1350455-53-6Relevant articles and documents
Discovery of potent and highly selective thienopyridine janus kinase 2 inhibitors
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
supporting information; experimental part, p. 8440 - 8450 (2012/02/14)
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. (Figure presented)
