The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C₄ position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC₅₀ = 20/376/204/46 nM) and mTOR (IC₅₀ = 189 nM), potent functional suppression of AKT phosphorylation (IC₅₀ = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C₄ sulfone chain and a fluorine on the C₆ aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.

中文翻译：

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基于磺酰基取代的吗啉代嘧啶类化合物的口服生物利用型PI3K / mTOR双重抑制剂的发现

发现和优化一系列在C ₄位置含有各种磺酰基侧链的2-吗啉代-嘧啶衍生物，从而将化合物26鉴定为有效的双重PI3K / mTOR抑制剂。它对PI3Kα/β/γ/δ（IC ₅₀ = 20/376/204/46 nM）和mTOR（IC ₅₀ = 189 nM）表现出很高的抑制活性，对AKT磷酸化的有效功能抑制（IC ₅₀ = 196 nM），对一组癌细胞具有出色的抗增殖作用。酶数据和模型模拟表明，C ₄砜链上的环丙基环和C ₆上的氟氨基吡啶基部分分别负责其维持的PI3K活性和增强的mTOR效能。此外，相对于剂量为15和30mg / kg的BKM120，化合物26在HT-29结肠直肠癌异种移植模型中以3.75和7.5mg / kg的日剂量显示出更高的效率。