Biogen Idec, 5200 Research Place, San Diego, CA 92122, USA.
Bioorg Med Chem Lett. 2012 Mar 1;22(5):2070-4. doi: 10.1016/j.bmcl.2012.01.019. Epub 2012 Jan 18.
Since the early 2000s, the Aurora kinases have become major targets of oncology drug discovery particularly Aurora-A and Aurora-B kinases (AKA/AKB) for which the selective inhibition in cells lead to different phenotypes. In addition to targeting these Aurora kinases involved in mitosis, CDK1 has been added as a primary inhibition target in hopes of enhancing the cytotoxicity of our chemotypes harboring the pyrazolopyrimidine core. SAR optimization of this series using the AKA, AKB and CDK1 biochemical assays led to the discovery of the compound 7h which combines strong potency against the 3 kinases with an acceptable microsomal stability. Finally, switching from a primary amide to a two-substituted pyrrolidine amide gave rise to compound 15a which exhibited the desired AKA/CDK1 inhibition phenotype in cells but showed moderate activity in animal models using HCT116 tumor cell lines.
自 21 世纪初以来，极光激酶已成为肿瘤药物发现的主要靶点，特别是极光-A 和极光-B 激酶（Aka/Akb），细胞中这些激酶的选择性抑制会导致不同的表型。除了靶向这些参与有丝分裂的极光激酶外，CDK1 也被添加为主要抑制靶点，希望增强含有吡唑并嘧啶核心的化学型的细胞毒性。使用 Aka、Akb 和 CDK1 生化测定对该系列进行 SAR 优化，发现了化合物 7h，它具有针对 3 种激酶的强大效力和可接受的微粒体稳定性。最后，将伯酰胺转化为双取代吡咯烷酰胺，得到化合物 15a，它在细胞中表现出所需的 Aka/CDK1 抑制表型，但在使用 HCT116 肿瘤细胞系的动物模型中显示出中等活性。
