Instituto de Química Medica-CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.
J Med Chem. 2011 Jun 23;54(12):4042-56. doi: 10.1021/jm1016279. Epub 2011 May 17.
Development of kinase-targeted therapies for central nervous system (CNS) diseases is a great challenge. Glycogen synthase kinase 3 (GSK-3) offers a great potential for severe CNS unmet diseases, being one of the inhibitors on clinical trials for different tauopathies. Following our hypothesis based on the enhanced reactivity of residue Cys199 in the binding site of GSK-3, we examine here the suitability of phenylhalomethylketones as irreversible inhibitors. Our data confirm that the halomethylketone unit is essential for the inhibitory activity. Moreover, addition of the halomethylketone moiety to reversible inhibitors turned them into irreversible inhibitors with IC(50) values in the nanomolar range. Overall, the results point out that these compounds might be useful pharmacological tools to explore physiological and pathological processes related to signaling pathways regulated by GSK-3 opening new avenues for the discovery of novel GSK-3 inhibitors.
开发针对中枢神经系统 (CNS) 疾病的激酶靶向疗法是一项巨大的挑战。糖原合酶激酶 3 (GSK-3) 为严重的 CNS 未满足的疾病提供了巨大的潜力，是临床试验中针对不同 tau 病的抑制剂之一。基于我们对 GSK-3 结合位点残基 Cys199 增强反应性的假设，我们在此检查了苯甲酰基甲基酮作为不可逆抑制剂的适用性。我们的数据证实，卤代甲基酮单元对于抑制活性是必不可少的。此外，将卤代甲基酮部分添加到可逆抑制剂中，可将其转化为具有纳摩尔范围内 IC50 值的不可逆抑制剂。总的来说，这些结果表明，这些化合物可能是有用的药理学工具，可用于探索与 GSK-3 调节的信号通路相关的生理和病理过程，为发现新型 GSK-3 抑制剂开辟了新途径。
