Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
Bioorg Med Chem Lett. 2012 Aug 1;22(15):4967-74. doi: 10.1016/j.bmcl.2012.06.033. Epub 2012 Jun 16.
mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.
mTOR 是细胞信号转导下游多种生长因子的关键调节因子。mTOR/PI3K/AKT 通路在人类癌症中经常发生突变，因此是一个重要的肿瘤靶点。在此，我们报告了我们发现 ATP 竞争性 mTOR 抑制剂的项目的进展，与我们之前的先导化合物相比，这些抑制剂具有更好的药代动力学性质和选择性。通过靶向 SAR 和结构指导设计，确定了新的咪唑并吡啶和咪唑并哒嗪骨架，这些骨架在细胞测定中表现出对 mTOR 的优越抑制作用，与密切相关的 PIKK 家族相比具有选择性，并且与我们之前报道的苯并咪唑系列相比，体内清除率得到改善。
