Abstract：
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 LockdownPro with increased membrane permeability and prodrug-like properties. LockdownPro 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.
摘要：
磷酸酶PPM1F是通过微调整联蛋白活性和肌动蛋白细胞骨架结构的细胞粘附调节剂。这种酶在人类肿瘤中的表达升高与高侵袭性有关。增强的转移，预后不良。因此，PPM1F是药物干预的目标，然而缺乏这种酶的抑制剂。这里,我们使用高通量筛选来识别锁定，一种可逆和非竞争性PPM1F抑制剂。锁定对于PPM1F是选择性的，因为该化合物在体外不会抑制其他蛋白磷酸酶，也不会在PPM1F敲除细胞中诱导其他表型。重要的是,如通过PPM1F底物的磷酸化增加和整合素依赖性细胞过程的破坏所评估的，锁定处理的胶质母细胞瘤细胞完全重新确立了PPM1F缺陷型细胞的表型。酯修饰产生具有增加的膜渗透性和前药样性质的LockdownPro。LockdownPro抑制PPM1F过表达人类癌细胞的组织侵袭，验证PPM1F作为治疗靶标，并提供控制肿瘤细胞播散的接入点。
