Institute for Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming", 34 Fleming Street, 16672 Vari, Greece.
proACTINA SA, 20 Delfon Street, 15125 Athens, Greece.
Int J Mol Sci. 2023 Jul 10;24(14):11290. doi: 10.3390/ijms241411290.
Receptor activator of nuclear factor-κB ligand (RANKL) has been actively pursued as a therapeutic target for osteoporosis, given that RANKL is the master mediator of bone resorption as it promotes osteoclast differentiation, activity and survival. We employed a structure-based virtual screening approach comprising two stages of experimental evaluation and identified 11 commercially available compounds that displayed dose-dependent inhibition of osteoclastogenesis. Their inhibitory effects were quantified through TRAP activity at the low micromolar range (IC < 5 μΜ), but more importantly, 3 compounds displayed very low toxicity (LC > 100 μΜ). We also assessed the potential of an -(1-aryl-1-indol-5-yl)aryl-sulfonamide scaffold that was based on the structure of a hit compound, through synthesis of 30 derivatives. Their evaluation revealed 4 additional hits that inhibited osteoclastogenesis at low micromolar concentrations; however, cellular toxicity concerns preclude their further development. Taken together with the structure-activity relationships provided by the hit compounds, our study revealed potent inhibitors of RANKL-induced osteoclastogenesis of high therapeutic index, which bear diverse scaffolds that can be employed in hit-to-lead optimization for the development of therapeutics against osteolytic diseases.
核因子-κB 受体激活剂配体（RANKL）一直是骨质疏松症治疗靶点的研究热点，因为 RANKL 是骨吸收的主要介质，可促进破骨细胞分化、活性和存活。我们采用了一种基于结构的虚拟筛选方法，包括两个实验评估阶段，鉴定出 11 种具有商业可用性的化合物，这些化合物对破骨细胞生成呈剂量依赖性抑制作用。它们的抑制作用通过 TRAP 活性在低微摩尔范围内（IC < 5 μM）进行定量，但更重要的是，其中 3 种化合物显示出非常低的毒性（LC > 100 μM）。我们还评估了基于一个命中化合物结构的 -(1-芳基-1-吲哚-5-基)芳基-磺酰胺支架的潜力，通过合成 30 种衍生物。它们的评估结果揭示了另外 4 种在低微摩尔浓度下抑制破骨细胞生成的新化合物；然而，细胞毒性问题排除了它们的进一步发展。结合命中化合物提供的结构-活性关系，我们的研究揭示了具有高治疗指数的 RANKL 诱导的破骨细胞生成的有效抑制剂，这些抑制剂具有不同的骨架，可以用于命中到先导化合物的优化，以开发针对溶骨性疾病的治疗药物。
