Field S Denise, Arkin Jacob, Li Jing, Jones Lyn H
Medicine Design, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.
ACS Chem Biol. 2017 May 19;12(5):1183-1187. doi: 10.1021/acschembio.7b00116. Epub 2017 Mar 22.
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.
PF-956980此前已在众多基于细胞的实验中用作JAK3选择性化学探针。在此，我们报告称，PF-956980不仅是一种泛JAK ATP竞争性抑制剂，而且还会导致人原代免疫细胞中内源性JAK2和JAK3蛋白水平选择性降低（呈时间依赖性），而其他JAK家族成员（JAK1和TYK2）则保持不变。我们发现PF-956980选择性地下调JAK2和JAK3 mRNA，这与在蛋白质水平观察到的变化相对应。这项工作突出了开发同时调节其同源结合蛋白表达的药理抑制剂的治疗机会。
