Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors

Citations Over TimeTop 13% of 2011 papers

Abstract

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.

Related Papers

• → Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases(2016)353 cited
• → Janus kinases and their role in growth and disease(1999)73 cited
• → Dehydrocrenatidine Is a Novel Janus Kinase Inhibitor(2015)11 cited
• → The Jak/Stat Signaling Pathway Is Downregulated at Febrile Temperatures(2012)9 cited
• → Towards Selective Inhibitors of Janus Kinase 3: Identification of a Novel Structural Variation between Janus Kinases 2 and 3(2012)1 cited