DNMT1 maintains the parental DNA methylation pattern on newly replicated hemimethylated DNA. The failure of this maintenance process causes aberrant DNA methylation that affects transcription and contributes to the development and progression of cancers such as acute myeloid leukemia. Here, we structurally characterized a set of newly discovered DNMT1-selective, reversible, non-nucleoside inhibitors that bear a core 3,5-dicyanopyridine moiety, as exemplified by GSK3735967, to better understand their mechanism of inhibition. All of the dicyanopydridine-containing inhibitors examined intercalate into the hemimethylated DNA between two CpG base pairs through the DNA minor groove, resulting in conformational movement of the DNMT1 active-site loop. In addition, GSK3735967 introduces two new binding sites, where it interacts with and stabilizes the displaced DNMT1 active-site loop and it occupies an open aromatic cage in which trimethylated histone H4 lysine 20 is expected to bind. Our work represents a substantial step in generating potent, selective, and non-nucleoside inhibitors of DNMT1.

中文翻译：

---

含有 DNMT1 选择性非核苷抑制剂的二氰基吡啶的结构表征。

DNMT1 在新复制的半甲基化 DNA 上保持亲本 DNA 甲基化模式。这种维持过程的失败会导致异常的 DNA 甲基化，从而影响转录并导致癌症（如急性髓性白血病）的发生和发展。在这里，我们在结构上表征了一组新发现的 DNMT1 选择性、可逆、非核苷抑制剂，这些抑制剂具有核心 3,5-二氰基吡啶部分，例如 GSK3735967，以更好地了解它们的抑制机制。所有检测的含二氰基吡啶的抑制剂均通过 DNA 小沟插入两个 CpG 碱基对之间的半甲基化 DNA，导致 DNMT1 活性位点环的构象运动。此外，GSK3735967 引入了两个新的绑定站点，在那里它与置换的 DNMT1 活性位点环相互作用并稳定它，它占据一个开放的芳香族笼，其中三甲基化组蛋白 H4 赖氨酸 20 预计会结合。我们的工作代表了在生成 DNMT1 的有效、选择性和非核苷抑制剂方面迈出的重要一步。