Discovery of potent and highly selective thienopyridine Janus kinase 2 inhibitors.
Article Details
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Schenkel LB, Huang X, Cheng A, Deak HL, Doherty E, Emkey R, Gu Y, Gunaydin H, Kim JL, Lee J, Loberg R, Olivieri P, Pistillo J, Tang J, Wan Q, Wang HL, Wang SW, Wells MC, Wu B, Yu V, Liu L, Geuns-Meyer S
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. Epub 2011 Nov 16.
- PubMed ID
- 22087750 [ View in 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Tofacitinib Non-receptor tyrosine-protein kinase TYK2 IC 50 (nM) 52 N/A N/A Details Tofacitinib Non-receptor tyrosine-protein kinase TYK2 IC 50 (nM) 1200 N/A N/A Details Tofacitinib Tyrosine-protein kinase JAK2 IC 50 (nM) 4 N/A N/A Details Tofacitinib Tyrosine-protein kinase JAK2 IC 50 (nM) 682 N/A N/A Details Tofacitinib Tyrosine-protein kinase JAK2 IC 50 (nM) 265 N/A N/A Details Tofacitinib Tyrosine-protein kinase JAK2 IC 50 (nM) 155 N/A N/A Details Tofacitinib Tyrosine-protein kinase JAK3 IC 50 (nM) 0.6 N/A N/A Details Tofacitinib Tyrosine-protein kinase JAK3 IC 50 (nM) 54 N/A N/A Details