Multiple Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M (Palm M) block N-Ras depalmitoylation, but lack specificity and target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, a potent and selective covalent inhibitor of the ABHD17 family of depalmitoylases, and show that this compound impairs N-Ras depalmitoylation in human acute myeloid leukemia (AML) cells. ABD957 produced partial effects on N-Ras palmitoylation compared with Palm M, but was much more selective across the proteome, reflecting a plasma membrane-delineated action on dynamically palmitoylated proteins. Finally, ABD957 impaired N-Ras signaling and the growth of NRAS-mutant AML cells in a manner that synergizes with MAP kinase kinase (MEK) inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes as regulators of the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers.

包括 N-Ras 在内的多种 Ras 蛋白依赖于棕榈酰化/去棕榈酰化循环来调节其亚细胞运输和致癌性。一般脂肪酶抑制剂，如 Palmostatin M (Palm M)，可阻断 N-Ras 去棕榈酰化，但缺乏特异性，并且以几种表现出去棕榈酰化酶活性的酶为目标。在这里，我们描述了 ABD957，一种去棕榈酰酶 ABHD17 家族的有效且选择性共价抑制剂，并表明该化合物会损害人急性髓系白血病 (AML) 细胞中的 N-Ras 去棕榈酰化。与 Palm M 相比，ABD957 对 N-Ras 棕榈酰化产生部分影响，但在整个蛋白质组中的选择性更高，反映了质膜对动态棕榈酰化蛋白质的作用。最后，ABD957 以与 MAP 激酶激酶 (MEK) 抑制协同的方式损害 N-Ras 信号传导和NRAS突变 AML 细胞的生长。我们的研究结果揭示了 ABHD17 酶作为 N-Ras 棕榈酰化循环调节剂的令人惊讶的有限作用，并表明 ABHD17 抑制剂可能具有作为NRAS突变癌症的靶向治疗的价值。