We used NMR to show that the antipsychotic phenothiazine drugs promazine and promethazine bind to GDP-KRAS. Promazine also binds to oncogenic GDP-KRAS(G12D), and to wild type GppNHp-KRAS. A panel of additional phenothiazines bind to GDP-KRAS but with lower affinity than promazine or promethazine. Binding is most dependent on substitutions at C-2 of the tricyclic phenothiazine ring. Promazine was used to generate an NMR-driven HADDOCK model of the drug/GDP-KRAS complex. The structural model shows the tricyclic phenothiazine ring of promazine associates with the hydrophobic pocket p1 that is bordered by the central β sheet and Switch II in KRAS. Binding appears to stabilize helix 2 in a conformation that is similar to that seen in KRAS bound to other small molecules. Association of phenothiazines with KRAS may affect normal KRAS signaling that could contribute to multiple biological activities of these antipsychotic drugs. Moreover, the phenothiazine ring represents a new core scaffold on which to design modulators of KRAS activity.

我们使用核磁共振显示抗精神病吩噻嗪药物丙嗪和异丙嗪与 GDP-KRAS 结合。Promazine 还与致癌 GDP-KRAS(G12D) 和野生型 GppNHp-KRAS 结合。一组额外的吩噻嗪与 GDP-KRAS 结合，但亲和力低于丙嗪或异丙嗪。结合最依赖于三环吩噻嗪环 C-2 处的取代。Promazine 用于生成药物/GDP-KRAS 复合物的 NMR 驱动的 HADDOCK 模型。结构模型显示丙嗪的三环吩噻嗪环与疏水口袋 p1 相关联，该口袋 p1 与 KRAS 中的中央 β 折叠和 Switch II 相邻。结合似乎将螺旋 2 稳定在一种类似于 KRAS 与其他小分子结合的构象中。吩噻嗪与 KRAS 的关联可能会影响正常的 KRAS 信号，这可能有助于这些抗精神病药物的多种生物活性。此外，吩噻嗪环代表了一种新的核心支架，可在其上设计 KRAS 活性调节剂。