Discovery of potent and highly selective thienopyridine Janus kinase 2 inhibitors

  • J Med Chem. 2011 Dec 22;54(24):8440-50. doi: 10.1021/jm200911r.
Laurie B Schenkel  1 ,  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
Affiliations
  • 1. Department of Medicinal Chemistry, Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA. [email protected]
PMID: 22087750 DOI: 10.1021/jm200911r
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.