Discovery Medicinal Chemistry, Wyeth Research, Pearl River, New York 10965, USA.
J Med Chem. 2010 Jan 28;53(2):798-810. doi: 10.1021/jm9014982.
Herein we describe the identification and lead optimization of triazolopyrimidines as a novel class of potent dual PI3K/mTOR inhibitors, resulting in the discovery of 3 (PKI-402). Compound 3 exhibits good physical properties and PK parameters, low nanomolar potency against PI3Kalpha and mTOR, and excellent inhibition of cell proliferation in several human cancer cell lines. Furthermore, in vitro and in vivo biomarker studies demonstrated the ability of 3 to shut down the PI3K/Akt pathway and induce apoptosis in cancer cells. In addition, 3 showed excellent in vivo efficacy in various human cancer xenografts, validating suppression of PI3K/mTOR signaling as a potential anticancer therapy.
在此，我们描述了三氮并嘧啶的鉴定和先导优化，将其作为一类新型强效的 PI3K/mTOR 双重抑制剂，由此发现了化合物 3（PKI-402）。化合物 3 具有良好的物理性质和 PK 参数，对 PI3Kalpha 和 mTOR 的抑制活性达到纳摩尔级，对多种人源癌细胞系的增殖具有优异的抑制作用。此外，体外和体内生物标志物研究表明，化合物 3 能够阻断 PI3K/Akt 通路，并诱导癌细胞凋亡。此外，化合物 3 在多种人源肿瘤异种移植模型中表现出优异的体内疗效，验证了抑制 PI3K/mTOR 信号传导作为一种潜在的抗癌疗法的可行性。
