Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925, Alcorcón, Madrid, Spain.
Org Biomol Chem. 2019 Jan 23;17(4):916-929. doi: 10.1039/c8ob02990c.
In this article, we describe our efforts in the search of MMP2/CK2 dual targeting inhibitors. We have followed a rational drug design approach based on our experience in the selective inhibition of these two enzymes. We have successfully obtained highly active MMP2 (10, IC50 = 70 nM; 11, IC50 = 100 nM) and CK2 (16a, IC50 = 500 nM) inhibitors. However, structural fine tuning of these small molecules to simultaneously target both enzymes turned out to be an unattainable goal. Unexpectedly, we were lucky to identify new and selective MMP13 inhibitors (10, IC50 = 3.7 nM and 11, IC50 = 5.6 nM) with a novel TBB-derived scaffold. These compounds constitute an interesting starting point for further optimization.
在本文中，我们描述了寻找 MMP2/CK2 双重靶向抑制剂的努力。我们遵循了一种合理的药物设计方法，该方法基于我们在选择性抑制这两种酶方面的经验。我们已经成功获得了高度活性的 MMP2（10，IC50 = 70 nM；11，IC50 = 100 nM）和 CK2（16a，IC50 = 500 nM）抑制剂。然而，对这些小分子进行结构精细调整以同时针对两种酶是无法实现的目标。出乎意料的是，我们很幸运地发现了具有新型 TBB 衍生支架的新型和选择性 MMP13 抑制剂（10，IC50 = 3.7 nM 和 11，IC50 = 5.6 nM）。这些化合物为进一步优化提供了一个有趣的起点。
