Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors

作者：Schenkel Laurie B^*; Huang Xin; Cheng Alan; Deak Holly L; Doherty Elizabeth; Emkey Renee; Gu Yan; Gunaydin Hakan; Kim Joseph L; Lee Josie; Loberg Robert; Olivieri Philip; Pistillo Jeanne; Tang Jin; Wan Qian; Wang Hui Ling; Wang Shen Wu; Wells Mary C; Wu Bin; Yu Violeta; Liu Liqin; Geuns Meyer Stephanie

来源：Journal of Medicinal Chemistry, 2011, 54(24): 8440-8450.

DOI：10.1021/jm200911r

Developing Janus kinase 2 (Jak2) inhibitors has become a significant focus for small molecule drug discovery programs in recent years due to the identification of a Jak2 gain-of-function mutation in the majority of patients with myeloproliferative disorders (MPD). Here, we describe the discovery of a thienopyridine series of Jak2 inhibitors that culminates with compounds showing 100- to >500-fold selectivity over the related Jak family kinases in enzyme assays. Selectivity for Jak2 was also observed in TEL-Jak cellular assays, as well as in cytokine-stimulated peripheral blood mononuclear cell (PBMC) and whole blood assays. X-ray cocrystal structures of 8 and 19 bound to the Jak2 kinase domain aided structure activity relationship efforts and, along with a previously reported small molecule X-ray cocrystal structure of the Jak1 kinase domain, provided structural rationale for the observed high levels of Jak2 selectivity.

• 出版日期2011-12-22