The specificity of JAK3 kinase inhibitors
The specificity of JAK3 kinase inhibitors
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DOI：
10.1182/blood-2007-09-115030
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发表时间：
2008-02-15
期刊：
影响因子：
20.3
通讯作者：
Kudlacz, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Changelian, Paul S.;Moshinsky, Deborah;Kudlacz, Elizabeth M.
PF-956980 是一种选择性 JAK3 抑制剂，其结构与 CP-690550 相关，CP-690550 是一种正在类风湿关节炎和预防同种异体移植排斥的临床试验中进行评估的化合物。 PF-956980 已针对一组 30 种激酶进行了评估，发现仅针对 JAK3 具有纳摩尔级效力。该化合物的细胞和全血活性与其在酶测定中的效力和选择性相一致。它在体内能有效抑制小鼠迟发型超敏反应。我们在同一组生化和细胞测定中比较了 2 种市售 JAK3 抑制剂（WHI-P131 和 WHI-P154），发现它们对 JAK3 既不有效，也没有选择性。两者均被发现是 EGF 受体激酶家族的纳摩尔抑制剂。由于这些化合物已在移植和自身免疫疾病文献的许多出版物中使用，因此在解释这些结果时应考虑它们的特异性。
PF-956980 is a selective inhibitor of JAK3, related in structure to CP-690550, a compound being evaluated in clinical trials for rheumatoid arthritis and prevention of allograft rejection. PF-956980 has been evaluated against a panel of 30 kinases, and found to have nanomolar potency against only JAK3. Cellular and whole blood activity of this compound parallels its potency and selectivity in enzyme assays. It was effective in vivo at inhibiting the delayed type hypersensivity reaction in mice. We compared 2 commercially available JAK3 inhibitors (WHI-P131 and WHI-P154) in the same panel of biochemical and cellular assays and found them to be neither potent nor selective for JAK3. Both were found to be nanomolar inhibitors of the EGF receptor family of kinases. As these compounds have been used in numerous publications in the transplant and autoimmune disease literature, their specificity should be considered when interpreting these results.