Activating mutations in the small GTPase NRAS are responsible for driving tumor growth in several cancers. Unfortunately, the development of NRAS inhibitors has proven difficult due to the lack of hydrophobic binding pockets on the protein’s surface. To overcome this limitation, we chose to target the post-translational S-palmitoyl modification of NRAS, which is required for its signaling activity. Utilizing an amphiphile-mediated depalmitoylation (AMD) strategy, we demonstrate the ability to directly cleave S-palmitoyl groups from NRAS and inhibit its function. C8 alkyl cysteine causes a dose-dependent decrease in NRAS palmitoylation and inhibits downstream signaling in melanoma cells with an activating mutation in NRAS. This compound reduces cell growth in NRAS-driven versus non-NRAS-driven melanoma lines and inhibits tumor progression in an NRAS-mutated melanoma xenograft mouse model. Our work demonstrates that AMD can effectively suppress NRAS activity and could represent a promising new avenue for discovering lead compounds for treatment of NRAS-driven cancers.

中文翻译：

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使用两亲亲核试剂通过直接脱棕榈酰化抑制黑色素瘤中的 NRAS 信号传导。

小 GTPase NRAS 中的激活突变负责驱动多种癌症的肿瘤生长。不幸的是，由于蛋白质表面缺乏疏水结合口袋，NRAS 抑制剂的开发已被证明是困难的。为了克服这一限制，我们选择针对 NRAS 的翻译后 S-棕榈酰修饰，这是其信号活动所必需的。利用两亲介导的脱棕榈酰化 (AMD) 策略，我们展示了直接从 NRAS 裂解 S-棕榈酰基并抑制其功能的能力。C8 烷基半胱氨酸导致 NRAS 棕榈酰化的剂量依赖性降低，并抑制黑色素瘤细胞中的下游信号传导，具有 NRAS 中的激活突变。该化合物减少了 NRAS 驱动的黑色素瘤系与非 NRAS 驱动的黑色素瘤系中的细胞生长，并抑制了 NRAS 突变的黑色素瘤异种移植小鼠模型中的肿瘤进展。我们的工作表明，AMD 可以有效抑制 NRAS 活性，并且可以代表发现用于治疗 NRAS 驱动的癌症的先导化合物的有前途的新途径。