Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors

详细信息    查看全文

• 作者：Laurie B. Schenkel ; Xin Huang ; Alan Cheng ; Holly L. Deak ; Elizabeth Doherty ; Renee Emkey ; Yan Gu ; Hakan Gunaydin ; Joseph L. Kim ; Josie Lee ; Robert Loberg ; Philip Olivieri ; Jeanne Pistillo ; Jin Tang ; Qian Wan ; Hui-Ling Wang ; Shen-Wu Wang ; Mary C. Wells ; Bin Wu ; Violeta Yu ; Liqin Liu ; Stephanie Geuns-Meyer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8440-8450
• 全文大小：456K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

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鈥揳ctivity 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.