PI3K/Akt/mTOR signaling pathway plays an important role in cancer cell growth and survival. In this study, a new class of molecules with skeleton of 4-phenyl-2H-benzo[b] [1,4]oxazin-3(4H)-one were designed and synthesized targeting this pathway. Bioassays showed that, among all the molecules, 8d-1 was a pan-class I PI3K/mTOR inhibitor with an IC₅₀ of 0.63 nM against PI3Kα. In a wide panel of protein kinases assays, no off-target interactions of 8d-1 were identified. 8d-1 was orally available, and displayed favorable pharmacokinetic parameters in mice (oral bioavailability of 24.1%). In addition, 8d-1 demonstrated significant efficiency in Hela/A549 tumor xenograft models (TGI of 87.7% at dose of 50 mg/kg in Hela model) without causing significant weight loss and toxicity during 30 days treatment. Based on the bioassays, compound 8d-1 could be used as an anti-cancer drug candidate.

PI3K / Akt / mTOR信号通路在癌细胞的生长和存活中起着重要的作用。在这项研究中，针对这一途径，设计并合成了具有4-苯基-2H-苯并[ b ] [1,4]恶嗪-3（4H）-one骨架的一类新分子。生物测定法显示，在所有分子中，8d-1是泛类I PI3K / mTOR抑制剂，对PI3Kα的IC ₅₀为0.63 nM。在广泛的蛋白激酶测定中，未鉴定出脱靶的8d-1相互作用。8d-1可口服，在小鼠中显示出良好的药代动力学参数（口服生物利用度为24.1％）。另外8d-1证明在Hela / A549肿瘤异种移植模型中具有显着效率（在Hela模型中，在50 mg / kg剂量下，TGI为87.7％），在治疗30天期间未引起明显的体重减轻和毒性。基于生物测定，化合物8d-1可用作抗癌药物候选物。