Phosphatase PPM1F is a regulator of cell adhesion by fine-tuning integrin activity and actin cytoskeleton structures. Elevated expression of this enzyme in human tumors is associated with high invasiveness, enhanced metastasis, and poor prognosis. Thus, PPM1F is a target for pharmacological intervention, yet inhibitors of this enzyme are lacking. Here, we use high-throughput screening to identify Lockdown, a reversible and non-competitive PPM1F inhibitor. Lockdown is selective for PPM1F, because this compound does not inhibit other protein phosphatases in vitro and does not induce additional phenotypes in PPM1F knockout cells. Importantly, Lockdown-treated glioblastoma cells fully re-capitulate the phenotype of PPM1F-deficient cells as assessed by increased phosphorylation of PPM1F substrates and corruption of integrin-dependent cellular processes. Ester modification yields Lockdown^Pro with increased membrane permeability and prodrug-like properties. Lockdown^Pro suppresses tissue invasion by PPM1F-overexpressing human cancer cells, validating PPM1F as a therapeutic target and providing an access point to control tumor cell dissemination.

磷酸酶 PPM1F 是一种通过微调整合素活性和肌动蛋白细胞骨架结构来调节细胞粘附的调节剂。这种酶在人类肿瘤中的表达升高与高侵袭性、增强的转移和不良预后有关。因此，PPM1F 是药物干预的靶点，但缺乏这种酶的抑制剂。在这里，我们使用高通量筛选来识别 Lockdown，一种可逆且非竞争性的 PPM1F 抑制剂。Lockdown 对 PPM1F 具有选择性，因为该化合物在体外不会抑制其他蛋白磷酸酶并且不会在 PPM1F 敲除细胞中诱导额外的表型。重要的是，通过 PPM1F 底物的磷酸化增加和整合素依赖性细胞过程的破坏来评估，锁定处理的胶质母细胞瘤细胞完全重现了 PPM1F 缺陷细胞的表型。酯改性产生具有增加的膜渗透性和前药样特性的Lockdown ^{Pro 。}Lockdown ^Pro抑制过表达 PPM1F 的人类癌细胞的组织侵袭，验证 PPM1F 作为治疗靶点并提供控制肿瘤细胞传播的接入点。