Medicinal Chemistry, Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA.
Bioorg Med Chem Lett. 2010 Jan 15;20(2):636-9. doi: 10.1016/j.bmcl.2009.11.051. Epub 2009 Dec 5.
Series of purine and pyrazolo[3,4-d]pyrimidine inhibitors of phosphatidylinositol-3-kinases (PI3K) have been prepared. The optimized purine inhibitors show good potency in a PI3K p110alpha (PI3K-alpha) fluorescence polarization assay with good selectivity versus PI3K p110gamma (PI3K-gamma) and the mammalian target of rapamycin (mTOR). The related pyrazolo[3,4-d]pyrimidines show potent PI3K-alpha and mTOR inhibition with good selectivity versus PI3K-gamma. Representative compounds showed activity in a cellular proliferation assay against Caco-2 colorectal, LoVo colorectal and PC3MM2 prostate adenocarcinoma cancer cells. Signaling through the PI3K pathway was confirmed via inhibition of phospho-AKT in MDA-361 cells.
已经制备了一系列嘌呤和吡唑并[3,4-d]嘧啶磷脂酰肌醇-3-激酶（PI3K）抑制剂。优化的嘌呤抑制剂在 PI3K p110alpha（PI3K-alpha）荧光偏振测定中表现出良好的效力，对 PI3K p110gamma（PI3K-gamma）和雷帕霉素靶蛋白（mTOR）具有良好的选择性。相关的吡唑并[3,4-d]嘧啶显示出对 PI3K-alpha 和 mTOR 的有效抑制作用，对 PI3K-gamma 具有良好的选择性。代表性化合物在针对 Caco-2 结直肠、LoVo 结直肠和 PC3MM2 前列腺腺癌癌细胞的细胞增殖测定中表现出活性。通过抑制 MDA-361 细胞中的磷酸化 AKT 来证实 PI3K 通路的信号传递。
