In Silico and In Cell Hybrid Selection of Nonrapalog Ligands to Allosterically Inhibit the Kinase Activity of mTORC1
In Silico and In Cell Hybrid Selection of Nonrapalog Ligands to Allosterically Inhibit the Kinase Activity of mTORC1
复制标题
DOI：
10.1021/acs.jmedchem.1c00536
复制
发表时间：
2022-01-27
影响因子：
7.3
通讯作者：
Miyatake, Hideyuki
中科院分区：
文献类型：
--
作者：
Shams, Raef;Matsukawa, Akihiro;Miyatake, Hideyuki
癌症特异性代谢改变过度激活哺乳动物/雷帕霉素机制靶点（mTOR）的激酶活性，以克服应激环境。雷帕霉素类似物，其变构抑制mTOR复合物1（mTORC 1），已被批准作为抗癌剂。然而，这些化合物的免疫抑制副作用导致促进肿瘤转移，从而限制了它们的治疗功效。我们首先报告了一个nonrapplasty抑制剂，WRX 606，确定了一个混合策略，在电脑和细胞的选择。我们的研究表明，WRX 606与FK 506结合蛋白12（FKBP 12）和mTOR的FKB-普雷帕霉素结合（FRB）结构域形成三元复合物，导致mTORC 1的变构抑制。WRX 606不仅抑制核糖体蛋白S6激酶1（S6 K1）的磷酸化，而且抑制eIF 4 E结合蛋白-1（4 E-BP 1）的磷酸化。因此，WRX 606有效地抑制了小鼠中的肿瘤生长而不促进转移。这些结果表明，WRX 606是一种有效的先导化合物，用于开发通过计算机和细胞方法发现的抗癌药物。
Cancer-specific metabolic alterations hyperactivate the kinase activity of the mammalian/mechanistic target of rapamycin (mTOR) for overcoming stressful environments. Rapalogs, which allosterically inhibit mTOR complex 1 (mTORC1), have been approved as anticancer agents. However, the immunosuppressive side effect of these compounds results in the promotion of tumor metastasis, thereby limiting their therapeutic efficacy. We first report a nonrapalog inhibitor, WRX606, identified by a hybrid strategy of in silico and in cell selections. Our studies showed that WRX606 formed a ternary complex with FK506-binding protein-12 (FKBP12) and FKB-Prapamycin-binding (FRB) domain of mTOR, resulting in the allosteric inhibition of mTORC1. WRX606 inhibited the phosphorylation of not only the ribosomal protein S6 kinase 1 (S6K1) but also eIF4E-binding protein-1 (4E-BP1). Hence, WRX606 efficiently suppressed tumor growth in mice without promotion of metastasis. These results suggest that WRX606 is a potent lead compound for developing anticancer drugs discovered by in silico and in cell methods.