Life/Health Division, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea.
Bioorg Med Chem Lett. 2011 May 15;21(10):3002-6. doi: 10.1016/j.bmcl.2011.03.044. Epub 2011 Mar 17.
A serine-threonine kinase IKK-2 plays an important role in activation of NF-κB through phosphorylation of the inhibitor of NF-κB (IκB). As NF-κB is a major transcription factor that regulates genes responsible for cell proliferation and inflammation, development of selective IKK-2 inhibitors has been an important area of anti-inflammatory and anti-cancer research. In this study, to obtain active and selective IKK-2 inhibitors, various substituents were introduced to a piperidinyl aminopyrimidine core structure. The structure-activity relationship study indicated that hydrogen, methanesulfonyl, and aminosulfonyl groups substituted at the piperidinylamino functionality provide high inhibitory activity against IKK-2. Also, morpholinosulfonyl and piperazinosulfonyl group substituted at the aromatic ring attached to the aminopyrimidine core significantly increased the inhibitory activity of the resulting derivatives. In particular, compound 17 with the aromatic piperazinosulfonyl substituent showed the most potent (IC(50)=1.30 μM) and selective (over other kinases such as p38α, p38β, JNK1, JNK2, JNK3, and IKK-1) inhibitory activity against IKK-2.
丝氨酸-苏氨酸激酶 IKK-2 通过磷酸化 NF-κB 的抑制剂（IκB）在 NF-κB 的激活中发挥重要作用。由于 NF-κB 是调节细胞增殖和炎症相关基因的主要转录因子，因此开发选择性 IKK-2 抑制剂一直是抗炎和抗癌研究的重要领域。在这项研究中，为了获得活性和选择性的 IKK-2 抑制剂，在哌啶基氨基嘧啶核心结构上引入了各种取代基。构效关系研究表明，哌啶基氨基功能团上取代的氢、甲磺酰基和氨磺酰基提供了对 IKK-2 的高抑制活性。此外，与氨基嘧啶核心相连的芳基上取代的吗啉磺酰基和哌嗪磺酰基基团显著提高了所得衍生物的抑制活性。特别是具有芳基哌嗪磺酰基取代基的化合物 17 对 IKK-2 表现出最强的（IC50=1.30 μM）和选择性（相对于其他激酶如 p38α、p38β、JNK1、JNK2、JNK3 和 IKK-1）抑制活性。
