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Updated: Mar 6, 2026

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Selective Downregulation of JAK2 and JAK3 by an ATP-Competitive pan-JAK Inhibitor
S Denise Field1, Jacob Arkin1, Jing Li1
1Medicine Design, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.
Abstract:
PF-956980 has been used previously as a JAK3-selective chemical probe in numerous cell-based experiments. Here, we report that not only is PF-956980 a pan-JAK ATP-competitive inhibitor but it also causes selective reduction of endogenous JAK2 and JAK3 protein levels in human primary immune cells (in a time-dependent manner), leaving the other JAK family members (JAK1 and TYK2) unchanged. We found that PF-956980 selectively downregulated JAK2 and JAK3 mRNA, corresponding to changes observed at the protein level. This work highlights therapeutic opportunities for the development of pharmacological inhibitors that also modulate the expression of their cognate binding proteins.
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