Herein, we report the identification and preclinical profile of a lead compound 10, (SPR519) as an equally potent dual inhibitor of PI3Kα and mTOR kinases. SPR519 exhibits an EC₅₀ of low sub-micromolar range among various tested cancer cell lines such as A2780 (0.23 μM), PC3 (0.48 μM), and SKOV3 (0.50 μM). When administrated orally, it shows a considerably high plasma exposure (area under curve: 26,858 nM/h at 1 mg/kg) in mice. Moreover, it is found to be safe in animals with a dose of 30 mg/kg BID for 12 days in the dose tolerance study. SPR519 did not show any CYP or hERG liability. The identified lead compound demonstrates significant efficacy and bioavailability in ovarian and colon cancer xenograft models when evaluated for dose-ranging efficacy studies, at a dose as low as 2.5 mg/kg.

中文翻译：

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SPR519作为PI3Kα和mTOR激酶的强效，选择性和口服生物利用抑制剂的发现和开发，用于治疗实体瘤。

在此，我们报告了作为PI3Kα和mTOR激酶同等有效的双重抑制剂的先导化合物10（SPR519）的鉴定和临床前研究。在各种测试的癌细胞系中，例如A2780（0.23μM），PC3（0.48μM）和SKOV3（0.50μM），SPR519表现出低亚微摩尔范围的EC ₅₀。当口服时，它在小鼠中显示出相当高的血浆暴露（曲线下的面积：在1 mg / kg时为26,858 nM / h）。此外，在剂量耐受性研究中发现以30 mg / kg BID的剂量在动物中安全12天是安全的。SPR519没有显示任何CYP或hERG责任。当对剂量范围功效研究进行评估时，以低至2.5 mg / kg的剂量进行评估时，所鉴定的先导化合物在卵巢和结肠癌异种移植模型中显示出显着的功效和生物利用度。