2. Academic Validation
  3. Discovery of potent and highly selective thienopyridine Janus kinase 2 inhibitors

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

Affiliation

  • 1 Department of Medicinal Chemistry, Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA. laurie.schenkel@amgen.com
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.

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