Department of Cancer Chemistry, Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
Bioorg Med Chem Lett. 2012 Mar 1;22(5):2063-9. doi: 10.1016/j.bmcl.2012.01.018. Epub 2012 Jan 14.
The design, synthesis and biological evaluation of a series of azabenzimidazole derivatives as TBK1/IKKε kinase inhibitors are described. Starting from a lead compound 1a, iterative design and SAR exploitation of the scaffold led to analogues with nM enzyme potencies against TBK1/IKKε. These compounds also exhibited excellent cellular activity against TBK1. Further structure-based design to improve selectivity over CDK2 and Aurora B resulted in compounds such as 5b-e. These probe compounds will facilitate study of the complex cancer biology of TBK1 and IKKε.
本文描述了一系列氮杂苯并咪唑衍生物作为 TBK1/IKKε 激酶抑制剂的设计、合成和生物评价。从先导化合物 1a 出发，通过对骨架进行迭代设计和 SAR 研究，得到了对 TBK1/IKKε 具有纳摩尔酶活性的类似物。这些化合物对 TBK1 也表现出优异的细胞活性。进一步基于结构的设计以提高对 CDK2 和 Aurora B 的选择性，得到了化合物如 5b-e。这些探针化合物将有助于研究 TBK1 和 IKKε 的复杂癌症生物学。
