Medicinal Chemistry, Amgen Inc, 360 Binney St, Cambridge, MA 02142, USA.
Bioorg Med Chem Lett. 2011 Apr 1;21(7):2064-70. doi: 10.1016/j.bmcl.2011.02.007. Epub 2011 Feb 12.
mTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3Kα. When tested in a panel of cancer cell lines displaying various mutations, a selective inhibitor from this series inhibited cellular proliferation with a mean IC(50) of 0.41 μM. Lead compound 42 demonstrated up to 83% inhibition of mTOR substrate phosphorylation in a murine pharmacodynamic model.
mTOR 是 PI3K/AKT 通路的一部分，是细胞生长和存活的核心调节剂。由于许多癌症显示与 mTOR 信号通路相关的突变，因此 mTOR 已成为肿瘤治疗的一个重要靶点。在此，我们报告了三嗪苯并咪唑抑制剂的发现，该抑制剂对 mTOR 激酶活性的抑制作用比结构同源的激酶 PI3Kα 高 200 倍。在一系列显示各种突变的癌细胞系中进行测试时，该系列中的一种选择性抑制剂以平均 IC50 为 0.41 μM 的浓度抑制细胞增殖。先导化合物 42 在小鼠药效学模型中显示出高达 83%的 mTOR 底物磷酸化抑制作用。
