A series of Torin2, a second-generation ATP-competitive inhibitor, analogues were biologically characterized to identify their potential for ATR and mTOR kinase inhibition. Compound SPK 98 was observed to inhibit ATR/mTOR kinase selectively over ATM kinase in HCT 116 cell line. In addition to that, SPK 98 on 30 min incubation with human, mice and rat liver microsomes showed improved properties with an increased half-life (a maximum T ½ of 157 min) and internal clearance in mouse as compared to Torin2. Further, SPK 98 was also noticed to indulge in inducing premature chromatin condensation as a result of ATR/mTOR kinase inhibition at 50 nM. In a nutshell, our work presents the identification and characterization of SPK 98, a small molecule inhibitor, which exhibits improved specific inhibition for ATR at a lower concentration than Torin2.

一系列第二代ATP竞争性抑制剂Torin2的类似物经过生物学表征，以鉴定其潜在的ATR和mTOR激酶抑制作用。在HCT 116细胞系中，观察到化合物SPK 98相对于ATM激酶选择性抑制ATR / mTOR激酶。除此之外，与Torin2相比，与人，小鼠和大鼠肝微粒体温育30分钟时，SPK 98表现出改善的特性，具有延长的半衰期（最大T½为157分钟）和内部清除率。此外，还发现由于50 nM的ATR / mTOR激酶抑制作用，SPK 98会引起过早的染色质凝聚。简而言之，我们的工作提出了SPK 98（一种小分子抑制剂）的鉴定和表征，它以比Torin2更低的浓度表现出对ATR的改善的特异性抑制。