Download MendeleyDiscovery of potent and highly selective thienopyridine janus kinase 2 inhibitors.
Schenkel, L.B., Huang, X., Cheng, A., Deak, H.L., Doherty, E., Emkey, R., Gu, Y., Gunaydin, H., Kim, J.L., Lee, J., Loberg, R., Olivieri, P., Pistillo, J., Tang, J., Wan, Q., Wang, H.L., Wang, S.W., Wells, M.C., Wu, B., Yu, V., Liu, L., Geuns-Meyer, S.(2011) J Med Chem 54: 8440-8450
- PubMed: 22087750
- DOI: https://doi.org/10.1021/jm200911r
- Primary Citation of Related Structures:
3TJC, 3TJD - PubMed 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.
Organizational Affiliation:
Department of Medicinal Chemistry, Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA. laurie.schenkel@amgen.com
