We report here the discovery of a novel series of selective mTOR kinase inhibitors and the identification of CC214-2, a compound with demonstrated anti-tumor activity upon oral dosing in a PC3 prostate cancer xenograft model. A series of 4,6-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were discovered through a core modification of our original compound series. Analogs from this series have excellent mTOR potency and maintain selectivity over the related PI3Kα lipid kinase. Compounds such as CC214-2 were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC3 cancer cells, in vitro and in vivo.

我们在这里报告了一系列新的选择性mTOR激酶抑制剂的发现和CC214-2的鉴定，CC214-2是一种在PC3前列腺癌异种移植模型中口服给药后具有抗肿瘤活性的化合物。通过对我们原始化合物系列进行核心修饰，发现了一系列4,6-二取代-3,4-二氢吡嗪并[2,3- b ]吡嗪-2（1 H）-。该系列的类似物具有出色的mTOR效能，并保持对相关PI3Kα脂质激酶的选择性。发现诸如CC214-2的化合物在体外和体内均可阻断PC3癌细胞中的mTORC1（pS6）和mTORC2（pAktS473）信号传导。