Selective Downregulation of JAK2 and JAK3 by an ATP-Competitive pan-JAK Inhibitor.
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.
Medicine Design, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.
S Denise
SD
Field
Medicine Design, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.
Jacob
J
Arkin
Medicine Design, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.
Jing
J
Li
Medicine Design, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.
Lyn H
0000-0002-8388-5865
LH
Jones
D000255:Adenosine Triphosphate / Q000378:metabolism; D001667:Binding, Competitive; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D007107:Immune System / Q000166:cytology; D053614:Janus Kinase 2 / Q000032:analysis / Q000235:genetics*; D053616:Janus Kinase 3 / Q000032:analysis / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects
C554945:PF 956980; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D012333:RNA, Messenger; D000255:Adenosine Triphosphate; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053616:Janus Kinase 3