托法替布及其类似物作为组蛋白激酶PRK1（PKN1）的抑制剂。
Tofacitinib and analogs as inhibitors of the histone kinase PRK1 (PKN1).
作者信息
Ostrovskyi Dmytro, Rumpf Tobias, Eib Julia, Lumbroso Alexandre, Slynko Inna, Klaeger Susan, Heinzlmeir Stephanie, Forster Michael, Gehringer Matthias, Pfaffenrot Ellen, Bauer Silke Mona, Schmidtkunz Karin, Wenzler Sandra, Metzger Eric, Kuster Bernhard, Laufer Stefan, Schüle Roland, Sippl Wolfgang, Breit Bernhard, Jung Manfred
机构信息
Institute of Organic Chemistry, Albert-Ludwigs-University Freiburg, Albertstraße 21, 79104 Freiburg im Breisgau, Germany.
Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
出版信息
Future Med Chem. 2016 Sep;8(13):1537-51. doi: 10.4155/fmc-2016-0132. Epub 2016 Aug 30.
AIM
The histone kinase PRK1 has been identified as a potential target to combat prostate cancer but selective PRK1 inhibitors are lacking. The US FDA -approved JAK1-3 inhibitor tofacitinib also potently inhibits PRK1 in vitro.
RESULTS
We show that tofacitinib also inhibits PRK1 in a cellular setting. Using tofacitinib as a starting point for structure-activity relationship studies, we identified a more potent and another more selective PRK1 inhibitor compared with tofacitinib. Furthermore, we found two potential PRK1/JAK3-selectivity hotspots.
CONCLUSION
The identified inhibitors and the selectivity hotspots lay the basis for the development of selective PRK1 inhibitors. The identification of PRK1, but also of other cellular tofacitinib targets, has implications on its clinical use and on future development of tofacitinib-like JAK inhibitors. [Formula: see text].
目的
组蛋白激酶PRK1已被确定为对抗前列腺癌的潜在靶点，但目前缺乏选择性PRK1抑制剂。美国食品药品监督管理局（FDA）批准的JAK1 - 3抑制剂托法替布在体外也能有效抑制PRK1。
结果
我们发现托法替布在细胞环境中也能抑制PRK1。以托法替布为结构 - 活性关系研究的起点，我们鉴定出了一种比托法替布更有效以及另一种更具选择性的PRK1抑制剂。此外，我们发现了两个潜在的PRK1/JAK3选择性热点。
结论
所鉴定出的抑制剂和选择性热点为选择性PRK1抑制剂的开发奠定了基础。PRK1以及其他细胞内托法替布靶点的鉴定，对其临床应用以及托法替布样JAK抑制剂的未来发展具有重要意义。[公式：见正文]
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