Drug Design and Discovery Center, University of Namur, FUNDP, Namur, Belgium.
Bioorg Med Chem Lett. 2010 Aug 1;20(15):4515-20. doi: 10.1016/j.bmcl.2010.06.027. Epub 2010 Jun 8.
As a wide variety of pro-inflammatory cytokines are involved in the development of rheumatoid arthritis (RA), there is an urgent need for the discovery of novel therapeutic strategies. Among these, the inhibition of the NF-kappaB inducing kinase (NIK), a key enzyme of the NF-kappaB alternative pathway activation, represents a potential interesting approach. In fact, NIK is involved downstream of many tumor necrosis factor receptors (TNFR) like CD40, RANK or LTbetaR, implicated in the pathogenesis of RA. But, up to now, the number of reported putative NIK inhibitors is extremely limited. In this work, we report a virtual screening (VS) study combining various filters including high-throughput docking using a 3D-homology model and ranking by using different scoring functions. This work led to the identification of two molecular fragments, 4H-isoquinoline-1,3-dione (5) and 2,7-naphthydrine-1,3,6,8-tetrone (6) which inhibit NIK with an IC(50) value of 51 and 90 microM, respectively. This study opens new perspectives in the field of the NF-kappaB alternative pathway inhibition.
由于多种促炎细胞因子参与了类风湿关节炎（RA）的发生发展，因此急需寻找新的治疗策略。在这些策略中，抑制核因子 κB 诱导激酶（NIK）是一种很有前景的方法，因为它是 NF-κB 替代途径激活的关键酶。事实上，NIK 是许多肿瘤坏死因子受体（TNFR）如 CD40、RANK 或 LTβR 的下游成分，而这些受体在 RA 的发病机制中起作用。但是，到目前为止，已报道的潜在 NIK 抑制剂数量非常有限。在这项工作中，我们报告了一项虚拟筛选（VS）研究，该研究结合了多种筛选方法，包括使用三维同源模型的高通量对接和使用不同评分函数的排序。这项工作确定了两个分子片段，4H-异喹啉-1,3-二酮（5）和 2,7-萘啶-1,3,6,8-四酮（6），它们对 NIK 的抑制作用的 IC50 值分别为 51 和 90 μM。这项研究为 NF-κB 替代途径抑制领域开辟了新的前景。
