EN4 directly targets MYC in cells, reduces MYC and MAX thermal stability, inhibits MYC transcriptional activity, downregulates multiple MYC transcriptional targets, and impairs tumorigenesis. We also show initial structure-activity relationships of EN4 and identify compounds that show improved potency. Overall, we identify a unique ligandable site within an intrinsically disordered region of MYC that leads to inhibition of MYC transcriptional activity.

MYC 是大多数人类癌症的主要致癌转录驱动因子，由于 MYC 的大部分本质上是无序的，因此直接靶向仍然难以处理。在这里，我们进行了半胱氨酸反应性共价配体筛选，以鉴定可能在体外破坏 MYC 与其 DNA 共有序列结合并损害 MYC原位转录活性的化合物在细胞中。我们已经确定了一种共价配体 EN4，它在预测的蛋白质固有无序区域内靶向 MYC 的半胱氨酸 171。我们表明 EN4 直接靶向细胞中的 MYC，降低 MYC 和 MAX 热稳定性，抑制 MYC 转录活性，下调多个 MYC 转录靶标，并损害肿瘤发生。我们还展示了 EN4 的初始结构-活性关系，并确定了显示增强效力的化合物。总体而言，我们在 MYC 的内在无序区域内确定了一个独特的可配位位点，导致 MYC 转录活性的抑制。