The dual PI3Kα/ m TOR inhibitors represent a promising molecularly targeted therapy for cancer. Here, we documented the discovery of new 2,4-disubstituted quinazoline analogs as potent dual PI3Kα/sm TOR inhibitors. Our structure based chemistry endeavor yielded six excellent compounds 9e, 9f, 9g, 9k, 9m, and 9o with single/double digit nanomolar IC₅₀ values against both enzymes and acceptable aqueous solubility and stability to oxidative metabolism. One of those analogs, 9m, possessed a sulfonamide substituent, which has not been described for this chemical scaffold before. The short direct synthetic routes, structure–activity relationship, in vitro 2D cell culture viability assays against normal fibroblasts and 3 breast cancer cell lines, and in vitro 3D culture viability assay against MCF7 cells for this series are described.

中文翻译：

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新型双取代喹唑啉作为靶向乳腺癌的双重 PI3Kalpha/mTOR 抑制剂的发现和 SAR

双 PI3Kα/m TOR 抑制剂代表了一种有前途的癌症分子靶向治疗。在这里，我们记录了新的 2,4-二取代喹唑啉类似物作为有效的双重 PI3Kα/sm TOR 抑制剂的发现。我们基于结构的化学努力产生了六种优异的化合物9e、9f、9g、9k、9m和9o，其对两种酶的IC ₅₀值为单位/两位数，并且具有可接受的水溶性和氧化代谢稳定性。其中一种类似物9m具有磺酰胺取代基，以前没有描述过这种化学支架。短直接合成路线，构效关系，体外描述了针对正常成纤维细胞和 3 个乳腺癌细胞系的 2D 细胞培养活力测定，以及针对该系列的 MCF7 细胞的体外3D 培养活力测定。